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ImportanceMany patients at high cardiovascular risk—women more commonly than men—are not receiving statins. Anecdotally, it is common for patients to not accept statin therapy recommendations by their clinicians. However, population-based data on nonacceptance of statin therapy by patients are lacking.ObjectivesTo evaluate sex disparities in nonacceptance of statin therapy and assess their association with low-density lipoprotein (LDL) cholesterol control.Design, Setting, and ParticipantsA retrospective cohort study was conducted from January 1, 2019, to December 31, 2022, of statin-naive patients with atherosclerotic cardiovascular disease, diabetes, or LDL cholesterol levels of 190 mg/dL (to convert to millimoles per liter, multiply by 0.0259) or more who were treated at Mass General Brigham between January 1, 2000, and December 31, 2018.ExposureRecommendation of statin therapy by the patient’s clinician, ascertained from the combination of electronic health record prescription data and natural language processing of electronic clinician notes.Main Outcomes and MeasuresTime to achieve an LDL cholesterol level of less than 100 mg/dL.ResultsOf 24 212 study patients (mean [SD] age, 58.8 [13.0] years; 12 294 women [50.8%]), 5308 (21.9%) did not accept the initial recommendation of statin therapy. Nonacceptance of statin therapy was more common among women than men (24.1% [2957 of 12 294] vs 19.7% [2351 of 11 918]; P P Conclusions and RelevanceThis cohort study suggests that nonacceptance of a statin therapy recommendation was common among patients at high cardiovascular risk and was particularly common among women. It was associated with significantly higher LDL cholesterol levels, potentially increasing the risk for cardiovascular events. Further research is needed to understand the reasons for nonacceptance of statin therapy by patients and to develop methods to ensure that all patients receive optimal therapy in accordance with their preferences and priorities.

In this paper we consider the metric power-law $f(R)\sim R^n $-gravity model for the four-dimensional metric tensor depending on two coordinates. We obtain exact analytical vacuum solutions for different values of $ n $. These solutions contain both non-stationary configurations of the travelling wave type and stationary ones, in particular, depending on one radial variable., Comment: 19 pages, 8 figures

Obesity is the most common chronic disease in the U.S. Patients with obesity have many cardiovascular risk factors, often modifiable. It is important to identify patients with obesity at high risk of atherosclerotic cardiovascular disease (ASCVD) to be able to appropriately direct treatment and resources. We conducted an observational study of EMR data of 399,360 adults with BMI ≥ 25 kg/m2 and without baseline ASCVD between 2000 and 2019. We first identified a literature-based pool of risk factors for ASCVD onset and conducted variable selection by applying least absolute shrinkage and selection operator (LASSO) penalized Cox regression with ten-fold cross-validation on an 80% training dataset. We estimated a regular Cox model on the training dataset with selected variables and evaluated model performance on the remaining 20% dataset. Over the mean of 7.4 years of follow-up, 37,424 (11.7%) of study patients developed ASCVD. The predictive model achieved a Harrell’s C-statistic of 0.81. The greatest risk of ASCVD onset was associated with older age (HR 2.16 per 1 SD = 15.4 years; 95% CI 2.13- 2.20), heart failure (HR 1.85; 95% CI 1.74-1.97), valvular heart disease (HR 1.61; 95% CI 1.53-1.68) and stimulant abuse (HR 1.60; 95% CI 1.41-1.81). Female sex was associated with a lower risk of ASCVD (HR 0.64; 95% CI 0.63-0.65). Patient characteristics found in >5% of patients that carried additional risk included history of smoking (39.9% of patients; HR 1.40; 95% CI 1.37-1.43), proteinuria (5.5%; HR 1.33; 95% CI 1.29-1.38) and hypertension (23.6%; HR 1.29; 95% CI 1.26-1.32). Each standard deviation increase in BMI (5.3 kg/m2) was associated with a 1.15-fold (95% CI 1.14-1.16) increase in the risk of ASCVD onset. It is feasible to use predictive modeling to identify patients with overweight and obesity at high ASCVD risk. This approach could be utilized to guide population management and clinical treatment decisions. Disclosure A. Turchin: Consultant; Self; Proteomics International, Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pfizer Inc., Sanofi, Stock/Shareholder; Self; Brio Systems. F. J. Morrison: None. M. Shubina: None. S. Shinde: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. N. Ahmad: Employee; Self; Eli Lilly and Company. H. Kan: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Bristol-Myers Squibb Company, GlaxoSmithKline plc. Funding Eli Lilly and Company

