ProPACC: Protocol for a Trial of Integrated Specialty Palliative Care for Critically Ill Older Adults.

BACKGROUND: Each year, approximately one million older adults die in American intensive care units (ICUs) or survive with significant functional impairment. Inadequate symptom management, surrogates' psychological distress and inappropriate healthcare use are major concerns. Pioneering work by Dr. J. Randall Curtis paved the way for integrating palliative care (PC) specialists to address these needs, but convincing proof of efficacy has not yet been demonstrated. DESIGN: We will conduct a multicenter patient-randomized efficacy trial of integrated specialty PC (SPC) vs. usual care for 500 high-risk ICU patients over age 60 and their surrogate decision-makers from five hospitals in Pennsylvania. INTERVENTION: The intervention will follow recommended best practices for inpatient PC consultation. Patients will receive care from a multidisciplinary SPC team within 24 hours of enrollment that continues until hospital discharge or death. SPC clinicians will meet with patients, families, and the ICU team every weekday. SPC and ICU clinicians will jointly participate in proactive family meetings according to a predefined schedule. Patients in the control arm will receive routine ICU care. OUTCOMES: Our primary outcome is patient-centeredness of care, measured using the modified Patient Perceived Patient-Centeredness of Care scale. Secondary outcomes include surrogates' psychological symptom burden and health resource utilization. Other outcomes include patient survival, as well as interprofessional collaboration. We will also conduct prespecified subgroup analyses using variables such as PC needs, measured by the Needs of Social Nature, Existential Concerns, Symptoms, and Therapeutic Interaction scale. CONCLUSIONS: This trial will provide robust evidence about the impact of integrating SPC with critical care on patient, family, and health system outcomes.

The peripheral dopamine 2 receptor antagonist domperidone attenuates ethanol enhancement of dopamine levels in the nucleus accumbens.

BACKGROUND: Dopamine neuron firing in the ventral tegmental area (VTA) and dopamine release in the nucleus accumbens have been implicated in reward learning. Ethanol is known to increase both dopamine neuron firing in the VTA and dopamine levels in the nucleus accumbens. Despite this, some discrepancies exist between the dose of ethanol required to enhance firing in vivo and ex vivo. In the present study we investigated the effects of peripheral dopamine 2 subtype receptor antagonism on ethanol's effects on dopamine neurotransmission. METHODS: Plasma catecholamine levels were assessed following ethanol administration across four different doses of EtOH. Microdialysis and voltammetry were used to assess the effects of domperidone pretreatment on ethanol-mediated increases in dopamine release in the nucleus accumbens. A place conditioning paradigm was used to assess conditioned preference for ethanol and whether domperidone pretreatment altered this preference. Open-field and loss-of-righting reflex paradigms were used to assess the effects of domperidone on ethanol-induced sedation. A rotarod apparatus was used to assess the effects of domperidone on ethanol-induced motor impairment. RESULTS: Domperidone attenuated ethanol's enhancement of mesolimbic dopamine release under non-physiological conditions at intermediate (1.0 and 2.0 g/kg) doses of ethanol. Domperidone also decreased EtOH-induced sedation at 2.0 g/kg. Domperidone did not alter ethanol conditioned place preference nor did it affect ethanol-induced motor impairment. CONCLUSIONS: These results show that peripheral dopamine 2 receptors mediate some of the effects of ethanol on nonphysiological dopamine neurotransmission, although these effects are not related to the rewarding properties of ethanol.

Cardiac Amyloidosis Presenting as Biventricular Systolic Heart Failure.

A previously healthy octogenarian presented with new onset heart failure symptoms. Comprehensive multimodality imaging including complete echocardiography with longitudinal strain analysis, cardiac magnetic resonance imaging (cMRI), nuclear medicine pyrophosphate (99-mcTcPYP) scan along with biomarker, monoclonal protein analysis, and fat pad biopsy confirmed diagnosis of transthyretin cardiac amyloidosis.

Right Atrial Appendage Thrombus in Atrial Fibrillation: A Case Report and Review of the Literature.

