Necroptosis blockade prevents lung injury in severe influenza.

Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1-5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6-8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.

EXIST: EXamining rIsk of excesS adiposiTy-Machine learning to predict obesity-related complications.

Background: Obesity is associated with an increased risk of multiple conditions, ranging from heart disease to cancer. However, there are few predictive models for these outcomes that have been developed specifically for people with overweight/obesity. Objective: To develop predictive models for obesity-related complications in patients with overweight and obesity. Methods: Electronic health record data of adults with body mass index 25-80 kg/m2 treated in primary care practices between 2000 and 2019 were utilized to develop and evaluate predictive models for nine long-term clinical outcomes using a) Lasso-Cox models and b) a machine-learning method random survival forests (RSF). Models were trained on a training dataset and evaluated on a test dataset over 100 replicates. Parsimonious models of <10 variables were also developed using Lasso-Cox. Results: Over a median follow-up of 5.6 years, study outcome incidence in the cohort of 433,272 patients ranged from 1.8% for knee replacement to 11.7% for atherosclerotic cardiovascular disease. Harrell C-index averaged over replicates ranged from 0.702 for liver outcomes to 0.896 for death for RSF, and from 0.694 for liver outcomes to 0.891 for death for Lasso-Cox. The Harrell C-index for parsimonious models ranged from 0.675 for liver outcomes to 0.850 for knee replacement. Conclusions: Predictive modeling can identify patients at high risk of obesity-related complications. Interpretable Cox models achieve results close to those of machine learning methods and could be helpful for population health management and clinical treatment decisions.

Patient-provider discussions of bariatric surgery and subsequent weight changes and receipt of bariatric surgery.

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.

Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis.

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.

Switching of cardiac troponin I between nuclear and cytoplasmic localization during muscle differentiation.

The nuclear accumulation of proteins may depend on the presence of short targeting sequences, which are known as nuclear localization signals (NLSs). Here, we found that NLSs are predicted in some cytosolic proteins and examined the hypothesis that these NLSs may be functional under certain conditions. As a model, human cardiac troponin I (hcTnI) was used. After expression in cultured non-muscle or undifferentiated muscle cells, hcTnI accumulated inside nuclei. Several NLSs were predicted and confirmed by site-directed mutagenesis in hcTnI. Nuclear import occurred via the classical karyopherin-α/ß nuclear import pathway. However, hcTnI expressed in cultured myoblasts redistributed from the nucleus to the cytoplasm, where it was integrated into forming myofibrils after the induction of muscle differentiation. It appears that the dynamic retention of proteins inside cytoplasmic structures can lead to switching between nuclear and cytoplasmic localization.

Proliferation, cancer, and aging-novel functions of the nucleolar methyltransferase fibrillarin?

Fibrillarin is an essential nucleolar protein that catalyzes the 2'-O-methylation of ribosomal RNAs. Recently, experimental data have begun to accumulate that suggest that fibrillarin can influence various cellular processes, development of pathological processes, and even aging. The exact mechanism by which fibrillarin can influence these processes has not been found, but some experimental data indicate that up- or downregulation of fibrillarin can modify the ribosome structure and, thus, causе an alteration in relative efficiency with which various mRNAs are translated. Here, we discuss recent studies on the potential roles of fibrillarin in the regulation of cell proliferation, cancer progression, and aging.

Risk factors for lack of statin therapy in patients with diabetes and coronary artery disease.

BACKGROUND: 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. OBJECTIVE: To investigate prevalence and predictors of statin therapy in patients with combined diabetes and CAD. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Drivers of the Sex Disparity in Statin Therapy in Patients with Coronary Artery Disease: A Cohort Study.