Obesity is the most common chronic disease in the U.S. Patients with obesity are at high risk for type 2 diabetes mellitus (T2DM); however, many of their risk factors for T2DM are modifiable. It is important to identify patients with obesity at high risk for T2DM to appropriately direct treatment and resources. We conducted an observational study of EMR data of 399,711 adults with BMI ≥ 25 kg/m2 and without baseline T2DM between 2000 and 2019. We first identified a literature-based pool of risk factors for T2DM onset and conducted variable selection by applying LASSO penalized Cox regression with ten-fold cross-validation on an 80% training dataset. We estimated a regular Cox model on the training dataset with selected variables and evaluated model performance on the remaining 20% dataset. Over a mean of 7.4 years of follow-up, 38,898 (9.8%) study patients developed T2DM. The predictive model achieved a Harrell’s C-statistic of 0.81. The greatest risk of T2DM was associated with gestational diabetes (HR 2.53; 95% CI 2.12-3.01), Asian and Hispanic race/ethnicity (HRs 2.38 and 1.94; 95% CIs 2.24-2.53 and 1.86-2.02, respectively), family history of DM (HR 2.00; 95% CI 1.95-2.04) and PCOS (HR 1.84; 95% CI 1.63-2.07). Female sex (HR 0.77; 95% CI 0.75-0.79), having a partner (HR 0.90; 95% CI 0.88-0.92) or commercial insurance (HR 0.86; 95% CI 0.84-0.88) were associated with a lower risk of T2DM. Characteristics found in >5% of patients that carried additional risk included proteinuria (5.0% of patients; HR 1.53; 95% CI 1.47-1.59), hypertension (23.9%; HR 1.21; 95% CI 1.18-1.25), high cholesterol (11.9%; HR 1.19; 95% CI 1.15-1.23), and history of smoking (40.5%; HR 1.18; 95% CI 1.15-1.21). Each standard deviation increase in BMI (5.2 kg/m2) was associated with a 1.51-fold (95% CI 1.49-1.52) increase in T2DM onset. It is feasible to use predictive modeling to identify patients with overweight and obesity at high risk of T2DM. This approach could be utilized to guide population management and clinical treatment decisions. Disclosure A. Turchin: Consultant; Self; Proteomics International, Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pfizer Inc., Sanofi, Stock/Shareholder; Self; Brio Systems. F. J. Morrison: None. M. Shubina: None. S. Shinde: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. N. Ahmad: Employee; Self; Eli Lilly and Company. H. Kan: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Bristol-Myers Squibb Company, GlaxoSmithKline plc. Funding Eli Lilly and Company

OBJECTIVE The purpose of this study was to determine whether patients who discuss bariatric surgery with their providers are more likely to undergo the procedure and to lose weight. METHODS A retrospective cohort study of adults with BMI ≥ 35 kg/m2 treated between 2000 and 2015 was conducted to analyze the relationship between a discussion of bariatric surgery in the first year after study entry and weight changes (primary outcome) and receipt of bariatric surgery (secondary outcome) over 2 years after study entry. Natural language processing was used to identify the documentation of bariatric surgery discussion in electronic provider notes. RESULTS Out of 30,560 study patients, a total of 2,659 (8.7%) discussed bariatric surgery with their providers. The BMI of patients who discussed bariatric surgery decreased by 2.18 versus 0.21 for patients who did not (p < 0.001). In a multivariable analysis, patients who discussed bariatric surgery with their providers lost more weight (by 1.43 [change in BMI]; 95% CI: 1.29-1.57) and had greater odds (10.2; 95% CI: 9.0-11.6; p < 0.001) of undergoing bariatric surgery. CONCLUSIONS Clinicians rarely discussed bariatric surgery with their patients. Patients who did have this discussion were more likely to lose weight and to undergo bariatric surgery.

e14558 Background: The PD-1/PD-L1 checkpoint axis is a validated target in oncology, and immunotherapy with antibody approaches have proven efficacy across various tumor types. Oral small-molecule inhibitors of PD-L1 may offer advantages over antibody approaches by enabling tunable on-target engagement and the potential for better tissue penetration and improved efficacy. Here we report the preclinical in vitro activity of small-molecule inhibitors of PD-L1 possessing a novel mechanism of action, favorable pharmacokinetics, and demonstrated in vivo efficacy in a mouse colon adenocarcinoma model. Methods: In vitro activity was assessed in a Jurkat T cell NFAT reporter assay and PD-L1 reduction was confirmed in CHO-K1 cells expressing human PD-L1 (CHO-K1-hPD-L1) and in peripheral blood mononuclear cells (PBMCs) from healthy donors. T cell activation assays were conducted with PBMCs from healthy donors. Non-specific cytokine release was evaluated in human whole blood. Pharmacokinetic (PK) evaluations were conducted in rodents and non-human primates (NHP). In vivo efficacy was evaluated in an MC38 tumor humanized PD-L1 and PD-1 mouse model. Results: Small-molecule inhibitors of PD-L1 were able to disrupt PD-1:PD-L1 and PD-L1:CD80 interactions through the reduction of PD-L1 expression on the cell surface via a novel internalization mechanism, resulting in PD-L1 degradation (EC50s ranged from 1.9 – 24 nM in CHO-K1-hPD-L1 and primary human myeloid cells). Lead PD-L1 inhibitors mediated potent activation of T cells in a NFAT reporter assay (EC50s of 13 and 18 nM) as well as dose responsive elevations in IL-2 production in human PBMCs stimulated with staphylococcal enterotoxin B. Compound treatment did not elicit non-specific cytokine release in human whole blood, supportive of favorable immune safety. PK profiles showed low systemic clearance in rodents and NHP. In an MC38 tumor model, once daily oral administration of compounds at 3, 10, and 30 mg/kg resulted in dose responsive tumor reduction that was associated with T cell activation and infiltration into tumors. Conclusions: Oral small-molecule PD-L1 inhibitors possessing a novel mechanism of action and the ability to mediate T cell activation in primary human immune cell types were identified. These compounds display in vivo anti-tumor efficacy comparable to anti-PD-L1 antibody and possess favorable preclinical profiles for further development, with the potential for all-oral treatment regimens for oncology.