Atrial fibrillation (Afib) is the most common abnormal heart rhythm in adults and has become a significant public health concern affecting 2% to 3% of the population in Europe and North America. Left atrial appendage (LAA) thrombi is the source of 90% of left-sided cardiac thrombi in patients with Afib, which can cause stroke and other systemic vascular events. Right atrial appendage (RAA) thrombi formation in Afib is much less common but complications include pulmonary embolism or paradoxical migration across patent foramen ovale with risk of systemic embolization. The prevalence and subsequent clinical complications of RAA thrombi formation in Afib patients is not well understood. Management of RAA thrombi should be similar to that of LAA thrombi which includes delaying cardioversion and anticoagulating with warfarin therapy to achieve international normalized ratio of 2 to 3.

Perceptions of Hyperoxemia and Conservative Oxygen Therapy in the Management of Acute Respiratory Failure.

Rationale: Mechanically ventilated patients in the intensive care unit (ICU) are often managed to maximize oxygenation, yet hyperoxemia may be deleterious to some. Little is known about how ICU providers weigh tradeoffs between hypoxemia and hyperoxemia when managing acute respiratory failure. Objectives: To define ICU providers' mental models for managing oxygenation for patients with acute respiratory failure and identify barriers and facilitators to conservative oxygen therapy. Methods: In two large U.S. tertiary care hospitals, we performed semistructured interviews with a purposive sample of ICU nurses, respiratory therapists, and physicians. We assessed perceptions of oxygenation management, hyperoxemia, and conservative oxygen therapies through interviews, which we audio recorded and transcribed verbatim. We analyzed transcripts for representative themes using an iterative thematic-analysis approach. Results: We interviewed 10 nurses, 10 respiratory therapists, 4 fellows, and 5 attending physicians before reaching thematic saturation. Major themes included perceptions of hyperoxemia, attitudes toward conservative oxygen therapy, and aspects of titrated-oxygen-therapy implementation. Many providers did not recognize the term "hyperoxemia," whereas others described a poor understanding; several stated they never encounter hyperoxemia clinically. Concerns about hyperoxemia varied: some providers believed that typical ventilation strategies emphasizing progressive lowering of the fraction of inspired oxygen mitigated worries about excess oxygen administration, whereas others maintained that hyperoxemia is harmful only to patients with chronic lung disease. Almost all interviewees expressed familiarity with lower oxygen saturations in chronic obstructive pulmonary disease. Cited barriers to conservative oxygen therapy included concerns about hypoxemia, particularly among nurses and respiratory therapists; perceptions that hyperoxemia is not harmful; and a lack of clear evidence supporting conservative oxygen therapy. Interviewees suggested that interprofessional education and convincing clinical trial evidence could facilitate uptake of conservative oxygenation. Conclusions: This study describes attitudes toward hyperoxemia and conservative oxygen therapy. These preferences and uncertain benefits and risks of conservative oxygen therapy should be considered during future implementation efforts. Successful oxygen therapy implementation most likely will require 1) improving awareness of hyperoxemia's effects, 2) normalizing lower saturations in patients without chronic lung disease, 3) addressing ingrained beliefs regarding oxygen management and oxygen's safety, and 4) using interprofessional education to obtain buy-in across providers and inform the ICU team.

Generic Protocols for the Analytical Validation of Next-Generation Sequencing-Based ctDNA Assays: A Joint Consensus Recommendation of the BloodPAC's Analytical Variables Working Group.

Liquid biopsy, particularly the analysis of circulating tumor DNA (ctDNA), has demonstrated considerable promise for numerous clinical intended uses. Successful validation and commercialization of novel ctDNA tests have the potential to improve the outcomes of patients with cancer. The goal of the Blood Profiling Atlas Consortium (BloodPAC) is to accelerate the development and validation of liquid biopsy assays that will be introduced into the clinic. To accomplish this goal, the BloodPAC conducts research in the following areas: Data Collection and Analysis within the BloodPAC Data Commons; Preanalytical Variables; Analytical Variables; Patient Context Variables; and Reimbursement. In this document, the BloodPAC's Analytical Variables Working Group (AV WG) attempts to define a set of generic analytical validation protocols tailored for ctDNA-based Next-Generation Sequencing (NGS) assays. Analytical validation of ctDNA assays poses several unique challenges that primarily arise from the fact that very few tumor-derived DNA molecules may be present in circulation relative to the amount of nontumor-derived cell-free DNA (cfDNA). These challenges include the exquisite level of sensitivity and specificity needed to detect ctDNA, the potential for false negatives in detecting these rare molecules, and the increased reliance on contrived samples to attain sufficient ctDNA for analytical validation. By addressing these unique challenges, the BloodPAC hopes to expedite sponsors' presubmission discussions with the Food and Drug Administration (FDA) with the protocols presented herein. By sharing best practices with the broader community, this work may also save the time and capacity of FDA reviewers through increased efficiency.

