Chromosomal instability drives metastasis through a cytosolic DNA response.

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.

Extended-Release Naltrexone and Case Management for Treatment of Alcohol Use Disorder in the Emergency Department.

STUDY OBJECTIVE: To assess the feasibility of initiating treatment for alcohol use disorder with extended-release naltrexone and case management services in the emergency department (ED) and measure the intervention's impact on daily alcohol consumption and quality of life. METHODS: This is a 12-week prospective open-label single-arm study of a multimodal treatment for alcohol use disorder consisting of monthly extended-release naltrexone injections and case management services initiated at an urban academic ED. Participants were actively drinking adult patients in ED with known or suspected alcohol use disorder and an AUDIT-C score more than 4. The main feasibility outcomes included the rates of participant enrollment, retention in the study, and continuing treatment after study completion. Efficacy outcomes were the change in daily alcohol consumption (drinks per day; 14 g ethanol per drink), measured by a 14-day timeline followback, and the change in quality of life measured with a single-item Kemp quality of life scale. RESULTS: One hundred seventy-nine patients were approached, and 32 were enrolled (18%). Of the 32 enrolled patients, 25 (78%) completed all visits, and 22 (69%) continued naltrexone after the trial. The mean baseline daily alcohol consumption was 7.6 drinks per day (interquartile range, 4.5, 13.4), and the mean quality of life was 3.6 (SD 1.7) on a 7-point scale. The median daily alcohol consumption change was -7.5 drinks per day (Hodges-Lehmann 95% confidence interval -8.6, -5.9). The mean quality of life change was 1.2 points (95% confidence interval 0.5, 1.9; P<.01). CONCLUSION: We found that initiation of treatment of alcohol use disorder with extended-release naltrexone and case management is feasible in an ED setting and observed significant reductions in drinking with improved quality of life in the short term. Multicenter randomized controlled trials are needed to further validate these findings.

SARS COV-2 anti-nucleocapsid and anti-spike antibodies in an emergency department healthcare worker cohort: September 2020 - April 2021.

BACKGROUND: Emergency department (ED) workers have an increased seroprevalence of SARS-CoV-2 antibodies. However, breakthrough infections in ED workers have led to a reduced workforce within a strained healthcare system. By measuring levels of IgG antibodies to the SARS-CoV-2 nucleocapsid and spike antigens in ED workers, we determined the incidence of infection and described the course of antibody levels. We also measured the antibody response to vaccination and examined factors associated with immunogenicity. METHODS: We conducted a prospective cohort study of ED workers conducted at a single ED from September 2020-April 2021. IgG antibodies to the SARS-CoV-2 nucleocapsid antigen were measured at baseline, 3, and 6 months, and IgG antibodies to the SARS-CoV-2 spike antigen were measured at 6 months. RESULTS: At baseline, we found 5 out of 139 (3.6%) participants with prior infection. At 6 months, 4 of the 5 had antibody results below the test manufacturer's positivity threshold. We identified one incident case of SARS-COV-2 infection out of 130 seronegative participants (0.8%, 95% CI 0.02-4.2%). In 131 vaccinated participants (125 BNT162b2, 6 mRNA-1273), 131 tested positive for anti-spike antibodies. We identified predictors of anti-spike antibody levels: time since vaccination, prior COVID-19 infection, age, and vaccine type. Each additional week since vaccination was associated with an 11.1% decrease in anti-spike antibody levels. (95% CI 6.2-15.8%). CONCLUSION: ED workers experienced a low incidence of SARS-CoV-2 infection and developed antibodies in response to vaccines and prior infection. Antibody levels decreased markedly with time since infection or vaccination.

Transradial access in acute myocardial infarction complicated by cardiogenic shock: Stratified analysis by shock severity.