Necroptosis is considered a fail-safe death modality deployed when apoptosis pathways are compromised, but whether necroptosis can limit a virus in the absence of apoptosis is unknown. This study demonstrates that necroptosis drives highly effective antiviral immunity when apoptosis is absent., Influenza A virus (IAV) activates ZBP1-initiated RIPK3-dependent parallel pathways of necroptosis and apoptosis in infected cells. Although mice deficient in both pathways fail to control IAV and succumb to lethal respiratory infection, RIPK3-mediated apoptosis by itself can limit IAV, without need for necroptosis. However, whether necroptosis, conventionally considered a fail-safe cell death mechanism to apoptosis, can restrict IAV—or indeed any virus—in the absence of apoptosis is not known. Here, we use mice selectively deficient in IAV-activated apoptosis to show that necroptosis drives robust antiviral immune responses and promotes effective virus clearance from infected lungs when apoptosis is absent. We also demonstrate that apoptosis and necroptosis are mutually exclusive fates in IAV-infected cells. Thus, necroptosis is an independent, “stand-alone” cell death mechanism that fully compensates for the absence of apoptosis in antiviral host defense.

Background Evidence suggests that insulin therapy of patients with type 2 diabetes mellitus (T2DM) is frequently discontinued. However, the reasons for discontinuing insulin and factors associated with insulin discontinuation in this patient population are not well understood. Methods We conducted a retrospective cohort study of adults with T2DM prescribed insulin between 2010 and 2017 at Partners HealthCare. Reasons for discontinuing insulin and factors associated with insulin discontinuation were studied using electronic medical records (EMR) data. Natural language processing (NLP) was applied to identify reasons from unstructured clinical notes. Factors associated with insulin discontinuation were extracted from structured EMR data and evaluated using multivariable logistic regression. Results Among 7009 study patients, 2957 (42.2%) discontinued insulin within 12 months after study entry. Most patients who discontinued insulin (2121 / 71.7%) had reasons for discontinuation documented. The most common reasons were improving blood glucose control (33.2%), achieved weight loss (18.5%) and initiation of non-insulin diabetes medications (16.7%). In multivariable analysis adjusted for demographics and comorbidities, patients were more likely to discontinue either basal or bolus insulin if they were on a basal-bolus regimen (OR 1.6, 95% CI 1.3 to 1.8; p p Conclusions In this large real-world evidence study conducted in an area with a high penetration of health insurance, insulin discontinuation countenanced by healthcare providers was common. In most cases it was linked to achievement of glycemic control, achieved weight loss and initiation of other diabetes medications. Factors associated with and stated reasons for insulin discontinuation were different from those previously described for non-adherence to insulin therapy, identifying it as a distinct clinical phenomenon.

OBJECTIVE To investigate the association between ambulatory medication reconciliation and health care utilization in patients with diabetes. RESEARCH DESIGN AND METHODS In this retrospective cohort analysis, we studied adults taking at least one diabetes medication treated in primary care practices affiliated with two academic medical centers between 2000 and 2014. We assessed the relationship between the fraction of outpatient diabetes medications reconciled over a 6-month period and the composite primary outcome of combined frequency of emergency department (ED) visits and hospitalizations over the subsequent 6 months. RESULTS Among 261,765 reconciliation assessment periods contributed by 31,689 patients, 176,274 (67.3%), 27,775 (10.6%), and 57,716 (22.1%) had all, some, or none of the diabetes medications reconciled, respectively. Patients with all, some, or no diabetes medications reconciled had 0.354, 0.377, and 0.384 primary outcome events per 6 months, respectively (P < 0.0001). In a multivariable analysis adjusted for demographics and comorbidities, having some or all versus no diabetes medications reconciled was associated with a lower risk of the primary outcome (rate ratio 0.94 [95% CI 0.90–0.98; P = 0.0046] vs. 0.92 [0.89–0.95; P < 0.0001], respectively). Introduction of feedback to individual providers was associated with a significant increase in the odds of all diabetes medications being reconciled (2.634 [2.524–2.749]; P < 0.0001). CONCLUSIONS A higher fraction of reconciled outpatient diabetes medications was associated with a lower frequency of ED visits and hospitalizations. Individual performance feedback could help to achieve more comprehensive medication reconciliation.

AIM To determine the relationship between decline of insulin therapy by individuals with type 2 diabetes and subsequent blood glucose control. METHODS We retrospectively studied adults with type 2 diabetes and suboptimal (HbA1c ≥ 53 mmol/mol [7.0%]) glycaemic control followed at two academic hospitals between 2000 and 2014 who were recommended insulin therapy. Decline of insulin therapy recommendations was identified using natural language processing of provider notes. Time to HbA1c < 53 mmol/mol (7.0%) served as the primary outcome. RESULTS Of 5307 study participants, 2267 (42.7%) declined insulin therapy. Median time to HbA1c control in individuals who declined vs. started insulin therapy was 50 vs. 38 months, respectively (P < 0.001). In multivariable analysis, decline of insulin therapy was associated with hazard ratio for HbA1c control of 0.89 (95% CI 0.82 to 0.97; P = 0.008). Participants were more likely to accept insulin therapy recommendations if they had diabetes complications (OR 1.32; 95% CI 1.13 to 1.53; P < 0.001) or a higher HbA1c (OR 1.10; 95% CI 1.07 to 1.13; P < 0.001), and less likely if they were older (OR 0.81; 95% CI 0.76 to 0.86; P < 0.001) or were taking more non-insulin diabetes medications (OR 0.78; 95% CI 0.74 to 0.83; P < 0.001). CONCLUSIONS Individuals with uncontrolled type 2 diabetes who declined insulin therapy subsequently had worse glycaemic control. These findings highlight the need to improve our understanding of the relationship of this common but poorly explored clinical phenomenon to blood glucose control and ultimately diabetes complications.

