Outcomes With Single-Site Dual-Lumen Versus Multisite Cannulation for Adults With COVID-19 Respiratory Failure Receiving Venovenous Extracorporeal Membrane Oxygenation.

OBJECTIVES: To determine whether multisite versus single-site dual-lumen (SSDL) cannulation is associated with outcomes for COVID-19 patients requiring venovenous extracorporeal membrane oxygenation (VV-ECMO). DESIGN: Retrospective analysis of the Extracorporeal Life Support Organization Registry. Propensity score matching (2:1 multisite vs SSDL) was used to control for confounders. PATIENTS: The matched cohort included 2,628 patients (1,752 multisite, 876 SSDL) from 170 centers. The mean ( sd ) age in the entire cohort was 48 (11) years, and 3,909 (71%) were male. Patients were supported with mechanical ventilation for a median (interquartile range) of 79 (113) hours before VV-ECMO support. INTERVENTIONS: None. MEASUREMENTS: The primary outcome was 90-day survival. Secondary outcomes included survival to hospital discharge, duration of ECMO support, days free of ECMO support at 90 days, and complication rates. MAIN RESULTS: There was no difference in 90-day survival (49.4 vs 48.9%, p = 0.66), survival to hospital discharge (49.8 vs 48.2%, p = 0.44), duration of ECMO support (17.9 vs 17.1 d, p = 0.82), or hospital length of stay after cannulation (28 vs 27.4 d, p = 0.37) between multisite and SSDL groups. More SSDL patients were extubated within 24 hours (4% vs 1.9%, p = 0.001). Multisite patients had higher ECMO flows at 24 hours (4.5 vs 4.1 L/min, p < 0.001) and more ECMO-free days at 90 days (3.1 vs 2.0 d, p = 0.02). SSDL patients had higher rates of pneumothorax (13.9% vs 11%, p = 0.03). Cannula site bleeding (6.4% vs 4.7%, p = 0.03), oxygenator failure (16.7 vs 13.4%, p = 0.03), and circuit clots (5.5% vs 3.4%, p = 0.02) were more frequent in multisite patients. CONCLUSIONS: In this retrospective study of COVID-19 patients requiring VV-ECMO, 90-day survival did not differ between patients treated with a multisite versus SSDL cannulation strategy and there were only modest differences in major complication rates. These findings do not support the superiority of either cannulation strategy in this setting.

Wdr59 promotes or inhibits TORC1 activity depending on cellular context.

Target of Rapamycin Complex I (TORC1) is a central regulator of metabolism in eukaryotes that responds to a wide array of negative and positive inputs. The GTPase-activating protein toward Rags (GATOR) signaling pathway acts upstream of TORC1 and is comprised of two subcomplexes. The trimeric GATOR1 complex inhibits TORC1 activity in response to amino acid limitation by serving as a GTPase-activating protein (GAP) for the TORC1 activator RagA/B, a component of the lysosomally located Rag GTPase. The multi-protein GATOR2 complex inhibits the activity of GATOR1 and thus promotes TORC1 activation. Here we report that Wdr59, originally assigned to the GATOR2 complex based on studies performed in tissue culture cells, unexpectedly has a dual function in TORC1 regulation in Drosophila. We find that in the ovary and the eye imaginal disc brain complex, Wdr59 inhibits TORC1 activity by opposing the GATOR2-dependent inhibition of GATOR1. Conversely, in the Drosophila fat body, Wdr59 promotes the accumulation of the GATOR2 component Mio and is required for TORC1 activation. Similarly, in mammalian HeLa cells, Wdr59 prevents the proteolytic destruction of GATOR2 proteins Mio and Wdr24. Consistent with the reduced levels of the TORC1-activating GATOR2 complex, Wdr59KOs HeLa cells have reduced TORC1 activity which is restored along with GATOR2 protein levels upon proteasome inhibition. Taken together, our data support the model that the Wdr59 component of the GATOR2 complex functions to promote or inhibit TORC1 activity depending on cellular context.