Serratia marcescens Endocarditis with Perivalvular Abscess Presenting as Atrioventricular Block.

Serratia marcescens is an aerobic, Gram-negative bacillus first identified in 1819 (Yeung et al. 2018). S. marcescens infective endocarditis is extremely rare accounting for only 0.14% of all cases (Phadke and Jacob 2016, Hadano et al. 2012, Nikolakopoulos et al. 2019). We present the case of a 33-year-old male with a past medical history of Hodgkin lymphoma, nonischemic cardiomyopathy ejection fraction of 25-30%, severe aortic stenosis, hepatitis C, and active intravenous (IV) drug abuse who was admitted following a motor vehicle accident. Approximately 10 days into his admission, he developed a 39.5 degree Celsius fever, which prompted collection of blood cultures. These cultures were positive (2 out of 2) for S. marcescens for which he was treated with intravenous cefepime. Soon after this diagnosis, patient developed a complete AV block. Given the instability of the patient, he required emergent placement of a temporary pacing wire. Transesophageal echocardiogram was ordered and revealed an aortic root abscess. Given the comorbidities and active IV drug use, conservative management was pursued. Although rare, trends suggest that this pathogen may be on the rise. Further research is needed to better understand how to effectively manage this pathogen.

A reference map of the human binary protein interactome.

Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype-phenotype relationships1,2. Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. The integration of HuRI with genome3, transcriptome4 and proteome5 data enables cellular function to be studied within most physiological or pathological cellular contexts. We demonstrate the utility of HuRI in identifying the specific subcellular roles of protein-protein interactions. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms that might underlie tissue-specific phenotypes of Mendelian diseases. HuRI is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes.

Strap Performance of N95 Filtering Facepiece Respirators After Multiple Decontamination Cycles.

The Battelle Critical Care Decontamination System™ (CCDS™) decontaminates N95 filtering facepiece respirators (FFRs) using vapor phase hydrogen peroxide (VPHP) for reuse when there is a critical supply shortage. The Battelle CCDS received an Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA) in March 2020. This research focused on evaluating the mechanical properties of the straps as an indicator of respirator fit. The objective was to characterize the load generated by the straps following up to 20 don/doff and decontamination cycles in Battelle's CCDS. In general, the measured loads at 50 and 100% strains after 20 cycles were similar (±15%) to the as-received controls. Qualitatively, reductions in the load may be associated with loss of elasticity in the straps, potentially reducing the ability to obtain a proper fit. However, small changes in strap elasticity may not affect the ability to obtain a proper fit given the potential for variation in strap length and positioning on the head. Regardless, prior to reusing a N95 respirator, it is important to complete a visual inspection to ensure it is not damaged, malformed, or soiled. If so, it is recommended to discard the respirator and use a different one. Similarly, the respirator should be discarded if the wearer cannot obtain a proper fit during the user seal check.

Endocarditis caused by Stenotrophomonas maltophilia-A rare presentation of an emerging opportunistic pathogen.

First isolated in 1943, Stenotrophomonas maltophilia (S. maltophilia) has historically been of little significance as it was considered a pathogen of low virulence noted to rarely infect immunocompromised hosts. However, over the last 30 years the prevalence of infection caused by the organism has increased significantly. Bacterial endocarditis from S. maltophilia remains exceedingly rare with only a small number of reported cases in the literature. This case involves a 27 year old male with sickle cell anemia with an indwelling right subclavian port who presented to the emergency department with myalgias, fever, and chills. His initial blood cultures grew Gram negative rods later identified as S. maltophilia. Transthoracic echocardiogram showed a mass in the right atrium. Transesophageal echocardiogram revealed a large C-shaped mass with attachment to the tricuspid annulus, mitral valve wall, and port tip in right atrium. The patient underwent sternotomy with removal of the vegetation to prevent embolization. He was treated with intravenous ciprofloxacin and oral trimethoprim/sulfamethoxazole to complete a full 6 weeks of therapy, making a full recovery. This report will further explore the unique presentation of this pathogen along with its epidemiology, resistance mechanisms, risk factors for infection, diagnosis, and appropriate antimicrobial treatment.

Protein Interactomics by Two-Hybrid Methods.