BACKGROUND: Transradial access (TRA) is associated with improved survival and reduced vascular complications in acute myocardial infarction (AMI). Limited data exist regarding TRA utilization and outcomes for AMI complicated by cardiogenic shock (CS). We sought to assess the safety, feasibility, and clinical outcomes of TRA in AMI-CS. METHODS: One-hundred and fifty-three patients with AMI-CS were stratified into tertiles of disease severity using the CardShock score. The primary endpoint was successful percutaneous coronary intervention (PCI), defined as Thrombolysis in Myocardial Infarction III flow with survival to 30 days. RESULTS: Mean age was 66 years, 72% were men, and 47% had diabetes. TRA was the preferred access site in patients with low and intermediate disease severity. Overall, 50 (32%) patients experienced major adverse cardiac and cerebrovascular events; most events (78%) occurred in patients undergoing transfemoral access (TFA) in the intermediate-high tertiles of CS severity. Of the 41 (27%) total bleeding events, 32% occurred at the coronary angiography access site, of which 92% were in the TFA group. The use of ultrasound (US) guidance for TFA resulted in reduced coronary access-site bleeding (8.5 vs. 33.0%, p = .01). In a hierarchical logistic regression model, utilizing TRA did not result in lower odds of successful PCI (Odds ratio [OR]: 1.36; 95% confidence interval [CI]: 0.54-3.40). CONCLUSION: This study suggests that TRA is feasible across the entire spectrum of AMI-CS and is associated with reduced coronary access-site bleeding. In addition, US-guided TFA is associated with reductions in access-site bleeding and vascular complications. Concerted efforts should be made to incorporate vascular access protocols into existing CS algorithms in dedicated shock care centers.

Impact of a Critical Care Specialist Intervention on First Pass Success for Emergency Airway Management Outside the ICU.

BACKGROUND: There has been limited investigation into the procedural outcomes of patients undergoing emergent endotracheal intubation (EEI) by a critical care medicine (CCM) specialist outside the intensive care unit (ICU). We hypothesized that EEI outside an ICU would be associated with lower rates of first pass success (FPS) as compared to inside an ICU. METHODS: We performed a retrospective cohort study of all adult patients admitted to our academic medical center between January 1, 2016, and July 31, 2018, who underwent EEI by a CCM practitioner. The primary outcome of FPS was identified in the EEI procedure note. Secondary outcomes included difficult intubation (> 2 attempts at laryngoscopy) and mortality following EEI. RESULTS: In total, 1958 patients (1035 [52.9%] inside ICU and 923 [47.1%]) outside an ICU) were included in the final cohort. Unadjusted rate of FPS was not different between patients intubated out of the ICU and patients intubated inside of the ICU (689 [74.7%] vs 775 [74.9%]; P = .91). There was also no difference in FPS between groups after adjusting for predictors of difficult intubation and baseline covariates (odds ratio: 0.95; 95% confidence interval, 0.75-1.2, P = .65). Mortality of patients undergoing EEI out of the ICU was higher at each examined time interval following EEI. DISCUSSION: For EEI done by CCM practitioners, rate of FPS is not different between patients undergoing EEI outside an ICU as compared to inside an ICU. Despite the lack of difference between rates of procedural success, patient mortality following EEI outside an ICU is higher than EEI inside an ICU at all examined time points during hospitalization.

Fenofibrate prevents skeletal muscle loss in mice with lung cancer.

The cancer anorexia cachexia syndrome is a systemic metabolic disorder characterized by the catabolism of stored nutrients in skeletal muscle and adipose tissue that is particularly prevalent in nonsmall cell lung cancer (NSCLC). Loss of skeletal muscle results in functional impairments and increased mortality. The aim of the present study was to characterize the changes in systemic metabolism in a genetically engineered mouse model of NSCLC. We show that a portion of these animals develop loss of skeletal muscle, loss of adipose tissue, and increased inflammatory markers mirroring the human cachexia syndrome. Using noncachexic and fasted animals as controls, we report a unique cachexia metabolite phenotype that includes the loss of peroxisome proliferator-activated receptor-α (PPARα) -dependent ketone production by the liver. In this setting, glucocorticoid levels rise and correlate with skeletal muscle degradation and hepatic markers of gluconeogenesis. Restoring ketone production using the PPARα agonist, fenofibrate, prevents the loss of skeletal muscle mass and body weight. These results demonstrate how targeting hepatic metabolism can prevent muscle wasting in lung cancer, and provide evidence for a therapeutic strategy.

