Management of Pericardial Effusion in Patients With Solid Tumor: An Algorithmic, Multidisciplinary Approach Results in Reduced Mortality After Paradoxical Hemodynamic Instability.

OBJECTIVE: This study compared outcomes in patients with solid tumor treated for pericardial effusion with surgical drainage versus interventional radiology (IR) percutaneous drainage and compared incidence of paradoxical hemodynamic instability (PHI) between cohorts. BACKGROUND: Patients with advanced-stage solid malignancies may develop large pericardial effusions requiring intervention. PHI is a fatal and underreported complication that occurs following pericardial effusion drainage. METHODS: Clinical characteristics and outcomes were compared between patients with solid tumors who underwent s urgical drainage or IR percutaneous drainage for pericardial effusion from 2010 to 2020. RESULTS: Among 447 patients, 243 were treated with surgical drainage, of which 27 (11%) developed PHI, compared with 7 of 204 patients (3%) who were treated with IR percutaneous drainage ( P =0.002); overall incidence of PHI decreased during the study period. Rates of reintervention (30-day: 1% vs 4%; 90-day: 4% vs 6%, P =0.7) and mortality (30-day: 21% vs 17%, P =0.3; 90-day: 39% vs 37%, P =0.7) were not different between patients treated with surgical drainage and IR percutaneous drainage. For both interventions, OS was shorter among patients with PHI than among patients without PHI (surgical drainage, median [95% confidence interval] OS, 0.89 mo [0.33-2.1] vs 6.5 mo [5.0-8.9], P <0.001; IR percutaneous drainage, 3.7 mo [0.23-6.8] vs 5.0 mo [4.0-8.1], P =0.044). CONCLUSIONS: With a coordinated multidisciplinary approach focusing on prompt clinical and echocardiographic evaluation, triage with bias toward IR percutaneous drainage than surgical drainage and postintervention intensive care resulted in lower incidence of PHI and improved outcomes.

Improving Tobacco Cessation Rates Using Inline Clinical Decision Support.

BACKGROUND: Tobacco use is a significant cause of morbidity and mortality in the United States. Even brief advice from a clinician can significantly influence cessation rates among tobacco users, but clinicians often miss opportunities to provide this simple intervention. OBJECTIVES: The intent of this quality improvement project was to increase tobacco cessation among tobacco users by nudging clinicians using a clinical decision support (CDS) tool. METHODS: We developed a CDS tool using principles of user-centered design and the CDS Five Rights to dynamically insert actionable information about current tobacco users into the Assessment and Plan section of clinicians' notes. We conducted a retrospective analysis of patients at four primary care practices in the Denver Metro area evaluating the impact of the CDS tool on time to tobacco cessation. A multivariable Cox proportional-hazards model was used in this determination. Kaplan-Meier curves were used to estimate tobacco cessation probabilities at 90, 180, and 365 days. RESULTS: We analyzed 5,644 patients with a median age of 45 years, most of whom lived in an urban location (99.5%) and the majority of whom were males (60%). The median follow-up time for patients was 16 months. After adjustment for age, gender, practice site, and patient location (rural, urban), the intervention group had significantly greater risk of tobacco cessation compared to those in the control group (hazard ratio: 1.22, 95% confidence interval: 1.08-1.36; p = 0.001). CONCLUSION: This study suggests a CDS intervention which respects the CDS Five Rights and incorporates user-centered design can affect tobacco use rates. Future work should expand the target population of this CDS tool and continue a user-centered, iterative design process.

Lipid droplet turnover at the lysosome inhibits growth of hepatocellular carcinoma in a BNIP3-dependent manner.

