Summary Influenza A virus (IAV) is an RNA virus that is cytotoxic to most cell types in which it replicates. IAV activates the host kinase RIPK3, which induces cell death via parallel pathways of necroptosis, driven by the pseudokinase MLKL, and apoptosis, dependent on the adaptor proteins RIPK1 and FADD. How IAV activates RIPK3 remains unknown. We report that DAI (ZBP-1/DLM-1), previously implicated as a cytoplasmic DNA sensor, is essential for RIPK3 activation by IAV. Upon infection, DAI recognizes IAV genomic RNA, associates with RIPK3, and is required for recruitment of MLKL and RIPK1 to RIPK3. Cells lacking DAI or containing DAI mutants deficient in nucleic acid binding are resistant to IAV-triggered necroptosis and apoptosis. DAI-deficient mice fail to control IAV replication and succumb to lethal respiratory infection. These results identify DAI as a link between IAV replication and RIPK3 activation, and implicate DAI as a sensor of RNA viruses.

Background Systematic data on discontinuation of statins in routine practice of medicine are limited. Objective To investigate reasons for statin discontinuation and the role of statin-related events (clinical events / symptoms thought to have been caused by statins) in routine care settings. Design A retrospective cohort study Setting Practices affiliated with one of two academic hospitals. Patients Adults who received a statin prescription between 01/01/2000 and 12/31/2008. Measurements Information on reasons for statin discontinuations was obtained from a combination of structured electronic medical record (EMR) entries and analysis of electronic provider notes by validated software. Results Statins were discontinued at least temporarily for 57,292 out of 107,835 patients. Statin-related events were documented for 18,778 (17.4%) patients. Statins were discontinued at least temporarily by 11,124 of these patients, 6,579 (59.1%) of whom were rechallenged with a statin over the subsequent 12 months. Most patients who were rechallenged (92.2%) were still taking a statin 12 months after the statin-related event. Among the 2,721 patients who were rechallenged with the same statin to which they had a statin-related event, 1,295 (47.6%) were on the same statin 12 months later, including 996 on the same or higher dose. Limitation Statin discontinuations and statin-related events were assessed in practices affiliated with two academic medical centers. Utilization of secondary data could have led to missing or misinterpreted data as a result of incomplete documentation. Natural language processing tools used to compensate for the low (30%) proportion of reasons for statin discontinuation documented in structured EMR fields are not perfectly accurate. Conclusion Statin-related events are commonly reported and often lead to their discontinuation. However, most patients who are rechallenged can tolerate statins long-term. This suggests that many of the statin-related events may have other etiologies, are tolerable or may be specific to individual statins rather than the entire drug class.

Highlights d Replicating influenza A virus (IAV) produces Z-RNAs d IAV Z-RNAs are sensed by host ZBP1 in the nucleus d ZBP1 activates MLKL in the nucleus, triggering nuclear envelope rupture d MLKL-induced nuclear rupture and necroptosis drive IAV disease severity Authors

OBJECTIVEHypoglycemia is associated with adverse outcomes in mixed populations of patients in intensive care units. It is not known whether the same risks exist for diabetic patients who are less severely ill. In this study, we aimed to determine whether hypoglycemic episodes are associated with higher mortality in diabetic patients hospitalized in the general ward.RESEARCH DESIGN AND METHODSThis retrospective cohort study analyzed 4,368 admissions of 2,582 patients with diabetes hospitalized in the general ward of a teaching hospital between January 2003 and August 2004. The associations between the number and severity of hypoglycemic (≤50 mg/dl) episodes and inpatient mortality, length of stay (LOS), and mortality within 1 year after discharge were evaluated.RESULTSHypoglycemia was observed in 7.7% of admissions. In multivariable analysis, each additional day with hypoglycemia was associated with an increase of 85.3% in the odds of inpatient death (P = 0.009) and 65.8% (P = 0.0003) in the odds of death within 1 year from discharge. The odds of inpatient death also rose threefold for every 10 mg/dl decrease in the lowest blood glucose during hospitalization (P = 0.0058). LOS increased by 2.5 days for each day with hypoglycemia (P < 0.0001).CONCLUSIONSHypoglycemia is common in diabetic patients hospitalized in the general ward. Patients with hypoglycemia have increased LOS and higher mortality both during and after admission. Measures should be undertaken to decrease the frequency of hypoglycemia in this high-risk patient population.