Advance Care Planning, Shared Decision Making, and Serious Illness Conversations in Onconephrology.

Advance care planning, shared decision making, and serious illness conversations are communication processes designed to promote patient-centered care. In onconephrology, patients face a series of complex medical decisions regarding their care at the intersection of oncology and nephrology. Clinicians who aim to ensure that patient preferences and values are integrated into treatment planning must work within a similarly complex care team comprising multiple disciplines. In this review, we describe key decision points in a patient's care trajectory, as well as guidance on how and when to engage in advance care planning, shared decision making, and serious illness discussions. Further research on these processes in the complex context of onconephrology is needed.

A case series: the outcomes, support duration, and graft function recovery after VA-ECMO use in primary graft dysfunction after heart transplantation.

Primary graft dysfunction (PGD) is a rare complication associated with high mortality after heart transplantation, which may require veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) support. A standardized definition for PGD was developed by the International Society of Heart and Lung Transplantation in 2014. Due to limited reports using this definition, the detailed outcomes after VA-ECMO support remain unclear. Therefore, we retrospectively analyzed our single-center outcomes of PGD following VA-ECMO support. Between September 2014 and August 2018, 160 patients underwent heart transplantation in our single center. Nine PGD patients required VA-ECMO support, with an incidence of 5.6%. Pre-operative recipient/donor demographics, intra-operative variables, timing of VA-ECMO initiation and support duration, graft function recovery during 30 days after heart transplant, VA-ECMO complications, and survival were analyzed. The indication for VA-ECMO support was biventricular failure for all nine patients. Six patients had severe PGD requiring intra-operative VA-ECMO, while two patients had moderate PGD and one patient had mild PGD requiring post-operative VA-ECMO. All cohorts were successfully decannulated in a median of 10 days. Survival to discharge rate was 88.9%. One-year survival rate was 85.7%. Left ventricular ejection fraction recovered to normal within 30 days in all PGD patients. Our study showed VA-ECMO support led to high survival and timely graft function recovery in all cohorts. Further larger research can clarify the detailed effects of VA-ECMO support which may lead to standardized indication of VA-ECMO support for PGD patients.

Prospective Observational Study Comparing Sepsis-2 and Sepsis-3 Definitions in Predicting Mortality in Critically Ill Patients.

BACKGROUND: Sepsis definitions have evolved, but there is a lack of consensus over adoption of the most recent definition, Sepsis-3. We sought to compare Sepsis-2 and Sepsis-3 in the classification of patients with sepsis and mortality risk at 30 days. METHODS: We used the following definitions: Sepsis-2 (≥2 systemic inflammatory response syndrome criteria + infection), Sepsis-3 (prescreening by quick Sequential Organ Failure Assessment [qSOFA] of ≥2 of 3 criteria followed by the complete score change ≥2 + infection), and an amended Sepsis-3 definition, iqSOFA (qSOFA ≥2 + infection). We used χ 2 or Wilcoxon rank-sum tests, receiver-operator characteristic curves, and survival analysis. RESULTS: We enrolled 176 patients (95% in an intensive care unit, 38.6% female, median age 61.4 years). Of 105 patients classified by Sepsis-2 as having sepsis, 80 had sepsis per Sepsis-3 or iqSOFA (kappa = 0.72; 95% confidence interval [CI], 0.62-0.82). Twenty-five (14.8%) died (20 of 100 with sepsis per Sepsis-2 [20%], and 20 of 77 [26.0%] with sepsis per Sepsis-3 or iqSOFA). Results for Sepsis-3 and iqSOFA were identical. The area under the curve of receiver-operator characteristic (ROC) curves for identifying those who died were 0.54 (95% CI, 0.41-0.68) for Sepsis-2, 0.84 (95% CI, 0.74-0.93) for Sepsis-3, and 0.69 (95% CI, 0.60-0.79) for iqSOFA (P < .01). Hazard ratios for death associated with sepsis were greatest for sepsis or septic shock per Sepsis-3. CONCLUSIONS: Sepsis-3 and iqSOFA were better at predicting death than Sepsis-2. Using the SOFA score might add little advantage compared with the simpler iqSOFA score.