Hepatic steatosis is a major etiological factor in hepatocellular carcinoma (HCC), but factors causing lipid accumulation leading to HCC are not understood. We identify BNIP3 (a mitochondrial cargo receptor) as an HCC suppressor that mitigates against lipid accumulation to attenuate tumor cell growth. Targeted deletion of Bnip3 decreased tumor latency and increased tumor burden in a mouse model of HCC. This was associated with increased lipid in bnip3-/- HCC at early stages of disease, while lipid did not accumulate until later in tumorigenesis in wild-type mice, as Bnip3 expression was attenuated. Low BNIP3 expression in human HCC similarly correlated with increased lipid content and worse prognosis than HCC expressing high BNIP3. BNIP3 suppressed HCC cell growth by promoting lipid droplet turnover at the lysosome in a manner dependent on BNIP3 binding LC3. We have termed this process "mitolipophagy" because it involves the coordinated autophagic degradation of lipid droplets with mitochondria.

Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation.

Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, underlie ALS, IBM, and other neurodegenerative diseases. Here, we characterize 4 potentially novel HNRNPA1 mutations (yielding 3 protein variants: *321Eext*6, *321Qext*6, and G304Nfs*3) and 2 known HNRNPA1 mutations (P288A and D262V), previously connected to ALS and MSP, in a broad spectrum of patients with hereditary motor neuropathy, ALS, and myopathy. We establish that the mutations can have different effects on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics. P288A accelerated fibrillization and decelerated SG disassembly, whereas *321Eext*6 had no effect on fibrillization but decelerated SG disassembly. By contrast, G304Nfs*3 decelerated fibrillization and impaired liquid phase separation. Our findings suggest different underlying pathomechanisms for HNRNPA1 mutations with a possible link to clinical phenotypes.

Higher-order organization of biomolecular condensates.

A guiding principle of biology is that biochemical reactions must be organized in space and time. One way this spatio-temporal organization is achieved is through liquid-liquid phase separation (LLPS), which generates biomolecular condensates. These condensates are dynamic and reactive, and often contain a complex mixture of proteins and nucleic acids. In this review, we discuss how underlying physical and chemical processes generate internal condensate architectures. We then outline the diverse condensate architectures that are observed in biological systems. Finally, we discuss how specific condensate organization is critical for specific biological functions.

Novel metrics for relating personal heat exposure to social risk factors and outdoor ambient temperature.

A more precise understanding of individual-level heat exposure may be helpful to advance knowledge about heat-health impacts and effective intervention strategies, especially in light of projected increases in the severity and frequency of extreme heat events. We developed and interrogated different metrics for quantifying personal heat exposure and explored their association with social risk factors. To do so, we collected simultaneous personal heat exposure data from 64 residents of metropolitan Phoenix, Arizona. From these data, we derived five exposure metrics: Mean Individually Experienced Temperature (IET), Maximum IET, Longest Exposure Period (LEP), Percentage Minutes Above Threshold (PMAT), and Degree Minutes Above Threshold (DMAT), and calculated each for Day Hours, Night Hours, and All Hours of the study period. We then calculated effect sizes for the associations between those metrics and four social risk factors: neighborhood vulnerability, income, home cooling type, and time spent outside. We also investigated exposure misclassification by constructing linear regression models of observations from a regional weather station and hourly IET for each participant. Our analysis revealed that metric choice and timeframe added depth and nuance to our understanding of differences in exposure within and between populations. We found that time spent outside and income were the two risk factors most strongly associated with personal heat exposure. We also found evidence that Mean IET is a good, but perhaps not optimal, measure for assessing group differences in exposure. Most participants' IETs were poorly correlated with regional weather station observations and the slope and correlation coefficient for linear regression models between regional weather station data and IETs varied widely among participants. We recommend continued efforts to investigate personal heat exposure, especially in combination with physiological indicators, to improve our understanding of links between ambient temperatures, social risk factors, and health outcomes.

BNIP3-dependent mitophagy promotes cytosolic localization of LC3B and metabolic homeostasis in the liver.