Influenza A viruses (IAV) are members of the Orthomyxoviridae family of negative-sense RNA viruses. The greatest diversity of IAV strains is found in aquatic birds, but a subset of strains infects other avian as well as mammalian species, including humans. In aquatic birds, infection is largely restricted to the gastrointestinal tract and spread is through feces, while in humans and other mammals, respiratory epithelial cells are the primary sites supporting productive replication and transmission. IAV triggers the death of most cell types in which it replicates, both in culture and in vivo. When well controlled, such cell death is considered an effective host defense mechanism that eliminates infected cells and limits virus spread. Unchecked or inopportune cell death also results in immunopathology. In this review, we discuss the impact of cell death in restricting virus spread, supporting the adaptive immune response and driving pathogenesis in the mammalian respiratory tract. Recent studies have begun to shed light on the signaling pathways underlying IAV-activated cell death. These pathways, initiated by the pathogen sensor protein ZBP1 (also called DAI and DLM1), cause infected cells to undergo apoptosis, necroptosis, and pyroptosis. We outline mechanisms of ZBP1-mediated cell death signaling following IAV infection.

Insulin is an important part of treatment of type 2 diabetes mellitus (T2DM). Nevertheless, reasons for discontinuation of insulin therapy are poorly understood. We conducted a real-world-evidence analysis of EMR data at Partners HealthCare to study adults with T2DM who were prescribed insulin between 2010 and 2016. Reasons for insulin discontinuation were identified from a combination of structured EMR data and natural language processing analysis of EMR notes using a validated tool (sensitivity 76.9% and positive predictive value 89.7%). The mean age of study patients was 60.2 years; 52.7% were male. Among 7,009 study patients, 2,957 (42.2%) discontinued insulin within 12 months after study start. In multivariable logistic regression analysis adjusted for demographics and comorbidities, patients were more likely to discontinue either basal or bolus insulin if they were on a basal-bolus regimen compared to basal only (OR 1.56, 95% CI 1.33 to 1.83; p < 0.001) or if they were being seen by an endocrinologist (OR 2.58; 95% CI 2.22 to 2.99; p < 0.001). Most patients (2,121/71.7%) had one or more reasons for discontinuation documented. The most common reasons were improving blood glucose (BG) control (33.2%), weight loss (likely ultimately also leading to lower BG) (18.5%) and initiation of non-insulin diabetes medications (16.7%). In multivariable analysis, patients were more likely to stop insulin due to achievement of good BG control if they were treated by an endocrinologist (OR 2.52; 95% CI 2.11 to 3.00; p < 0.001) or by a female physician (OR 1.43; 95% CI 1.26 to 1.63; p < 0.001). This study represents a successful attempt to use natural language processing to understand reasons for insulin discontinuation. Insulin discontinuation is common, and particularly so for patients on a basal-bolus regimen. Achievement of glycemic control, weight loss and initiation of other diabetes medications were the most common reasons for insulin discontinuation. Disclosure J. Wu: None. F.J. Morrison: None. Z. Zhao: Employee; Self; Lilly Diabetes. X. He: Employee; Self; Eli Lilly and Company. M. Shubina: None. S. Malmasi: None. W. Ge: None. X. Peng: None. A. Turchin: Advisory Panel; Self; Monarch Medical Technologies. Research Support; Self; Eli Lilly and Company. Stock/Shareholder; Self; Brio Systems. Funding Eli Lilly and Company

Influenza A virus (IAV) is a lytic RNA virus that triggers receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated pathways of apoptosis and mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis in infected cells. ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. Cell death induced by nuclear MLKL was a potent activator of neutrophils, a cell type known to drive inflammatory pathology in virulent IAV disease. Consequently, MLKL-deficient mice manifest reduced nuclear disruption of lung epithelia, decreased neutrophil recruitment into infected lungs, and increased survival following a lethal dose of IAV. These results implicate Z-RNA as a new pathogen-associated molecular pattern and describe a ZBP1- initiated nucleus-to-plasma membrane “inside-out” death pathway with potentially pathogenic consequences in severe cases of influenza.

OBJECTIVE To investigate the relationship between lifestyle counseling in primary care settings and clinical outcomes in patients with diabetes. RESEARCH DESIGN AND METHODS We retrospectively studied hyperglycemic adults with diabetes treated at primary care practices between 2000 and 2014. We analyzed the relationship between frequency of lifestyle counseling (identified using natural language processing of electronic notes) and a composite outcome of death and cardiovascular events during subsequent follow-up. RESULTS Among patients with monthly counseling or more, 10-year cumulative incidence of the primary outcome was 33.0% compared with 38.1% for less than monthly counseling (P = 0.0005). In multivariable analysis, higher frequency of lifestyle counseling was associated with lower incidence of the primary outcome (hazard ratio 0.88 [95% CI 0.82–0.94]; P < 0.001). CONCLUSIONS More frequent lifestyle counseling was associated with a lower incidence of cardiovascular events and death among patients with diabetes.