The GATOR2 Component Wdr24 Regulates TORC1 Activity and Lysosome Function.

TORC1 is a master regulator of metabolism in eukaryotes that responds to multiple upstream signaling pathways. The GATOR complex is a newly defined upstream regulator of TORC1 that contains two sub-complexes, GATOR1, which inhibits TORC1 activity in response to amino acid starvation and GATOR2, which opposes the activity of GATOR1. While the GATOR1 complex has been implicated in a wide array of human pathologies including cancer and hereditary forms of epilepsy, the in vivo relevance of the GATOR2 complex remains poorly understood in metazoans. Here we define the in vivo role of the GATOR2 component Wdr24 in Drosophila. Using a combination of genetic, biochemical, and cell biological techniques we demonstrate that Wdr24 has both TORC1 dependent and independent functions in the regulation of cellular metabolism. Through the characterization of a null allele, we show that Wdr24 is a critical effector of the GATOR2 complex that promotes the robust activation of TORC1 and cellular growth in a broad array of Drosophila tissues. Additionally, epistasis analysis between wdr24 and genes that encode components of the GATOR1 complex revealed that Wdr24 has a second critical function, the TORC1 independent regulation of lysosome dynamics and autophagic flux. Notably, we find that two additional members of the GATOR2 complex, Mio and Seh1, also have a TORC1 independent role in the regulation of lysosome function. These findings represent a surprising and previously unrecognized function of GATOR2 complex components in the regulation of lysosomes. Consistent with our findings in Drosophila, through the characterization of a wdr24-/- knockout HeLa cell line we determined that Wdr24 promotes lysosome acidification and autophagic flux in mammalian cells. Taken together our data support the model that Wdr24 is a key effector of the GATOR2 complex, required for both TORC1 activation and the TORC1 independent regulation of lysosomes.

Physician report cards and rankings yield long-lasting hand hygiene compliance exceeding 90%.

INTRODUCTION: Hand hygiene is an effective, low-cost intervention that prevents the spread of multidrug-resistant bacteria. Despite mandatory education and reminders, compliance by physicians in our hospital remained stubbornly low. Our objective was to study whether surveillance by our unit coordinator (secretary) paired with regular feedback to chiefs of service would increase physician hand hygiene compliance in the ICU. METHOD: The ICU unit coordinator was trained to observe and measure hand hygiene compliance. Data were collected on hand hygiene compliance at room entry and exit for 9 months. Percentage compliance for each medical and surgical subspecialty was reported to chiefs of service at the end of each month. Comparative rankings by service were widely distributed throughout the physician organization and the medical center. RESULTS: The hand hygiene compliance rate among physicians increased from 65.1% to 91.6% during the study period (p < 0.0001). More importantly in the succeeding 24 months after study completion, physician hand hygiene compliance remained >90% in every month. CONCLUSIONS: Physician hand hygiene compliance increased as a consequence of the surveillance conducted by a full-time ICU team member, leading to a highly significant increase in the number of observations. In turn, this allowed for specific comparative monthly feedback to individual chiefs of service. Over the next 2 years after the study ended, these gains were sustained, suggesting an enduring culture change in physician behavior.

Critical Care Issues of the Geriatric Patient.

Medical care of the geriatric patient is an important area of focus as the population ages and life expectancy increases. In particular, critical care of the geriatric patient will be especially affected, because geriatric patients will consume most critical care beds in the future and subsequently require increased use of resources. This review focuses on the physiologic effects of aging on all body systems. Focus on frailty and its effect on recovery from critical illness and its potential to modify the course of patient care will be important areas of research in the future.

oskar RNA plays multiple noncoding roles to support oogenesis and maintain integrity of the germline/soma distinction.