Mitophagy formed the basis of the original description of autophagy by Christian de Duve when he demonstrated that GCG (glucagon) induced macroautophagic/autophagic turnover of mitochondria in the liver. However, the molecular basis of liver-specific activation of mitophagy by GCG, or its significance for metabolic stress responses in the liver is not understood. Here we show that BNIP3 is required for GCG-induced mitophagy in the liver through interaction with processed LC3B; an interaction that is also necessary to localize LC3B out of the nucleus to cytosolic mitophagosomes in response to nutrient deprivation. Loss of BNIP3-dependent mitophagy caused excess mitochondria to accumulate in the liver, disrupting metabolic zonation within the liver parenchyma, with expansion of zone 1 metabolism at the expense of zone 3 metabolism. These results identify BNIP3 as a regulator of metabolic homeostasis in the liver through its effect on mitophagy and mitochondrial mass distribution.Abbreviations: ASS1, arginosuccinate synthetase; BNIP3, BCL2/adenovirus E1B interacting protein 3; CV, central vein; GCG - glucagon; GLUL, glutamate- ammonia ligase (glutamine synthetase); HCQ, hydroxychloroquine; LIR, LC3-interacting region; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta; mtDNA:nucDNA, ratio of mitochondrial DNA to nuclear DNA; PV, periportal vein; TOMM20, translocase of outer mitochondrial membrane protein 20.

Transforming Population-Based Depression Care: a Quality Improvement Initiative Using Remote, Centralized Care Management.

INTRODUCTION: With the growing prevalence of value-based contracts, health systems are incentivized to consider population approaches to service delivery, particularly for chronic conditions like depression. To this end, UW Medicine implemented the Depression-Population Approach to Health (PATH) program in primary care (PC) as part of a system-wide Center for Medicare and Medicaid Innovation (CMMI) quality improvement (QI) initiative. AIM: To examine the feasibility of a pilot PATH program and its impact on clinical and process-of-care outcomes. SETTING: A large, diverse, geographically disparate academic health system in Western Washington State including 28 PC clinics across five networks. PROGRAM DESCRIPTION: The PATH program was a population-level, centralized, measurement-based care intervention that utilized a clinician to provide remote monitoring of treatment progress via chart review and facilitate patient engagement when appropriate. The primary goals of the program were to improve care engagement and increase follow-up PHQ-9 assessments for patients with depression and elevated initial PHQ-9 scores. PROGRAM EVALUATION: We employed a prospective, observational study design, including commercially insured adult patients with new depression diagnoses and elevated initial PHQ-9 scores. The pilot intervention group, consisting of accountable care network (ACN) self-enrollees (N = 262), was compared with a similar commercially insured cohort (N = 2527) using difference-in-differences analyses adjusted for patient comorbidities, initial PHQ-9 score, and time trends. The PATH program was associated with three times the odds of PHQ-9 follow-up (OR 3.28, 95% CI 1.79-5.99), twice the odds of a follow-up PC clinic visit (OR 1.74, 95% CI 0.99-3.08), and twice the odds of treatment response, defined as reduction in PHQ-9 score by ≥ 50% (OR 2.02, 95% CI 0.97-4.21). DISCUSSION: Our results demonstrate that a centralized, remote care management initiative is both feasible and effective for large academic health systems aiming to improve depression outcome ascertainment, treatment engagement, and clinical care.

Achieving 70% Hypertension Control: How Hard Can It Be?

BACKGROUND: Although decades of research support hypertension treatment, studies guiding the successful implementation of programs to control blood pressure (BP) in real-world primary care settings are sparse. METHODS: In this study a multicomponent intervention was implemented, with the following goals: (1) achieve 70% control of hypertension within 18 months, (2) use the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework to evaluate the implementation of the program, and (3) assess additional actions that could have been undertaken to achieve control among those who remained uncontrolled. RESULTS: Of 786 patients, 597 achieved BP control (75.9%; improvement of 20.9 percentage points). For RE-AIM outcomes, (1) staff performed outreach for all uncontrolled patients, with 75.3% making follow-up appointments, and 61.3% attending at least one appointment; (2) the proportion of faculty with at least 70% control increased from 26.7% to 87.5%, indicating significant physician adoption; (3) implementation outcomes were mixed, with four of six medical assistant BP training sessions completed, outreach calls performed in 16 of 18 months, but only 24 patients referred to the patient counseling and medication management program. For maintenance, 70% control was maintained for a 7-month observation period. The research team determined that 16.8% of those uncontrolled could have had additional actions taken to achieve control. CONCLUSION: The goal of 70% control was achieved, improving control by 20.9 percentage points over 18 months. The RE-AIM framework evaluation demonstrated successful implementation and likely contributed to achievement of the target. The chart review findings revealed that a minority of patients could have additional interventions provided by the primary care practice.