Obesity is the most common chronic disease in the U.S. Patients with obesity have many risk factors for cancer, often modifiable. It is important to identify patients with obesity at high risk of cancer to be able to appropriately direct treatment and resources. Given that the risk pool is large, it is imperative to identify a clinically meaningful metric for risk stratification to help guide interventions. We conducted an observational study of electronic medical records data for 394,161 adults aged between 18 and 80, with BMI ≥ 25 kg/m2 and without baseline history of cancer between 2000 and 2019. We first identified a literature-based pool of risk factors for cancer onset and conducted variable selection by applying least absolute shrinkage and selection operator (LASSO) penalized Cox regression with ten-fold cross-validation on an 80% training dataset. Effects of the selected variables on risk of cancer (excluding non-melanoma skin cancer) onset were assessed using Cox regression on the 80% training dataset. The resulting model accuracy was evaluated using Cox regression on a withheld 20% validation dataset. Participants had a mean age of 46.7 (SD: 15.5) years and mean body mass index (BMI) of 30.5 (SD: 5.4) kg/m2; 51.9% were women. Over a mean of 7.5 years of follow-up, 34,679 (8.8%) of study patients developed cancer. The predictive model achieved a Harrell’s C-statistic of 0.73. The greatest risk of cancer incidence was associated with HIV infection (HR 2.22; 95% CI 1.88–2.63; 0.27% of patients), older age (HR 2.05 per 1 SD = 15.5 years; 95% CI 2.01- 2.09), hepatitis C infection (HR 1.48; 95% CI 1.34–1.63; 0.96% of patients), and family history of cancer (HR 1.44; 95% CI 1.41–1.48; 42.5% of patients). Additional patient characteristics found in >5% of patients that also carried risk included proteinuria (5.8% of patients; HR 1.23; 95% CI 1.18–1.29) and history of smoking (40.7% of patients; HR 1.20; 95% CI 1.17–1.23). Each standard deviation increase in BMI (5.4 kg/m2) was associated with a hazard ratio of 1.06 (95% CI 1.05–1.07) for incident cancer. It is feasible to use predictive modeling to identify patients with overweight and obesity at high cancer risk. This approach could be utilized to guide population management and clinical treatment decisions.

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 (ZBP1/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.

Influenza A viruses (IAV) are members of the Orthomyxoviridae family of negative-sense RNA viruses. The greatest diversity of IAV strains is found in aquatic birds, but a subset of strains infects other avian as well as mammalian species, including humans. In aquatic birds, infection is largely restricted to the gastrointestinal tract and spread is through feces, while in humans and other mammals, respiratory epithelial cells are the primary sites supporting productive replication and transmission. IAV triggers the death of most cell types in which it replicates, both in culture and in vivo. When well controlled, such cell death is considered an effective host defense mechanism that eliminates infected cells and limits virus spread. Unchecked or inopportune cell death also results in immunopathology. In this review, we discuss the impact of cell death in restricting virus spread, supporting the adaptive immune response and driving pathogenesis in the mammalian respiratory tract. Recent studies have begun to shed light on the signaling pathways underlying IAV-activated cell death. These pathways, initiated by the pathogen sensor protein ZBP1 (also called DAI and DLM1), cause infected cells to undergo apoptosis, necroptosis, and pyroptosis. We outline mechanisms of ZBP1-mediated cell death signaling following IAV infection.

Objective To characterize the relationship between body mass index (BMI) and all-cause mortality among adults with hypertension. Methods We conducted a retrospective cohort study of adults with hypertension from The Health Improvement Network primary care research database in the United Kingdom. Mortality rates within each BMI category were compared after adjustment for age, sex, pre existing medical conditions, smoking, alcohol use, and socioeconomic status. Results During a median follow-up period of 8.0 years, 34,354 deaths occurred (8.8%) among the 388,724 study patients. In multivariable analysis that included interaction terms between smoking, heavy alcohol use, preexisting cardiovascular disease and chronic obstructive pulmonary disease (COPD), and BMI category to account for these conditions' association with increased mortality at lower BMI levels, a U-shaped relationship was observed between BMI and mortality, with no difference in mortality in overweight (25.0–29.9 kg/m2) versus normal (18.5–24.9 kg/m2) BMI (risk ratio 1.00, 95% confidence interval 0.95 to 1.04, P = 0.80). In multivariable analysis that used narrower BMI categories, lowest mortality was observed between BMI of 23.0 and 26.9 kg/m2. Conclusions Patients with hypertension who have no history of smoking, heavy alcohol use, cardiovascular disease, or COPD have lowest mortality between BMI of 23.0 and 26.9 kg/m2.