A Chemoproteomic Strategy for Direct and Proteome-Wide Covalent Inhibitor Target-Site Identification.

Despite recent clinical successes for irreversible drugs, potential toxicities mediated by unpredictable modification of off-target cysteines represents a major hurdle for expansion of covalent drug programs. Understanding the proteome-wide binding profile of covalent inhibitors can significantly accelerate their development; however, current mass spectrometry strategies typically do not provide a direct, amino acid level readout of covalent activity for complex, selective inhibitors. Here we report the development of CITe-Id, a novel chemoproteomic approach that employs covalent pharmacologic inhibitors as enrichment reagents in combination with an optimized proteomic platform to directly quantify dose-dependent binding at cysteine-thiols across the proteome. CITe-Id analysis of our irreversible CDK inhibitor THZ1 identified dose-dependent covalent modification of several unexpected kinases, including a previously unannotated cysteine (C840) on the understudied kinase PKN3. These data streamlined our development of JZ128 as a new selective covalent inhibitor of PKN3. Using JZ128 as a probe compound, we identified novel potential PKN3 substrates, thus offering an initial molecular view of PKN3 cellular activity. CITe-Id provides a powerful complement to current chemoproteomic platforms to characterize the selectivity of covalent inhibitors, identify new, pharmacologically addressable cysteine-thiols, and inform structure-based drug design programs.

Rib Fracture Diagnosis in the Panscan Era.

STUDY OBJECTIVE: With increased use of chest computed tomography (CT) in trauma evaluation, traditional teachings in regard to rib fracture morbidity and mortality may no longer be accurate. We seek to determine rates of rib fracture observed on chest CT only; admission and mortality of patients with isolated rib fractures, rib fractures observed on CT only, and first or second rib fractures; and first or second rib fracture-associated great vessel injury. METHODS: We conducted a planned secondary analysis of 2 prospectively enrolled cohorts of the National Emergency X-Radiography Utilization Study chest studies, which evaluated patients with blunt trauma who were older than 14 years and received chest imaging in the emergency department. We defined rib fractures and other thoracic injuries according to CT reports and followed patients through their hospital course to determine outcomes. RESULTS: Of 8,661 patients who had both chest radiograph and chest CT, 2,071 (23.9%) had rib fractures, and rib fractures were observed on chest CT only in 1,368 cases (66.1%). Rib fracture patients had higher admission rates (88.7% versus 45.8%; mean difference 42.9%; 95% confidence interval [CI] 41.4% to 44.4%) and mortality (5.6% versus 2.7%; mean difference 2.9%; 95% CI 1.8% to 4.0%) than patients without rib fracture. The mortality of patients with rib fracture observed on chest CT only was not statistically significantly different from that of patients with fractures also observed on chest radiograph (4.8% versus 5.7%; mean difference -0.9%; 95% CI -3.1% to 1.1%). Patients with first or second rib fractures had significantly higher mortality (7.4% versus 4.1%; mean difference 3.3%; 95% CI 0.2% to 7.1%) and prevalence of concomitant great vessel injury (2.8% versus 0.6%; mean difference 2.2%; 95% CI 0.6% to 4.9%) than patients with fractures of ribs 3 to 12, and the odds ratio of great vessel injury with first or second rib fracture was 4.4 (95% CI 1.8 to 10.4). CONCLUSION: Under trauma imaging protocols that commonly incorporate chest CT, two thirds of rib fractures were observed on chest CT only. Patients with rib fractures had higher admission rates and mortality than those without rib fractures. First or second rib fractures were associated with significantly higher mortality and great vessel injury.

Characterization of Two Species of Trypanosomatidae from the Honey Bee Apis mellifera: Crithidia mellificae Langridge and McGhee, and Lotmaria passim n. gen., n. sp.