Comprehensive identification of direct, physical interactions between biological macromolecules, such as protein-protein, protein-DNA, and protein-RNA interactions, is critical for our understanding of the function of gene products as well as the global organization and interworkings of various molecular machines within the cell. The accurate and comprehensive detection of direct interactions, however, remains a huge challenge due to the inherent structural complexity arising from various post-transcriptional and translational modifications coupled with huge heterogeneity in concentration, affinity, and subcellular location differences existing for any interacting molecules. This has created a need for developing multiple orthogonal and complementary assays for detecting various types of biological interactions. In this introduction, we discuss the methods developed for measuring different types of molecular interactions with an emphasis on direct protein-protein interactions, critical issues for generating high-quality interactome datasets, and the insights into biological networks and human diseases that current interaction mapping efforts provide. Further, we will discuss what future might lie ahead for the continued evolution of two-hybrid methods and the role of interactomics for expanding the advancement of biomedical science.

A Rare Report of Infectious Emphysematous Aortitis Secondary to Clostridium septicum without Prior Vascular Intervention.

The term "mycotic aneurysm" was first used by Osler in 1882 to describe a mushroom-shaped aneurysm in subacute bacterial endocarditis. Mycotic aneurysms account for only 2.6% of all aneurysms of the aorta. Rarer still are anaerobic infections secondary to organisms such as Clostridium septicum, which results in emphysematous aortitis. The vast majority of emphysematous aortic infections occur as a result of instrumentation; however, in this case we present an infection de novo. A 75-year-old male presented with a 2-week history of progressive fatigue and chest pain that then developed into constitutional symptoms. Chest radiograph demonstrated an obvious widened mediastinum. CT angiogram of his chest then confirmed this finding as well as significant periaortic gas and focal outpouching. Numerous diverticuli with inflammatory changes consistent with diverticulitis was observed on CT abdomen. Blood cultures returned positive for Clostridium septicum. Definitive treatment was discussed including debridement and graft insertion; however, patient decided on conservative management and was discharged on intravenous antibiotics. Unfortunately, as in most cases of emphysematous aortitis that do not undergo surgical management, the patient succumbed to his illness. The lesson provided will be the epidemiology of emphysematous aortitis, presentation, diagnosis, management, and prognosis through a case report.

Neurodevelopmental outcomes in infants undergoing general anesthesia.

PURPOSE: Preclinical data strongly suggest that all agents used for general anesthesia (GA) have detrimental effects on the developing brain. However, clinical data are unclear. The purpose of this study was to use a cohort of infants who underwent GA and understand their neurodevelopmental outcomes. METHODS: A cohort of infants who underwent GA was selected between 2010 and 2011, and a control group was created. Data regarding GA, procedures, and outcomes were collected in 2015. The cohort was divided into controls, GA without surgery, GA and surgery once, and multiple general anesthetics. Both univariate and multivariate analysis were performed, and a p value of less than 0.05 was considered significant. RESULTS: 457 patients, 121 controls, and 336 cases were included. Median follow-up was 5.1years. While developmental delay and the need for speech therapy were higher with GA, this did not correlate with the duration of GA. Patients having GA for MRI had the poorest outcomes. Multivariate analysis using combined binary outcome measures for psychiatric and neurologic outcomes did not show any significant difference for duration of anesthesia, age at anesthesia, or induction and maintenance agents. CONCLUSIONS: These data suggest that GA during the first year of life may have few significant neurodevelopmental effects compared to controls. Additionally, the duration of GA did not correlate with neurodevelopmental outcomes. TYPE OF STUDY: Retrospective Case Control Cohort Study. LEVEL OF EVIDENCE: 3 b (according to Oxford Center for EBM Levels of Evidence, March 2009, http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/).

Anticoagulation for the Pregnant Patient with a Mechanical Heart Valve, No Perfect Therapy: Review of Guidelines for Anticoagulation in the Pregnant Patient.