The Drosophila oskar (osk) mRNA is unusual in that it has both coding and noncoding functions. As an mRNA, osk encodes a protein required for embryonic patterning and germ cell formation. Independent of that function, the absence of osk mRNA disrupts formation of the karyosome and blocks progression through oogenesis. Here we show that loss of osk mRNA also affects the distribution of regulatory proteins, relaxing their association with large RNPs within the germline, and allowing them to accumulate in the somatic follicle cells. This and other noncoding functions of the osk mRNA are mediated by multiple sequence elements with distinct roles. One role, provided by numerous binding sites in two distinct regions of the osk 3' UTR, is to sequester the translational regulator Bruno (Bru), which itself controls translation of osk mRNA. This defines a novel regulatory circuit, with Bru restricting the activity of osk, and osk in turn restricting the activity of Bru. Other functional elements, which do not bind Bru and are positioned close to the 3' end of the RNA, act in the oocyte and are essential. Despite the different roles played by the different types of elements contributing to RNA function, mutation of any leads to accumulation of the germline regulatory factors in the follicle cells.

Childhood trauma and personal mastery: their influence on emotional reactivity to everyday events in a community sample of middle-aged adults.

Childhood trauma is associated with premature declines in health in midlife and old age. Pathways that have been implicated, but less studied include social-emotional regulation, biological programming, and habitual patterns of thought and action. In this study we focused on childhood trauma's influence via alterations in social-emotional regulation to everyday life events, a pathway that has been linked to subsequent health effects. Data from a 30-day daily diary of community residents who participated in a study of resilience in Midlife (n = 191, Mage = 54, SD = 7.50, 54% women) was used to examine whether self-reports of childhood trauma were associated with daily well-being, as well as reported and emotional reactivity to daily negative and positive events. Childhood trauma reports were associated with reporting lower overall levels of and greater variability in daily well-being. Childhood trauma was linked to greater reports of daily negative events, but not to positive events. Focusing on emotional reactivity to daily events, residents who reported higher levels of childhood trauma showed stronger decreases in well-being when experiencing negative events and also stronger increases in well-being with positive events. For those reporting childhood trauma, higher levels of mastery were associated with stronger decreases in well-being with negative events and stronger increases in well-being with positive events, suggesting that mastery increases sensitivity to daily negative and positive events. Our results suggest that childhood trauma may lead to poorer health in midlife through disturbances in the patterns of everyday life events and responses to those events. Further, our findings indicate that mastery may have a different meaning for those who experienced childhood trauma. We discuss social-emotional regulation as one pathway linking childhood trauma to health, and psychosocial resources to consider when building resilience-promoting interventions for mitigating the detrimental health effects of childhood trauma.

TORC1 regulators Iml1/GATOR1 and GATOR2 control meiotic entry and oocyte development in Drosophila.

In single-cell eukaryotes the pathways that monitor nutrient availability are central to initiating the meiotic program and gametogenesis. In Saccharomyces cerevisiae an essential step in the transition to the meiotic cycle is the down-regulation of the nutrient-sensitive target of rapamycin complex 1 (TORC1) by the increased minichromosome loss 1/ GTPase-activating proteins toward Rags 1 (Iml1/GATOR1) complex in response to amino acid starvation. How metabolic inputs influence early meiotic progression and gametogenesis remains poorly understood in metazoans. Here we define opposing functions for the TORC1 regulatory complexes Iml1/GATOR1 and GATOR2 during Drosophila oogenesis. We demonstrate that, as is observed in yeast, the Iml1/GATOR1 complex inhibits TORC1 activity to slow cellular metabolism and drive the mitotic/meiotic transition in developing ovarian cysts. In iml1 germline depletions, ovarian cysts undergo an extra mitotic division before meiotic entry. The TORC1 inhibitor rapamycin can suppress this extra mitotic division. Thus, high TORC1 activity delays the mitotic/meiotic transition. Conversely, mutations in Tor, which encodes the catalytic subunit of the TORC1 complex, result in premature meiotic entry. Later in oogenesis, the GATOR2 components Mio and Seh1 are required to oppose Iml1/GATOR1 activity to prevent the constitutive inhibition of TORC1 and a block to oocyte growth and development. To our knowledge, these studies represent the first examination of the regulatory relationship between the Iml1/GATOR1 and GATOR2 complexes within the context of a multicellular organism. Our data imply that the central role of the Iml1/GATOR1 complex in the regulation of TORC1 activity in the early meiotic cycle has been conserved from single cell to multicellular organisms.