Trypanosomatids are increasingly recognized as prevalent in European honey bees (Apis mellifera) and by default are attributed to one recognized species, Crithidia mellificae Langridge and McGhee, 1967. We provide reference genetic and ultrastructural data for type isolates of C. mellificae (ATCC 30254 and 30862) in comparison with two recent isolates from A. mellifera (BRL and SF). Phylogenetics unambiguously identify strains BRL/SF as a novel taxonomic unit distinct from C. mellificae strains 30254/30862 and assign all four strains as lineages of a novel clade within the subfamily Leishmaniinae. In vivo analyses show strains BRL/SF preferably colonize the hindgut, lining the lumen as adherent spheroids in a manner identical to previous descriptions from C. mellificae. Microscopy images show motile forms of C. mellificae are distinct from strains BRL/SF. We propose the binomial Lotmaria passim n. gen., n. sp. for this previously undescribed taxon. Analyses of new and previously accessioned genetic data show C. mellificae is still extant in bee populations, however, L. passim n. gen., n. sp. is currently the predominant trypanosomatid in A. mellifera globally. Our findings require that previous reports of C. mellificae be reconsidered and that subsequent trypanosomatid species designations from Hymenoptera provide genetic support.

Duality between predictability and reconstructability in complex systems.

Predicting the evolution of a large system of units using its structure of interaction is a fundamental problem in complex system theory. And so is the problem of reconstructing the structure of interaction from temporal observations. Here, we find an intricate relationship between predictability and reconstructability using an information-theoretical point of view. We use the mutual information between a random graph and a stochastic process evolving on this random graph to quantify their codependence. Then, we show how the uncertainty coefficients, which are intimately related to that mutual information, quantify our ability to reconstruct a graph from an observed time series, and our ability to predict the evolution of a process from the structure of its interactions. We provide analytical calculations of the uncertainty coefficients for many different systems, including continuous deterministic systems, and describe a numerical procedure when exact calculations are intractable. Interestingly, we find that predictability and reconstructability, even though closely connected by the mutual information, can behave differently, even in a dual manner. We prove how such duality universally emerges when changing the number of steps in the process. Finally, we provide evidence that predictability-reconstruction dualities may exist in dynamical processes on real networks close to criticality.

Characterization of Neospora caninum macrophage migration inhibitory factor.

The present study is the first characterization of Neospora caninum macrophage migration inhibitory factor (NcMIF). BLAST-N analysis of NcMIF revealed high similarity (87%) to the Toxoplasma gondii MIF. NcMIF was cloned and expressed in Escherichia coli in 3 forms, NcMIF (mature protein), NcMIFm (mutation of proline-2 to glycine), and NcMIFhis (addition of a polyhistidine tag at the N-terminus). None of these recombinant NcMIFs (rNcMIF) had tautomerase, oxidoreductase, or immunologic regulatory activities. rNcMIF was unable to compete with recombinant human MIF for a MIF receptor (CD74), suggesting that NcMIF does not bind to this MIF receptor. The glycine substitution for proline-2 of NcMIF resulted in increased retention time on SEC-HPLC and decreased formation of dimers and trimers. The addition of N-terminal HIS-tag led to increased formation of trimers. Immunofluorescence staining demonstrated that NcMIF was localized to the apical end of N. caninum tachyzoites. Immunoelectron microscopy further revealed that NcMIF was present in the micronemes, rhoptries, dense granules, and nuclei. NcMIF was abundant in the tachyzoite lysate and present in excretory and secretory antigen (ESAg) preparations. Total and secretory NcMIF was more abundant in a non-pathologic clone, Ncts-8, than in the wild type isolate (NC1). Furthermore, NcMIF release by the both isolates was increased in the presence of calcium ionophore. This differential production of NcMIF by the pathologic and non-pathologic isolates of N. caninum may suggest a critical role of this molecule in the infectious pathogenesis of this parasite.

Characterization and localization of an Eimeria-specific protein in Eimeria maxima.