Heart valve replacement with a mechanical valve requires lifelong anticoagulation. Guidelines currently recommend using a vitamin K antagonist (VKA) such as warfarin. Given the teratogenic effects of VKAs, it is often favorable to switch to heparin-derived therapies in pregnant patients since they do not cross the placenta. However, these therapies are known to be less effective anticoagulants subjecting the pregnant patient to a higher chance of a thrombotic event. Guidelines currently recommend pregnant women requiring more than 5 mg a day of warfarin be switched to alternative therapy during the first trimester. This case report highlights a patient who was switched to alternative therapy during her first pregnancy and suffered a devastating cerebrovascular accident (CVA). Further complicating her situation was during a subsequent pregnancy; this patient continued warfarin use during the first trimester and experienced multiple transient ischemic attacks (TIAs). This case highlights the increased risk of thrombotic events in pregnant patients with mechanical valves. It also highlights the difficulty of providing appropriate anticoagulation for the pregnant patient who has experienced thrombotic events on multiple anticoagulants.

Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.

While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs. The majority of isoform pairs share less than 50% of their interactions. In the global context of interactome network maps, alternative isoforms tend to behave like distinct proteins rather than minor variants of each other. Interaction partners specific to alternative isoforms tend to be expressed in a highly tissue-specific manner and belong to distinct functional modules. Our strategy, applicable to other functional characteristics, reveals a widespread expansion of protein interaction capabilities through alternative splicing and suggests that many alternative "isoforms" are functionally divergent (i.e., "functional alloforms").

Horizontal transfer of entire genomes via mitochondrial fusion in the angiosperm Amborella.

We report the complete mitochondrial genome sequence of the flowering plant Amborella trichopoda. This enormous, 3.9-megabase genome contains six genome equivalents of foreign mitochondrial DNA, acquired from green algae, mosses, and other angiosperms. Many of these horizontal transfers were large, including acquisition of entire mitochondrial genomes from three green algae and one moss. We propose a fusion-compatibility model to explain these findings, with Amborella capturing whole mitochondria from diverse eukaryotes, followed by mitochondrial fusion (limited mechanistically to green plant mitochondria) and then genome recombination. Amborella's epiphyte load, propensity to produce suckers from wounds, and low rate of mitochondrial DNA loss probably all contribute to the high level of foreign DNA in its mitochondrial genome.

Physical and genetic associations of the Irc20 ubiquitin ligase with Cdc48 and SUMO.

A considerable percentage of the genome is dedicated to the ubiquitin-proteasome system, with the yeast genome predicted to encode approximately 100 ubiquitin ligases (or E3s), and the human genome predicted to encode more than 600 E3s. The most abundant class of E3s consists of RING finger-containing proteins. Although many insights have been obtained regarding the structure and catalytic mechanism of the E3s, much remains to be learned about the function of the individual E3s. Here we characterize IRC20, which encodes a dual RING- and Snf/Swi family ATPase domain-containing protein in yeast that has been implicated in DNA repair. We found that overexpression of IRC20 causes two transcription-associated phenotypes and demonstrate that the Irc20 RING domain possesses ubiquitin E3 activity in vitro. Two mass spectrometry approaches were undertaken to identify Irc20-associated proteins. Wild-type Irc20 associated with Cdc48, a AAA-ATPase that serves as an intermediary in the ubiquitin-proteasome system. A second approach using a RING mutant derivative of Irc20 detected increased association of the Irc20 mutant with SUMO. These findings provide a foundation for understanding the roles of Irc20 in transcription and DNA repair.

Viable viral efficiency of N95 and P100 respirator filters at constant and cyclic flow.

The growing threat of an influenza pandemic presents a unique challenge to healthcare workers, emergency responders, and the civilian population. The Occupational Safety and Health Administration (OSHA) recommends National Institute for Occupational Safety and Health (NIOSH)-approved respirators to provide protection against infectious airborne viruses in various workplace settings. The filtration efficiency of selected NIOSH-approved particulate N95 and P100 filtering facepiece respirators (FFRs) and filter cartridges was investigated against the viable MS2 virus, a non-pathogenic bacteriophage, aerosolized from a liquid suspension. Tests were performed under two cyclic flow conditions (minute volumes of 85 and 135 L/min) and two constant flow rates (85 and 270 L/min). The mean penetrations of viable MS2 through the N95 and P100 FFRs/cartridges were typically less than 2 and 0.03%, respectively, under all flow conditions. All N95 and P100 FFR and cartridge models assessed in this study, therefore, met or exceeded their respective efficiency ratings of 95 and 99.97% against the viable MS2 test aerosol, even under the very high flow conditions. These NIOSH-approved FFRs and particulate respirators equipped with these cartridges can be anticipated to achieve expected levels of protection (consistent with their assigned protection factor) against airborne viral agents, provided that they are properly selected, fitted, worn, and maintained.