OBJECTIVE To establish quantitative characteristics of lifestyle counseling documentation associated with improved glycemic control in patients with diabetes. RESEARCH DESIGN AND METHODS We retrospectively studied 10,870 hyperglycemic (HbA1c ≥7.0% [53 mmol/mol]) adults with diabetes followed at primary care practices affiliated with two academic hospitals between 2000 and 2010. Documentation intensity was represented by the mean number of characters per note documenting lifestyle counseling. Heterogeneity was calculated as the normalized Levenshtein distance between lifestyle counseling sentences between consecutive notes. Cox proportional hazards model was constructed to assess association of heterogeneity and intensity of lifestyle counseling documentation to time to HbA1c RESULTS Comparing patients in the highest versus lowest tertile by documentation heterogeneity and documentation intensity, median time to HbA1c CONCLUSIONS Higher heterogeneity and intensity of lifestyle counseling documentation in provider notes were associated with better glycemic control. Further studies involving direct observation of patient care are needed to establish the nature of the relationship between documentation characteristics and patient outcomes.

Many patients can tolerate statin therapy after an adverse reaction. However, optimal patient selection criteria and methods of reattempting statin therapy after an adverse reaction are unknown.To identify patient and treatment characteristics associated with a successful statin reattempt after an adverse reaction.We retrospectively studied adults treated in primary care practices affiliated with 2 academic medical centers between 2000 and 2012 who reattempted statin therapy after an adverse reaction. Statin reattempts were considered successful if the patient had at least 2 statin prescriptions after discontinuation of the original statin, and had an active electronic medical record statin record at 2 years after the adverse reaction.Among 6196 patients included in the study, 4536 (73.2%) successfully reattempted statin therapy. In multivariable analysis, history of coronary artery disease, stroke, or diabetes (odds ratio [OR] 1.195; P = .008) and reattempted treatment with a different statin (OR 1.463; P .0001) were associated with greater odds of a successful reattempt. Adverse reaction during the first year after statin initiation (OR 0.721; P .0001) or myalgia or myopathy (OR 0.807; P = .001) as well as history of adverse reactions to nonstatin drugs (OR 0.908; P .0001) were associated with lower odds.Nature and timing of the adverse reaction, patient's medical history and the medication prescribed affected the likelihood of a successful reattempt of statin therapy after an adverse reaction. These findings suggest that a patient-centered approach to restarting statins should be considered for patients at high cardiovascular risk to improve the chances of success.

Background Many patients discontinue statin treatment, often after having a possible adverse reaction. The risks and benefits of continued statin therapy after an adverse reaction are not known. Objective To examine the relationship between continuation of statin therapy (any prescription within 12 months after an adverse reaction) and clinical outcomes. Design Retrospective cohort study. Setting Primary care practices affiliated with 2 academic medical centers. Participants Patients with a presumed adverse reaction to a statin between 2000 and 2011. Measurements Information on adverse reactions to statins was obtained from structured electronic medical record data or natural-language processing of narrative provider notes. The primary composite outcome was time to a cardiovascular event (myocardial infarction or stroke) or death. Results Most (81%) of the adverse reactions to statins were identified from the text of electronic provider notes. Among 28 266 study patients, 19 989 (70.7%) continued receiving statin prescriptions after the adverse reaction. Four years after the presumed adverse event, the cumulative incidence of the composite primary outcome was 12.2% for patients with continued statin prescriptions, compared with 13.9% for those without them (difference, 1.7% [95% CI, 0.8% to 2.7%]; P < 0.001). In a secondary analysis of 7604 patients for whom a different statin was prescribed after the adverse reaction, 2014 (26.5%) had a documented adverse reaction to the second statin, but 1696 (84.2%) of those patients continued receiving statin prescriptions. Limitations The risk for recurrent adverse reactions to statins could not be established for the entire sample. It was also not possible to determine whether patients actually took the statins. Conclusion Continued statin prescriptions after an adverse reaction were associated with a lower incidence of death and cardiovascular events. Primary Funding Source Chinese National Key Program of Clinical Science, National Natural Science Foundation of China, and Young Scientific Research Fund of Peking Union Medical College Hospital.

The programmed self-destruction of infected cells is a powerful antimicrobial strategy in metazoans. For decades, apoptosis represented the dominant mechanism by which the virus-infected cell was thought to undergo programmed cell death. More recently, however, new mechanisms of cell death have been described that are also key to host defense. One such mechanism in vertebrates is programmed necrosis, or "necroptosis", driven by receptor-interacting protein kinase 3 (RIPK3). Once activated by innate immune stimuli, including virus infections, RIPK3 phosphorylates the mixed lineage kinase domain-like protein (MLKL), which then disrupts cellular membranes to effect necroptosis. Emerging evidence demonstrates that RIPK3 can also mediate apoptosis and regulate inflammasomes. Here, we review studies on the mechanisms by which viruses activate RIPK3 and the pathways engaged by RIPK3 that drive cell death.