Drug delivery to the peritoneum is hampered by rapid clearance, and could be improved by application of controlled release technology. We investigated the suitability for peritoneal use of micro- and nanoparticles of poly(lactic-co-glycolic) acid (PLGA), a biodegradable polymer with generally excellent biocompatibility commonly used for controlled drug release. We injected 90 kDa PLGA microparticles, 5-250 microm in diameter, into the murine peritoneum, in dosages of 10-100 mg (n=3-5 per group). We found a high incidence of polymeric residue and adhesions 2 weeks after injection (e.g., 50 mg of 5-microm microparticles caused adhesions in 83% of animals). Histology revealed chronic inflammation, with foreign body giant cells prominent with particles>5 microm in diameter. Five micrometer microspheres made from 54, 57, and 10 kDa PLGA (gamma irradiated) caused fewer adhesions (16.7%) with a similar incidence of residue. Nanoparticles (265 nm) of 90 kDa PLGA also caused much fewer adhesions (6.3% of animals), possibly because they were cleared from the peritoneum within 2 days, and sequestered in the spleen and liver, where foamy macrophages were noted. The effect of sterilization technique on the incidence of adhesion formation is also studied.

Background More frequent patient-provider encounters may lead to faster A1c, blood pressure and LDL control and improve outcomes but there are no guidelines for how frequently patients with diabetes should be seen. Methods This retrospective cohort study analyzed 26,496 patients with diabetes and elevated A1c, blood pressure, and/or LDL cholesterol treated by primary care physicians at two teaching hospitals between 1/1/2000 and 1/1/2009. Relationship between provider encounter (defined as a note in medical record) frequency and time to A1c, blood pressure and LDL control was assessed. Results Comparing patients who had encounters with their physicians between 1-2 weeks vs. 3-6 months, median time to A1c < 7.0% was 4.4 vs. 24.9 months (not on insulin) and 10.1 vs. 52.8 months (on insulin); median time to blood pressure < 130/85 mm Hg was 1.3 vs. 13.9 months; and median time to LDL < 100 mg/dL was 5.1 vs. 36.9 months, respectively (p < 0.0001 for all). In multivariable analysis, doubling the time between physician encounters led to a 35%, 17%, 87%, and 27% increase in median time to A1c (off and on insulin), blood pressure, and LDL targets, respectively (p < 0.0001 for all). Time to control decreased progressively as encounter frequency increased up to once every two weeks for most targets, consistent with pharmacodynamics of respective medication classes. Conclusions Biweekly primary care provider encounters are associated with fastest achievement of A1c, blood pressure, and LDL targets for patients with diabetes.

ObjeCtives To investigate the optimal systolic blood pressure goal above which new antihypertensive medications should be added or doses of existing medications increased ("systolic intensification threshold") and to determine the relation between delays in medication intensification and follow-up and the risk of cardiovascular events or death.

Abstract-The relationship between encounter frequency (average number of provider-patient encounters over a period of time) and blood pressure for hypertensive patients is unknown. We tested the hypothesis that shorter encounter intervals are associated with faster blood pressure normalization. We performed a retrospective cohort study of 5042 hypertensive patients with diabetes mellitus treated at primary care practices affiliated with 2 academic hospitals between 2000 and 2005. Distinct periods of continuously elevated blood pressure (Ն130/85 mm Hg) were studied. We evaluated the association of the average encounter interval with time to blood pressure normalization and rate of blood pressure decrease. Blood pressure of the patients with the average interval between encounters Յ1 month normalized after a median of 1.5 months at the rate of 28.7 mm Hg/month compared with 12.2 months at 2.6 mm Hg/month for the encounter interval Ͼ1 month (PϽ0.0001 for all). Median time to blood pressure normalization was 0.7 versus 1.9 months for the average encounter interval Յ2 weeks versus between 2 weeks and 1 month, respectively (PϽ0.0001).In proportional hazards analysis adjusted for patient demographics, initial blood pressure, and treatment intensification rate, a 1 month increase in the average encounter interval was associated with a hazard ratio of 0.764 for blood pressure normalization (PϽ0.0001). Shorter encounter intervals are associated with faster decrease in blood pressure and earlier blood pressure normalization. Greatest benefits were observed at encounter intervals (Յ2 weeks) shorter than what is currently recommended. (Hypertension. 2010;56:68-74.)Key Words: hypertension Ⅲ encounter frequency Ⅲ visit frequency Ⅲ outcomes E levated blood pressure is one of the major risk factors for macrovascular and microvascular complications in diabetic patients. 1-7 Treatment of hypertension decreases these risks 8 -12 and is highly cost-effective. 13,14 Despite abundant evidence of the benefits of lowering blood pressure, most patients with diabetes mellitus do not reach evidence-based treatment goals. [15][16][17] The reasons for this are not well understood.Current guidelines recommend that patients be followed up within a month when an elevated blood pressure is noted. 18 However, the intervals between provider-patient encounters are substantially longer. 19 -23 It is possible that this discrepancy between the guidelines and the practice of medicine contributes to the suboptimal outcomes in patients with hypertension. The currently available evidence on the relationship between encounter intervals and blood pressure is conflicting. Although a study of 400 patients by Guthmann et al 23 found a correlation between return visit interval and percentage of change in blood pressure, a smaller study of 100 patients by Parchman et al 24 failed to detect a statistically significant relationship. Furthermore, there are no data to provide guidance with respect to the optimal encounter interval for blood pressure control, and t...