Caprin controls follicle stem cell fate in the Drosophila ovary.

Adult stem cells must balance self-renewal and differentiation for tissue homeostasis. The Drosophila ovary has provided a wealth of information about the extrinsic niche signals and intrinsic molecular processes required to ensure appropriate germline stem cell renewal and differentiation. The factors controlling behavior of the more recently identified follicle stem cells of the ovary are less well-understood but equally important for fertility. Here we report that translational regulators play a critical role in controlling these cells. Specifically, the translational regulator Caprin (Capr) is required in the follicle stem cell lineage to ensure maintenance of this stem cell population and proper encapsulation of developing germ cells by follicle stem cell progeny. In addition, reduction of one copy of the gene fmr1, encoding the translational regulator Fragile X Mental Retardation Protein, exacerbates the Capr encapsulation phenotype, suggesting Capr and fmr1 are regulating a common process. Caprin was previously characterized in vertebrates as Cytoplasmic Activation/Proliferation-Associated Protein. Significantly, we find that loss of Caprin alters the dynamics of the cell cycle, and we present evidence that misregulation of CycB contributes to the disruption in behavior of follicle stem cell progeny. Our findings support the idea that translational regulators may provide a conserved mechanism for oversight of developmentally critical cell cycles such as those in stem cell populations.

miRNA-dependent translational repression in the Drosophila ovary.

BACKGROUND: The Drosophila ovary is a tissue rich in post-transcriptional regulation of gene expression. Many of the regulatory factors are proteins identified via genetic screens. The more recent discovery of microRNAs, which in other animals and tissues appear to regulate translation of a large fraction of all mRNAs, raised the possibility that they too might act during oogenesis. However, there has been no direct demonstration of microRNA-dependent translational repression in the ovary. METHODOLOGY/PRINCIPAL FINDINGS: Here, quantitative analyses of transcript and protein levels of transgenes with or without synthetic miR-312 binding sites show that the binding sites do confer translational repression. This effect is dependent on the ability of the cells to produce microRNAs. By comparison with microRNA-dependent translational repression in other cell types, the regulated mRNAs and the protein factors that mediate repression were expected to be enriched in sponge bodies, subcellular structures with extensive similarities to the P bodies found in other cells. However, no such enrichment was observed. CONCLUSIONS/SIGNIFICANCE: Our results reveal the variety of post-transcriptional regulatory mechanisms that operate in the Drosophila ovary, and have implications for the mechanisms of miRNA-dependent translational control used in the ovary.

Comparison of cognitive behavioral and mindfulness meditation interventions on adaptation to rheumatoid arthritis for patients with and without history of recurrent depression.