Sustaining the Collaborative Care Model (CoCM): Billing Newly Available CoCM CPT Codes in an Academic Primary Care System.

Novel Current Procedural Terminology (CPT) codes specific to the collaborative care model (CoCM) offer advantages over traditional billing options, but their uptake may require considerable billing and clinical workflow adjustments. This column presents a case study addressing the challenges of using these codes within the University of Washington Neighborhood Clinics (UWNC), an academically affiliated primary care clinic system in western Washington State. The UWNC experience thus far demonstrates that CoCM CPT codes can successfully be used in a large academic primary care system to help move this evidence-based service model toward financial sustainability.

Efficacy of continuous positive airway pressure (CPAP) in the prevention of cardiovascular events in patients with obstructive sleep apnea: Systematic review and meta-analysis.

Obstructive sleep apnea (OSA) commonly occurs in patients with increased cardiovascular (CV) risk, and continuous positive airway pressure (CPAP) is the preferred therapy for these patients. The aim of this review was to evaluate the efficacy of CPAP for CV prevention in OSA patients. We conducted a systematic review of randomized controlled trials (RCTs). Two independent reviewers explored different databases and evaluated the risk of bias. Outcomes were defined as the relative risk (RR) of major CV events (MACEs), CV mortality, myocardial infarction, unstable angina, stroke, atrial fibrillation (Afrib) and heart failure. We performed both subgroup and meta-regression analyses by sleepiness status, adherence, and OSA severity. The certainty of evidence was rated according to GRADE. A total of 8 RCTs and 5817 participants were included. The results showed an RR of 0.87 (CI, 0.70-1.10) for MACEs, an RR of 0.94 (CI, 0.62-1.43) for CV mortality, an RR of 1.04 (CI, 0.79-1.37) for myocardial infarction, an RR of 1.05 (CI, 0.51-2.15) for unstable angina, an RR of 0.92 (CI, 0.68-1.23) for heart failure, an RR of 0.94 (CI, 0.71-1.26) for stroke, and an RR of 0.94 (CI, 0.54-1.64) for Afrib. Subgroup analysis and meta-regression revealed no effect on our proposed outcomes. Although there is no evidence that CPAP therapy improves CV outcomes, concerns regarding risk of bias, CPAP adherence, and the population included in each RCT may have reduced the strength of the findings to support the benefit in all patients, and future research exploring these relevant outcomes is needed. REVIEW REGISTER: PROSPERO CRD42019145803.

Association between inflammatory bowel disease and chronic obstructive pulmonary disease: a systematic review and meta-analysis.

INTRODUCTION: There is evidence of an association between inflammatory bowel disease (IBD) and lung conditions such as chronic obstructive pulmonary disease (COPD). This systematic review and meta-analysis explored the risk of new onset IBD in patients with COPD and new onset COPD in IBD patients. METHODS: We performed a systematic review of observational studies exploring the risk of both associations. Two independent reviewers explored the EMBASE, MEDLINE, LILACS and DOAJ databases, and the risk of bias was evaluated using the ROBBINS-I tool. Data from included studies was pooled in a random effect meta-analysis following a DerSimonian-Laird method. The quality of the evidence was ranked using GRADE criteria. RESULTS: Four studies including a pooled population of 1355 new cases were included. We found association between new onset IBD in COPD population. The risk of bias was low in most of them. Only one study reported tobacco exposure as a potential confounding factor. The pooled risk ratio (RR) for a new diagnosis of IBD in COPD patients was 2.02 (CI, 1.56 to 2.63), I2 = 72% (GRADE: low). The subgroup analyses for Crohn's disease and ulcerative colitis yielded RRs of 2.29 (CI, 1.51 to 3.48; I2 = 62%), and 1.79 (CI, 1.39 to 2.29; I2 = 19%.), respectively. DISCUSSION: According to our findings, the risk of new onset IBD was higher in populations with COPD compared to the general population without this condition. Based on our analysis, we suggest a potential association between IBD and COPD; however, further research exploring the potential effect of confounding variables, especially cigarette smoking, is still needed. REVIEW REGISTER: (PROSPERO: CRD42018096624).