Background/Aims: Many patients with chronic kidney disease (CKD) do not receive lipid-lowering therapy despite their high cardiovascular risk. The reasons for this are unknown. Methods: We have conducted a retrospective cohort study of discontinuation of lipid-lowering drugs in patients with CKD stage 3 and higher treated in practices affiliated with two academic medical centers between 2000 and 2010. Information on medication discontinuation and its reasons was obtained from electronic medical records, including natural language processing of electronic notes using previously validated software. Results: Out of 14,034 patients in the study cohort, 10,072 (71.8%) stopped their lipid-lowering drugs at least once, and 2,444 (17.4%) stopped them for at least 1 month. Patients who had a comorbidity associated with higher cardiovascular risk were less likely to stop lipid-lowering drugs. Insurance request was the most common explicitly documented reason for discontinuation, and adverse reactions were the most common reason for long-term discontinuation. In a multivariable analysis, patients were more likely to stop a lipid-lowering drug because of an insurance request if they had government insurance and they were also more likely to stop a lipid-lowering drug because of adverse reactions if they had a history of multiple adverse reactions to other medications. There was no significant relationship between CKD stage and the reason for discontinuation of lipid-lowering drugs. Conclusions: Patients with CKD frequently stop lipid-lowering drugs. Insurance requests and adverse reactions are common reasons for the discontinuation. Further research is needed to ensure appropriate lipid-lowering therapy for these individuals at high cardiovascular risk. i 2014 S. Karger AG, Basel

OBJECTIVE Studies have shown that patients without a consistent primary care provider have inferior outcomes. However, little is known about the mechanisms for these effects. This study aims to determine whether primary care physicians (PCPs) provide more frequent medication intensification, lifestyle counseling, and patient encounters than other providers in the primary care setting. RESEARCH DESIGN AND METHODS This retrospective cohort study included 584,587 encounters for 27,225 patients with diabetes and elevated A1C, blood pressure, and/or LDL cholesterol monitored for at least 2 years. Encounters occurred at primary care practices affiliated with two teaching hospitals in eastern Massachusetts. RESULTS Of the encounters documented, 83% were with PCPs, 13% were with covering physicians, and 5% were with midlevel providers. In multivariable analysis, the odds of medication intensification were 49% (P < 0.0001) and 26% (P < 0.0001) higher for PCPs than for covering physicians and midlevel providers, respectively, whereas the odds of lifestyle counseling were 91% (P < 0.0001) and 21% (P = 0.0015) higher. During visits with acute complaints, covering physicians were even less likely, by a further 52% (P < 0.0001), to intensify medications, and midlevel providers were even less likely, by a further 41% (P < 0.0001), to provide lifestyle counseling. Compared with PCPs, the hazard ratios for time to the next encounter after a visit without acute complaints were 1.11 for covering physicians and 1.19 for midlevel providers (P < 0.0001 for both). CONCLUSIONS PCPs provide better care through higher rates of medication intensification and lifestyle counseling. Covering physicians and midlevel providers may enable more frequent encounters when PCP resources are constrained.

Historical literature reports risk of fetal demise after diabetic ketoacidosis (DKA) in pregnancy as high as 25–60% (1,2). However, estimates have generally been based on small sample sizes, with limited investigation of other fetal outcomes or risk factors associated with poor fetal outcomes. We aimed to provide an updated assessment of the incidence and risk factors for fetal demise and other adverse outcomes in women with DKA during pregnancy. This retrospective cohort study included pregnancies between 1996 and 2015 with at least one DKA event in women with type 1 diabetes at one of three teaching hospitals in Boston. Data were collected through medical record review. Pregnancies were excluded if information on birth status (live or demise) and gestational age at birth or demise were unknown. Among the 77 DKA events in 64 pregnancies in 62 women included in the study, fetal demise, preterm …

Patients with both diabetes and coronary artery disease (CAD) have exceedingly high cardiovascular risk. Nevertheless, little is known about prevalence of statin therapy in this population and reasons why some patients may not be receiving this potentially life-saving treatment.To investigate prevalence and predictors of statin therapy in patients with combined diabetes and CAD.We conducted a retrospective cohort study of primary care patients with diabetes and CAD followed at 2 academic medical centers between 2000 and 2011. We used multivariable logistic regression to identify patient and provider characteristics associated with (1) statin initiation (any history of statin therapy) and (2) statin persistence (active statin prescription at the study end).Of 8488 study patients, 7427 (87.5%) ever received statins and 6212 (73.2%) had persistent statin therapy. Younger age (odds ratio [OR], 1.26 per decade), smoking (OR, 1.49) and cardiologist evaluation (OR, 2.26) were associated with statin initiation (P .0001 for all). Younger age (OR, 1.17), family history of CAD (OR, 1.39), no adverse reactions to statins (OR, 1.40; P .0001 for all), female sex (OR, 1.22; P = .005), history of smoking (OR, 1.22; P = .003), cardiologist evaluation (OR, 1.23; P = .002), and lower HbA1c (OR, 1.04; P = 0.003) were associated with persistent statin therapy. Only 362 (29.8%) of the 1215 patients without persistent statin therapy had tried at least 2 statins, and 58 (4.8%) tried 3 statins.Many patients with combined CAD and diabetes are not treated with statins, although in this very high-risk group, even moderate-intensity statins result in meaningful reductions in cardiovascular events. Higher cardiovascular risk and cardiologist evaluation were associated with higher prevalence of statin therapy.

OBJECTIVE In clinical trials, diet, exercise, and weight counseling led to short-term improvements in blood glucose, blood pressure, and cholesterol levels in patients with diabetes. However, little is known about the long-term effects of lifestyle counseling on patients with diabetes in routine clinical settings. RESEARCH DESIGN AND METHODS This retrospective cohort study of 30,897 patients with diabetes aimed to determine whether lifestyle counseling is associated with time to A1C, blood pressure, and LDL cholesterol control in patients with diabetes. Patients were included if they had at least 2 years of follow-up with primary care practices affiliated with two teaching hospitals in eastern Massachusetts between 1 January 2000 and 1 January 2010. RESULTS Comparing patients with face-to-face counseling rates of once or more per month versus less than once per 6 months, median time to A1C CONCLUSIONS Lifestyle counseling in the primary care setting is strongly associated with faster achievement of A1C, blood pressure, and LDL cholesterol control. These results confirm that the findings of controlled clinical trials are applicable to the routine care setting and provide evidence to support current treatment guidelines.