This research examined whether cognitive behavioral therapy and mindfulness interventions that target responses to chronic stress, pain, and depression reduce pain and improve the quality of everyday life for adults with rheumatoid arthritis (RA). The 144 RA participants were clustered into groups of 6-10 participants and randomly assigned to 1 of 3 treatments: cognitive behavioral therapy for pain (P); mindfulness meditation and emotion regulation therapy (M); or education-only group (E), which served as an attention placebo control. The authors took a multimethod approach, employing daily diaries and laboratory assessment of pain and mitogen-stimulated levels of interleukin-6 (IL-6), a proinflammatory cytokine. Participants receiving P showed the greatest Pre to Post improvement in self-reported pain control and reductions in the IL-6; both P and M groups showed more improvement in coping efficacy than did the E group. The relative value of the treatments varied as a function of depression history. RA patients with recurrent depression benefited most from M across several measures, including negative and positive affect and physicians' ratings of joint tenderness, indicating that the emotion regulation aspects of that treatment were most beneficial to those with chronic depressive features.

Personal mastery predicts pain, stress, fatigue, and blood pressure in adults with rheumatoid arthritis.

Among individuals with rheumatoid arthritis (RA), stress-associated disease flare can severely impact well-being. Psychological factors such as personal mastery may buffer an individual from the negative effects of those flares. We tested the hypothesis that a high sense of personal mastery would prospectively predict stress reactivity. Measures of pain,perceived stress, fatigue, and mean arterial pressure (MAP) were collected before, during, and after two interpersonal stressors conducted on 73 individuals with RA. Factor analysis of the personal mastery scale yielded two independent factors: a 5-item "fatalism" component and a 2-item "control" component. Individuals with high fatalism scores reported overall greater joint pain at baseline and those scoring high on control exhibited lower MAP, and reported less stress and fatigue at baseline. After controlling for baseline differences, those high in control exhibited greater MAP increase during stress, and less drop in pain when compared to those low in control. These results suggest that individuals high in control may be more susceptible to the effects of acute stress; however, the overall beneficial aspects of high control outweigh the acute negative effects. Personal mastery may play a role in the experience of pain, stress, and fatigue for people with RA.

Depression history, stress, and pain in rheumatoid arthritis patients.

This study examined the role of past episodes of depression on pain reports for patients with rheumatoid arthritis (RA) before and during stress induction. A history of major depressive episodes was assessed by diagnostic interviews for 138 RA patients, 74 who later participated in a set of laboratory procedures designed to induce interpersonal stress. Patients were evaluated by a rheumatologist and then asked to report joint and bodily pain throughout the laboratory study. We found that RA patients with a history of two or more episodes of major depression had more pain at baseline, and exhibited higher pain in response to the stress induction than did RA patients with either only one episode or no history of depression. Such findings provide new insight in the dynamic relationships between depression, stress, and pain.

Individual differences in emotional processing and reactivity to pain among older women with rheumatoid arthritis.

The purpose of the current study was to determine whether the relationship between pain and emotion may be better understood by identifying people who are more vulnerable to emotional dysregulation and those who are able to regulate emotion. Data were collected from 81 women diagnosed with rheumatoid arthritis. We assessed affect intensity, emotion regulation, active coping, neuroticism as well as weekly reports of pain, positive affect, and negative affect. Results indicated that the joint effects of emotion regulation and emotional intensity predicted emotional responses to pain. The current study suggests that the emotional impact of pain is related to emotional intensity which can be tempered by the ability to regulate emotion.

Uncertainty of illness relationships with mental health and coping processes in fibromyalgia patients.

Fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain condition poorly understood in terms of etiology and treatment by both physicians and patients. This condition of "uncertainty of illness" was examined as a variable involved in the adjustment of FMS patients, relating it to their depression, anxiety, affect, and coping styles. Fifty-one community-residing FMS patients provided self-report information on subsets of adjustment variables. Both cross-sectional and more dynamic longitudinal analyses showed that illness uncertainty was significantly associated with anxiety, negative affect, and avoidant and passive coping. Its positive relationship with depression was eliminated when a control variable, pain helplessness, was included as a covariate. Longitudinally, illness uncertainty interacted with interpersonally stressful daily events in predicting reports of reduced positive affect, suggesting that illness uncertainty acts as a risk factor for affective disturbances during stressful times. Implications of these results for therapeutic interventions are discussed.