BACKGROUND: Women are less likely to be prescribed statins than men. Existing reports explain only a fraction of this difference. We conducted a study to identify factors that account for sex differences in statin therapy among patients with coronary artery disease (CAD). METHODS AND RESULTS: We retrospectively studied 24,338 patients with CAD who were followed for at least a year between 2000 and 2011 at two academic medical centers. Women (9,006 / 37% of study patients) were less likely to either have initiated statin therapy (81.9% women vs. 87.7% men) or to have persistent statin therapy at the end of follow-up (67.0% women vs. 71.4% men). Women were older (72.9 vs. 68.4 years), less likely to have ever smoked (49.8% vs. 65.6%), less likely to have been evaluated by a cardiologist (57.5% vs. 64.5%) and more likely to have reported an adverse reaction to a statin (27.1% vs. 21.7%) (p < 0.0001 for all). In multivariable analysis, patients with history of smoking (OR 1.094; p 0.017), younger age (OR 1.013 / year), cardiologist evaluation (OR 1.337) and no reported adverse reactions to statins (OR 1.410) were more likely (p < 0.0001 for all) to have persistent statin therapy. Together, these four factors accounted for 90.4% of the sex disparity in persistent statin therapy. CONCLUSIONS: Several specific factors appear to underlie divergent statin therapy in women vs. men. Identifying such drivers may facilitate programmatic interventions and stimulate further research to overcome sex differences in applying proven interventions for cardiovascular risk reduction.

Body mass index and all-cause mortality in patients with hypertension.

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/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) . 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/m(2) .

Optimal systolic blood pressure target, time to intensification, and time to follow-up in treatment of hypertension: population based retrospective cohort study.

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. DESIGN: Retrospective cohort study. SETTING: Primary care practices in the United Kingdom, 1986-2010. PARTICIPANTS: 88 756 adults with hypertension from The Health Improvement Network nationwide primary care research database. MAIN OUTCOME MEASURES: Rates of acute cardiovascular events or death from any cause for patients with different hypertension treatment strategies (defined by systolic intensification threshold, time to intensification, and time to follow-up over the course of a 10 year treatment strategy assessment period) after adjustment for age, sex, smoking status, socioeconomic deprivation, history of diabetes, cardiovascular disease or chronic kidney disease, Charlson comorbidity index, body mass index, medication possession ratio, and baseline blood pressure. RESULTS: During a median follow-up of 37.4 months after the treatment strategy assessment period, 9985 (11.3%) participants had an acute cardiovascular event or died. No difference in risk of the outcome was seen between systolic intensification thresholds of 130-150 mm Hg, whereas systolic intensification thresholds greater than 150 mm Hg were associated with progressively greater risk (hazard ratio 1.21, 95% confidence interval 1.13 to 1.30; P<0.001 for intensification threshold of 160 mm Hg). Outcome risk increased progressively from the lowest (0-1.4 months) to the highest fifth of time to medication intensification (hazard ratio 1.12, 1.05 to 1.20; P=0.009 for intensification between 1.4 and 4.7 months after detection of elevated blood pressure). The highest fifth of time to follow-up (>2.7 months) was also associated with increased outcome risk (hazard ratio 1.18, 1.11 to 1.25; P<0.001). CONCLUSIONS: Systolic intensification thresholds higher than 150 mm Hg, delays of greater than 1.4 months before medication intensification after systolic blood pressure elevation, and delays of greater than 2.7 months before blood pressure follow-up after antihypertensive medication intensification were associated with increased risk of an acute cardiovascular event or death. These findings support the importance of timely medical management and follow-up in the treatment of patients with hypertension.

"Summary Page": a novel tool that reduces omitted data in research databases.

BACKGROUND: Data entry errors are common in clinical research databases. Omitted data are of particular concern because they are more common than erroneously inserted data and therefore could potentially affect research findings. However, few affordable strategies for their prevention are available. METHODS: We have conducted a prospective observational study of the effect of a novel tool called "Summary Page" on the frequency of correction of omitted data errors in a radiation oncology research database between July 2008 and March 2009. "Summary Page" was implemented as an optionally accessed screen in the database that visually integrates key fields in the record. We assessed the frequency of omitted data on the example of the Date of Relapse field. We considered the data in this field to be omitted for all records that had empty Date of Relapse field and evidence of relapse elsewhere in the record. RESULTS: A total of 1,156 records were updated and 200 new records were entered in the database over the study period. "Summary Page" was accessed for 44% of all updated records and for 69% of newly entered records. Frequency of correction of the omitted date of cancer relapse was six-fold higher in records for which "Summary Page" was accessed (p = 0.0003). CONCLUSIONS: "Summary Page" was strongly associated with an increased frequency of correction of omitted data errors. Further, controlled, studies are needed to confirm this finding and elucidate its mechanism of action.