Medical applications frequently contain a wide range of functionalities. Users are often unaware of all of the functionalities available. More effective ways of delivering information about available functionalities to the users are needed. We conducted a pseudo-randomized controlled trial to determine whether interruptive alerts will increase utilization of several functionalities by the users of the Pre-Admission Medication List (PAML) Builder application at two academic medical centers. In a log-linear model, alerts increased total utilization of the promoted functionalities per PAML built by 70% compared to the controls at the site level (p

Many e-prescribing systems allow for both structured and free-text fields in prescriptions, making possible internal discrepancies. This study reviewed 2914 electronic prescriptions that contained free-text fields. Internal discrepancies were found in 16.1% of the prescriptions. Most (83.8%) of the discrepancies could potentially lead to adverse events and many (16.8%) to severe adverse events, involving a hospital admission or death. Discrepancies in doses, routes or complex regimens were most likely to have a potential for a severe event (p=0.0001). Discrepancies between structured and free-text fields in electronic prescriptions are common and can cause patient harm. Improvements in electronic medical record design are necessary to minimize the risk of discrepancies and resulting adverse events.

OBJECTIVE Hypoglycemia 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 METHODS This 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. RESULTS Hypoglycemia 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). CONCLUSIONS Hypoglycemia 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.

Evidence suggests that many patients tolerate statin therapy after an adverse reaction. However, clinical outcomes of statin persistence after adverse reactions are unknown. We conducted a retrospective cohort analysis of the relationship between persistent statin therapy during 12 months after an adverse reaction, and cardiovascular (CV) events (myocardial infarctions and strokes) and death from any cause. We studied patients in primary care practices at two academic medical centers who reported an adverse reaction to a statin between 2000 and 2011 and were subsequently followed for at least 12 months. Adverse reactions to statins were identified using a combination of natural language processing of provider notes and EMR data. Among 28,279 study patients, 19,997 (70.7%) had persistent statin therapy after an adverse reaction. There were 10,203 (36.1%) patients at high CV risk (previous history of coronary artery disease (CAD), stroke or diabetes). Over a mean of 1,333 days of follow-up, 2,390 (8.45%) of patients suffered a CV event and 1,354 (4.8%) patients died. In univariate analysis, among patients at high CV risk 25.7% of patients who stopped statins reached composite primary outcome (CV event or death) vs. 19.6% of patients who had persistent statin therapy (Figure; p < 0.0001). In multivariable analysis adjusted for demographics, smoking status, Charlson Comorbidity Index, family history of stroke or CAD, blood pressure, body mass index, LDL cholesterol level, and renal function, persistent statin therapy was associated with a hazard ratio for primary outcome of 0.887 (95% CI 0.807 - 0.976; p=0.014). Persistent statin therapy was not associated with increased time to primary outcome in either univariate or multivariable analysis among patients with low baseline CV risk. Persistent statin therapy after a reported adverse reaction to a statin was associated with longer time to CV event or death in patients at high but not low CV risk.

In this paper we investigate the one-dimensional parabolic-parabolic Patlak-Keller-Segel model of chemotaxis. For the case when the diffusion coefficient of chemical substance is equal to two, in terms of travelling wave variables the reduced system appears integrable and allows the analytical solution. We obtain the exact soliton solutions, one of which is exactly the one-soliton solution of the Korteweg-de Vries equation., 9 pages; 12 figures

We present an easy tractable way to calculate maximal correlation range for a Sarmanov distribution with given marginals. For Kendall's τ, rank correlation and median concordance coefficients, we found maximum attainable ranges within the Sarmanov family of distributions.

To characterize the relationship between body mass index (BMI) and all-cause mortality among adults with hypertension.We conducted a retrospective cohort study of adults with hypertension from The Health Improvement Network primary care research database in the United Kingdom. Mortality rates within each BMI category were compared after adjustment for age, sex, pre existing medical conditions, smoking, alcohol use, and socioeconomic status.During a median follow-up period of 8.0 years, 34,354 deaths occurred (8.8%) among the 388,724 study patients. In multivariable analysis that included interaction terms between smoking, heavy alcohol use, preexisting cardiovascular disease and chronic obstructive pulmonary disease (COPD), and BMI category to account for these conditions' association with increased mortality at lower BMI levels, a U-shaped relationship was observed between BMI and mortality, with no difference in mortality in overweight (25.0-29.9 kg/m(2) ) versus normal (18.5-24.9 kg/m(2) ) BMI (risk ratio 1.00, 95% confidence interval 0.95 to 1.04, P = 0.80). In multivariable analysis that used narrower BMI categories, lowest mortality was observed between BMI of 23.0 and 26.9 kg/m(2) .Patients with hypertension who have no history of smoking, heavy alcohol use, cardiovascular disease, or COPD have lowest mortality between BMI of 23.0 and 26.9 kg/m(2) .