Efficacy of continuous positive airway pressure (CPAP) preventing type 2 diabetes mellitus in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and insulin resistance: a systematic review and meta-analysis.

BACKGROUND: Obstructive sleep apnea/hypopnea syndrome (OSAHS) is a very common, yet undiagnosed, breathing disorder that has many more implications besides disrupted sleep. Its role as an independent risk factor for metabolic abnormalities such as insulin resistance (IR) and impaired glucose tolerance is becoming increasingly recognized. The main treatment for OSAHS is continuous positive airway pressure (CPAP), however the impact of CPAP on IR and glucose metabolism is still debated. OBJECTIVES: Compile all available evidence regarding the effect of CPAP on IR in non-diabetic OSA patients. METHODS: A literature search in Medline, Epistemonikos and the Cochrane Controlled Trial Register were searched through March 2018. We included Randomized Controlled Trials (RCTs) comparing CPAP treatment with sham CPAP, placebo or no treatment in non-diabetic adults with OSAHS. Risk of Bias was evaluated using Cochrane tool and a meta-analysis evaluating the efficacy of CPAP in both HOMA index and fasting glucose was done. Certain of evidence was rated using GRADE approach. RESULTS: Nine studies consisting of 443 participants were included. CPAP treatment significantly improved HOMA index (Mean difference = -0.39 Ui (CI, -0.69 to -0.08), p < 0.05. I2 = 57% (GRADE = LOW). However, CPAP showed no significant changes in fasting glucose (GRADE = LOW). CONCLUSION: This systematic review and meta-analysis shows evidence that metabolic disturbances could be halted and regressed with CPAP treatment in patients with insulin resistance and OSAHS. In conclusion, treatment with CPAP could improve HOMA IR index.

CPAP in patients with obstructive sleep apnea and type 2 diabetes mellitus: Systematic review and meta-analysis.

INTRODUCTION: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent condition across the world; it co-exists with others metabolic diseases, such as central obesity, dyslipidemia, and arterial hypertension. These associations increase the cardiovascular risk and mortality. Observational studies have reported a strength association between OSA and type 2 Diabetes Mellitus (T2DM) and continuous positive airway pressure (CPAP) is recommended for moderate to severe OSAHS. OBJECTIVE: To summarize the evidence of CPAP in T2DM patients with OSAHS. METHODS: A compressive search in Medline, Cochrane, Ovids, Epistemonikos, and DARE was performed. Two reviewers evaluated included studies, extracted data, carried out quality assessment and summarized the result. Pooled data was evaluated by meta-analysis and summaries of results and evidence grading were performed through the GRADE method. RESULTS: Six randomized controlled trials (RCTs), including a total of 581 participants. Treatment with CPAP showed no effectiveness regarding changing glycated hemoglobin (HbA1c) levels at 12 or 24 weeks after treatment; (Mean difference= -0.10; Confidence interval -0.25 to 0.04) (GRADE: MODERATE). Subgroup analysis by adherence to CPAP (> 4 hours or < 4 hours) confirmed these results. Other indirect outcomes, such as change in fasting glucose levels, were similar in CPAP population and placebo. DISCUSSION: This systematic review and meta-analysis evaluates the evidence regarding the efficacy of CPAP in patients with T2DM and OSAHS. In conclusion, CPAP does not improve glycemic control measure as HbA1c.

Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes.