A recently completed analysis of Eimeria maxima transcriptome identified a gene with homology to sequences expressed by E. tenella and E. acervulina but lacking homology with other organisms including other apicomplexans. This gene, designated Eimeria-specific protein (ESP), codes for a protein with a predicted molecular weight of 19 kDa. The ESP gene was cloned and the recombinant protein expressed in bacteria and purified for preparation of specific antisera. Quantitative RT-PCR showed transcription of ESP was low in unsporulated oocysts and after 24 h of sporulation. However, transcription nearly doubled after 48 h of sporulation and reached its highest levels in sporozoites (SZ) and merozoites (MZ). The protein was detectable by Western blot in both sporulated oocysts and in SZ and MZ. Immuno-localization by light microscopy identified ESP in paired structures in the anterior of SZ and MZ. Immuno-localization by electron microscopy identified ESP in MZ rhoptries but no specific staining of any SZ structures was detected. In addition, localization studies on intestinal sections recovered from birds 120-h post-infection indicates that oocysts do not stain with anti-ESP but staining of microgametocytes and developing oocysts was observed. The results indicate that ESP is associated with the rhoptry of E. maxima and that the protein may have functions in other developmental stages.

Phenobarbital treatment of alcohol withdrawal in the emergency department: A systematic review and meta-analysis.

OBJECTIVE: Despite frequent treatment of alcohol withdrawal syndrome (AWS) in the emergency department (ED), evidence for phenobarbital (PB) as an ED alternative therapy is mixed. We conducted a systematic review and meta-analysis comparing safety and efficacy of PB to benzodiazepines (BZDs) for treatment of AWS in the ED. METHODS: We searched articles and references published in English in PubMed, Web of Science, and Embase from inception through May 2022. We included randomized trials and cohort studies comparing treatment with PB to BZD controls and excluded studies focused on non-AWS conditions. Review was conducted by two blinded investigators and a third author; eight of 59 (13.6%) abstracts met inclusion criteria for review and meta-analysis using a random-effects model. Treatment superiority was evaluated through utilization, pharmacologic, and clinical outcomes. Primary outcomes for meta-analysis were the proportion of patients (1) admitted to the intensive care unit (ICU), (2) admitted to the hospital, (3) readmitted to the ED after discharge, and (4) who experienced adverse events. RESULTS: Eight studies (two randomized controlled trials, six retrospective cohorts) comprised data from 1507 patients in 2012 treatment encounters for AWS. All studies were included in meta-analysis for adverse events, seven for hospital admission, five for ICU admission, and three for readmission to the ED after discharge. Overall methodological quality was low-moderate, risk of bias moderate-high, and statistical heterogeneity moderate. Pooled relative risk of ICU admission for those treated with PB versus BZD was 0.92 (95% confidence interval [CI] 0.54-1.55). Risk for admission to the hospital was 0.98 (95% CI 0.89-1.07) and for any adverse event was 1.1 (95% CI 0.78-1.57); heterogeneity prevented meta-analysis for ED readmission. CONCLUSIONS: The current literature base does not show that treatment with PB significantly reduces ICU admissions, hospital admissions, ED readmissions, or adverse events in ED patients with AWS compared with BZDs alone.

Capnography-Assisted Learned, Monitored (CALM) breathing therapy for dysfunctional breathing in COPD: A bridge to pulmonary rehabilitation.

BACKGROUND: Although dyspnea is a primary symptom of chronic obstructive pulmonary disease (COPD), its treatment is suboptimal. In both COPD and acute anxiety, breathing patterns become dysregulated, contributing to abnormal CO2, dyspnea, and inefficient recovery from breathing challenges. While pulmonary rehabilitation (PR) improves dyspnea, only 1-2% of patients access it. Individuals with anxiety who use PR have worse outcomes. METHODS: We present the protocol of a randomized controlled trial designed to determine the feasibility and acceptability of a new, four-week mind-body intervention that we developed, called "Capnography-Assisted Learned, Monitored (CALM) Breathing," as an adjunct to PR. Eligible participants are randomized in a 1:1 ratio to either CALM Breathing program or Usual Care. CALM Breathing consists of 10 core, slow breathing exercises combined with real time biofeedback (of end-tidal CO2, respiratory rate, and airflow) and motivational interviewing. CALM Breathing promotes self-regulated breathing, linking CO2 changes to dyspnea and anxiety symptoms and targeting breathing efficiency and self-efficacy in COPD. Participants are randomized to CALM Breathing or a Usual Care control group. RESULTS: Primary outcomes include feasibility and acceptability metrics of recruitment efficiency, participant retention, intervention adherence and fidelity, PR facilitation, patient satisfaction, and favorable themes from interviews. Secondary outcomes include breathing biomarkers, symptoms, health-related quality of life, six-minute walk distance, lung function, mood, physical activity, and PR utilization and engagement. CONCLUSION: By disrupting the cycle of dyspnea and anxiety, and providing a needed bridge to PR, CALM Breathing may address a substantive gap in healthcare and optimize treatment for patients with COPD.

