Descriptive analysis of targeted carbapenemase genes and antibiotic susceptibility profiles among carbapenem-resistant Acinetobacter baumannii tested in the Antimicrobial Resistance Laboratory Network-United States, 2017-2020.

Acinetobacter baumannii is a Gram-negative bacillus that can cause severe and difficult-to-treat healthcare-associated infections. A. baumannii can harbor mobile genetic elements carrying genes that produce carbapenemase enzymes, further limiting therapeutic options for infections. In the United States, the Antimicrobial Resistance Laboratory Network (AR Lab Network) conducts sentinel surveillance of carbapenem-resistant Acinetobacter baumannii (CRAB). Participating clinical laboratories sent CRAB isolates to the AR Lab Network for characterization, including antimicrobial susceptibility testing and molecular detection of class A (Klebsiella pneumoniae carbapenemase), class B (Active-on-Imipenem, New Delhi metallo-ß-lactamase, and Verona integron-encoded metallo-ß-lactamase), and class D (Oxacillinase, blaOXA-23-like, blaOXA-24/40-like, blaOXA-48-like, and blaOXA-58-like) carbapenemase genes. During 2017‒2020, 6,026 CRAB isolates from 45 states were tested for targeted carbapenemase genes; 1% (64 of 5,481) of CRAB tested for targeted class A and class B genes were positive, but 83% (3,351 of 4,041) of CRAB tested for targeted class D genes were positive. The number of CRAB isolates carrying a class A or B gene increased from 2 of 312 (<1%) tested in 2017 to 26 of 1,708 (2%) tested in 2020. Eighty-three percent (2,355 of 2,846) of CRAB with at least one of the targeted carbapenemase genes and 54% (271 of 500) of CRAB without were categorized as extensively drug resistant; 95% (42 of 44) of isolates carrying more than one targeted gene had difficult-to-treat susceptibility profiles. CRAB isolates carrying targeted carbapenemase genes present an emerging public health threat in the United States, and their rapid detection is crucial to improving patient safety.IMPORTANCEThe Centers for Disease Control and Prevention has classified CRAB as an urgent public health threat. In this paper, we used a collection of >6,000 contemporary clinical isolates to evaluate the phenotypic and genotypic properties of CRAB detected in the United States. We describe the frequency of specific carbapenemase genes detected, antimicrobial susceptibility profiles, and the distribution of CRAB isolates categorized as multidrug resistant, extensively drug-resistant, or difficult to treat. We further discuss the proportion of isolates showing susceptibility to Food and Drug Administration-approved agents. Of note, 84% of CRAB tested harbored at least one class A, B, or D carbapenemase genes targeted for detection and 83% of these carbapenemase gene-positive CRAB were categorized as extensively drug resistant. Fifty-four percent of CRAB isolates without any of these carbapenemase genes detected were still extensively drug-resistant, indicating that infections caused by CRAB are highly resistant and pose a significant risk to patient safety regardless of the presence of one of these carbapenemase genes.

Genetic retargeting of E3 ligases to enhance CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapies are medical breakthroughs in cancer treatment. However, treatment failure is often caused by CAR T cell dysfunction. Additional approaches are needed to overcome inhibitory signals that limit anti-tumor potency. Here, we developed bifunctional fusion "degrader" proteins that bridge one or more target proteins and an E3 ligase complex to enforce target ubiquitination and degradation. Conditional degradation strategies were developed using inducible degrader transgene expression or small molecule-dependent E3 recruitment. We further engineered degraders to block SMAD-dependent TGFß signaling using a domain from the SARA protein to target both SMAD2 and SMAD3. SMAD degrader CAR T cells were less susceptible to suppression by TGFß and demonstrated enhanced anti-tumor potency in vivo. These results demonstrate a clinically suitable synthetic biology platform to reprogram E3 ligase target specificity for conditional, multi-specific endogenous protein degradation, with promising applications including enhancing the potency of CAR T cell therapy.

Chemical genetic control of cytokine signaling in CAR-T cells using lenalidomide-controlled membrane-bound degradable IL-7.

CAR-T cell therapy has emerged as a breakthrough therapy for the treatment of relapsed and refractory hematologic malignancies. However, insufficient CAR-T cell expansion and persistence is a leading cause of treatment failure. Exogenous or transgenic cytokines have great potential to enhance CAR-T cell potency but pose the risk of exacerbating toxicities. Here we present a chemical-genetic system for spatiotemporal control of cytokine function gated by the off-patent anti-cancer molecular glue degrader drug lenalidomide and its analogs. When co-delivered with a CAR, a membrane-bound, lenalidomide-degradable IL-7 fusion protein enforced a clinically favorable T cell phenotype, enhanced antigen-dependent proliferative capacity, and enhanced in vivo tumor control. Furthermore, cyclical pharmacologic combined control of CAR and cytokine abundance enabled the deployment of highly active, IL-7-augmented CAR-T cells in a dual model of antitumor potency and T cell hyperproliferation.