The reversible modification of cysteine residues by thioester formation with palmitate (S-palmitoylation) is an abundant lipid post-translational modification (PTM) in mammalian systems. S-palmitoylation has been observed on mitochondrial proteins, providing an intriguing potential connection between metabolic lipids and mitochondrial regulation. However, it is unknown whether and/or how mitochondrial S-palmitoylation is regulated. Here we report the development of mitoDPPs, targeted fluorescent probes that measure the activity levels of "erasers" of S-palmitoylation, acyl-protein thioesterases (APTs), within mitochondria of live cells. Using mitoDPPs, we discover active S-depalmitoylation in mitochondria, in part mediated by APT1, an S-depalmitoylase previously thought to reside in the cytosol and on the Golgi apparatus. We also find that perturbation of long-chain acyl-CoA cytoplasm and mitochondrial regulatory proteins, respectively, results in selective responses from cytosolic and mitochondrial S-depalmitoylases. Altogether, this work reveals that mitochondrial S-palmitoylation is actively regulated by "eraser" enzymes that respond to alterations in mitochondrial lipid homeostasis.

Expanding perspectives on the significance of mitophagy in cancer.

Mitophagy is a selective mode of autophagy in which mitochondria are specifically targeted for degradation at the autophagolysosome. Mitophagy is activated by stresses such as hypoxia, nutrient deprivation, DNA damage, inflammation and mitochondrial membrane depolarization and plays a role in maintaining mitochondrial integrity and function. Defects in mitophagy lead to mitochondrial dysfunction that can affect metabolic reprogramming in response to stress, alter cell fate determination and differentiation, which in turn affects disease incidence and etiology, including cancer. Here, we discuss how different mitophagy adaptors and modulators, including Parkin, BNIP3, BNIP3L, p62/SQSTM1 and OPTN, are regulated in response to physiological stresses and deregulated in cancers. Additionally, we explore how these different mitophagy control pathways coordinate with each other. Finally, we review new developments in understanding how mitophagy affects stemness, cell fate determination, inflammation and DNA damage responses that are relevant to understanding the role of mitophagy in cancer.

Autophagy Promotes Focal Adhesion Disassembly and Cell Motility of Metastatic Tumor Cells through the Direct Interaction of Paxillin with LC3.

Autophagy is a conserved catabolic process that plays a housekeeping role in eliminating protein aggregates and organelles and is activated during nutrient deprivation to generate metabolites and energy. Autophagy plays a significant role in tumorigenesis, although opposing context-dependent functions of autophagy in cancer have complicated efforts to target autophagy for therapeutic purposes. We demonstrate that autophagy inhibition reduces tumor cell migration and invasion in vitro and attenuates metastasis in vivo. Numerous abnormally large focal adhesions (FAs) accumulate in autophagy-deficient tumor cells, reflecting a role for autophagy in FA disassembly through targeted degradation of paxillin. We demonstrate that paxillin interacts with processed LC3 through a conserved LIR motif in the amino-terminal end of paxillin and that this interaction is regulated by oncogenic SRC activity. Together, these data establish a function for autophagy in FA turnover, tumor cell motility, and metastasis.

Detecting Microbial Dysbiosis Associated with Pediatric Crohn Disease Despite the High Variability of the Gut Microbiota.

The relationship between the host and its microbiota is challenging to understand because both microbial communities and their environments are highly variable. We have developed a set of techniques based on population dynamics and information theory to address this challenge. These methods identify additional bacterial taxa associated with pediatric Crohn disease and can detect significant changes in microbial communities with fewer samples than previous statistical approaches required. We have also substantially improved the accuracy of the diagnosis based on the microbiota from stool samples, and we found that the ecological niche of a microbe predicts its role in Crohn disease. Bacteria typically residing in the lumen of healthy individuals decrease in disease, whereas bacteria typically residing on the mucosa of healthy individuals increase in disease. Our results also show that the associations with Crohn disease are evolutionarily conserved and provide a mutual information-based method to depict dysbiosis.