Proteomic pleiotropy of OpgGH, an operon necessary for efficient growth of Salmonella enterica serovar typhimurium under low-osmotic conditions.

Salmonella enterica, a bacterial, food-borne pathogen of humans, can contaminate raw fruits and vegetables. Unfortunately for consumers, the bacteria can survive in water used to wash away contaminating bacteria. The ability to survive the low-osmotic conditions of the wash water is attributed to the OpgGH operon that leads to the production of osmotically regulated periplasmic glucans. Mutants lacking OpgGH grow slowly under low-osmotic conditions, but there are also unexpected traits such as abnormal flagellar motility and reduced virulence in mice. To get a broader understanding of these pleiotropic effects under low osmolarity, we examined the proteome of these mutants using high-throughput mass spectrometry. We identified approximately one-third of the proteins encoded by the genome and used label-free spectral counting to determine the relative amounts of proteins in wild-type cultures and mutants. Mutants had reduced amounts of proteins required for osmotic sensing, flagellar motility, purine and pyrimidine metabolism, oxidative energy production, and protein translation. By contrast, mutants had greater amounts of ABC transporters needed to balance cellular osmolarity. Hence, the effects of OpgGH reach across the proteome, and the data are consistent with the mutant phenotypes.

Gene expression profiling and shared promoter motif for cell wall-modifying proteins expressed in soybean cyst nematode-infected roots.

We hypothesized that soybean cyst nematode (SCN; Heterodera glycines) co-opts part or all of one or more innate developmental process in soybean (Glycine max) to establish its feeding structure, syncytium, in soybean roots. The syncytium is formed within the vascular bundle by partial degradation of cell walls and membranes between adjacent parenchyma cells. A mature syncytium incorporates as many as 200 cells into one large multinucleated cell. Gene expression patterns for several cell wall-modifying proteins were compared in multiple tissues undergoing major shifts in cell wall integrity. These included SCN-colonized roots, root tips where vascular differentiation occurs, flooded roots (aerenchyma), adventitious rooting in hypocotyls, and leaf abscission zones. A search in the 5' upstream promoters of these genes identified a motif (SCNbox1: WGCATGTG) common to several genes that were up-regulated in several different tissues. The polygalacturonase 11 promoters (GmPG11a/b) include the SCNbox1 motif. The expression pattern for GmPG11a was examined further in transgenic soybean containing a PG11a promoter fused to a ß-glucuronidase (GUS) reporter gene. GUS expression was highest in cells undergoing radial expansion in the stele and/or cell wall dissolution. GUS staining was not observed in cortical cells where a lateral root tip or a growing nematode emerged through the root cortex.

Effect of extended-release naltrexone on alcohol consumption: a systematic review and meta-analysis.

AIMS: The aims of this study were to (1) estimate the effect of extended-release naltrexone compared with placebo on alcohol consumption in patients with alcohol use disorder (AUD) and (2) conduct pre-planned subgroup analyses to test whether being abstinent when initiating treatment (lead-in abstinence) or the duration of treatment improves treatment efficacy. DESIGN: Systematic review and random-effects meta-analysis of blinded randomized placebo-controlled trials reporting the effect extended-release naltrexone on alcohol consumption. SETTING: Outpatient clinics. PARTICIPANTS: Seven trials evaluating a total of 1500 adults with AUD receiving monthly injections of either placebo or extended-release naltrexone at doses of 150-400 mg for 2-6 months and some form of behavioral therapy. MEASUREMENTS: Pooled weighted mean difference (WMD) in drinking days per month and heavy drinking days per month. FINDINGS: The WMD was -2.0 [95% confidence interval (CI) = -3.4, -0.6; P = 0.03] in favor of extended-release naltrexone for drinking days per month and -1.2 (95% CI = -0.2, -2.1; P = 0.02) for heavy drinking days per month, indicating that treatment resulted in two fewer drinking days per month and 1.2 fewer heavy drinking days per month compared with placebo. Trials not requiring lead-in abstinence and those lasting longer than 3 months reported larger reductions in heavy drinking days per month; WMD -2.0 (95% CI = -3.52, -0.48; P = 0.01) and -1.9 (95% CI = -3.2, -0.5; P = 0.01), respectively. In all cases, the I2 statistics (0-7.2%) did not suggest substantial heterogeneity. CONCLUSIONS: Extended-release naltrexone reduces drinking days and heavy drinking days per month compared with placebo. Reductions are larger with a longer duration of treatment.

Return Encounters in Emergency Department Patients Treated with Phenobarbital Versus Benzodiazepines for Alcohol Withdrawal.

INTRODUCTION: Phenobarbital has been successfully used in the emergency department (ED) to manage symptoms of alcohol withdrawal, but few studies have reported outcomes for ED patients who receive phenobarbital and are discharged. We compared return encounter rates in discharged ED patients with alcohol withdrawal who were treated with benzodiazepines and phenobarbital. METHODS: This is a retrospective cohort study conducted at a single academic medical center utilizing chart review of discharged ED patients with alcohol withdrawal from July 1, 2016, to June 30, 2019. Patients were stratified according to ED management with benzodiazepines, phenobarbital, or a combination of both agents. The primary outcome was return ED encounter within three days of the index ED encounter. Multivariate logistic regression identified significant covariates of an ED return encounter. RESULTS: Of 470 patients who were discharged with the diagnosis of alcohol withdrawal, 235 were treated with benzodiazepines, 133 with phenobarbital, and 102 with a combination of both. Baseline characteristics were similar among the groups. However, patients who received phenobarbital were provided significantly more lorazepam equivalents compared to patients who received benzodiazepines alone. Treatment with phenobarbital, alone or in combination with benzodiazepines, was associated with significantly lower odds of a return ED visit within three days compared with benzodiazepines alone [AOR 0.45 (95% CI 0.23, 0.88) p = 0.02 and AOR 0.33 (95% CI 0.15, 0.74) p = 0.007]. CONCLUSIONS: Patients who received phenobarbital for alcohol withdrawal were less likely to return to the ED within three days of the index encounter. Despite similar baseline characteristics, patients who received phenobarbital, with or without benzodiazepines, were provided greater lorazepam equivalents the ED.

A 52-Year-Old Man With Chest Pain and Dyspnea.

CASE PRESENTATION: A 52-year-old man came to the cardiac surgery clinic for pulmonary thromboendarterectomy (PTE) evaluation. He had initially appeared at an outside hospital 1 year earlier, with chest pain and shortness of breath. He had no known chronic conditions. A CT pulmonary angiogram (CTPA) at that time showed a filling defect at the bifurcation of the main pulmonary artery. A transthoracic echocardiogram revealed mild mitral valve regurgitation, but otherwise the results were normal. As he was hemodynamically stable and not hypoxemic, he was treated solely by anticoagulation. Despite adhering to prescribed apixaban, he developed progressive dyspnea and reduced exercise tolerance over the subsequent year. A repeat CTPA performed 12 months after the initial presentation showed a persistent filling defect at the level of the pulmonary artery bifurcation, with a new extension now completely occluding the right main pulmonary artery. A pulmonary angiogram confirmed this complete occlusion, and right heart catheterization revealed precapillary pulmonary hypertension, with a mean pulmonary artery pressure of 50 mm Hg. His anticoagulation was transitioned to enoxaparin for presumed apixaban treatment failure, and an investigation for hypercoagulable conditions was initiated. His lupus anticoagulant test result was positive, but he did not meet the criteria for antiphospholipid syndrome because he was negative for anticardiolipin and ß2-glycoprotein antibodies. Assays for antithrombin III, protein C, prothrombin gene, and factor V Leiden mutations produced normal results.