TheiaEuk: a species-agnostic bioinformatics workflow for fungal genomic characterization.

Introduction: The clinical incidence of antimicrobial-resistant fungal infections has dramatically increased in recent years. Certain fungal pathogens colonize various body cavities, leading to life-threatening bloodstream infections. However, the identification and characterization of fungal isolates in laboratories remain a significant diagnostic challenge in medicine and public health. Whole-genome sequencing provides an unbiased and uniform identification pipeline for fungal pathogens but most bioinformatic analysis pipelines focus on prokaryotic species. To this end, TheiaEuk_Illumina_PE_PHB (TheiaEuk) was designed to focus on genomic analysis specialized to fungal pathogens. Methods: TheiaEuk was designed using containerized components and written in the workflow description language (WDL) to facilitate deployment on the cloud-based open bioinformatics platform Terra. This species-agnostic workflow enables the analysis of fungal genomes without requiring coding, thereby reducing the entry barrier for laboratory scientists. To demonstrate the usefulness of this pipeline, an ongoing outbreak of C. auris in southern Nevada was investigated. We performed whole-genome sequence analysis of 752 new C. auris isolates from this outbreak. Furthermore, TheiaEuk was utilized to observe the accumulation of mutations in the FKS1 gene over the course of the outbreak, highlighting the utility of TheiaEuk as a monitor of emerging public health threats when combined with whole-genome sequencing surveillance of fungal pathogens. Results: A primary result of this work is a curated fungal database containing 5,667 unique genomes representing 245 species. TheiaEuk also incorporates taxon-specific submodules for specific species, including clade-typing for Candida auris (C. auris). In addition, for several fungal species, it performs dynamic reference genome selection and variant calling, reporting mutations found in genes currently associated with antifungal resistance (FKS1, ERG11, FUR1). Using genome assemblies from the ATCC Mycology collection, the taxonomic identification module used by TheiaEuk correctly assigned genomes to the species level in 126/135 (93.3%) instances and to the genus level in 131/135 (97%) of instances, and provided zero false calls. Application of TheiaEuk to actual specimens obtained in the course of work at a local public health laboratory resulted in 13/15 (86.7%) correct calls at the species level, with 2/15 called at the genus level. It made zero incorrect calls. TheiaEuk accurately assessed clade type of Candida auris in 297/302 (98.3%) of instances. Discussion: TheiaEuk demonstrated effectiveness in identifying fungal species from whole genome sequence. It further showed accuracy in both clade-typing of C. auris and in the identification of mutations known to associate with drug resistance in that organism.

The use of whole-genome sequencing and development of bioinformatics to monitor overlapping outbreaks of Candida auris in southern Nevada.

A Candida auris outbreak has been ongoing in Southern Nevada since August 2021. In this manuscript we describe the sequencing of over 200 C. auris isolates from patients at several facilities. Genetically distinct subgroups of C. auris were detected from Clade I (3 distinct lineages) and III (1 lineage). Open-source bioinformatic tools were developed and implemented to aid in the epidemiological investigation. The work herein compares three methods for C. auris whole genome analysis: Nullarbor, MycoSNP and a new pipeline TheiaEuk. We also describe a novel analysis method focused on elucidating phylogenetic linkages between isolates within an ongoing outbreak. Moreover, this study places the ongoing outbreaks in a global context utilizing existing sequences provided worldwide. Lastly, we describe how the generated results were communicated to the epidemiologists and infection control to generate public health interventions.

Barriers to completion of expanded carrier screening in an inner city population.

PURPOSE: The American College of Medical Genetics and Genomics emphasizes a "consistent and equitable approach for offering carrier screening." At our academic center, publicly insured prenatal patients underwent universal expanded carrier screening (ECS) to promote equitable care. The aim of the study was to evaluate rates, time, and barriers to complete ECS. This was defined as post-test counseling and partner testing after a patient was found heterozygous for a pathogenic variant. METHODS: In this descriptive retrospective cohort study from 2018 to 2021, patients were offered ECS, consisting of 283 recessive and X-linked genes. Heterozygotes were contacted by genetic counselors (≤5 attempts) for education and partner testing. Rates of counseling, partner testing, diagnostic procedures, follow-up times, and barriers to completion were assessed. RESULTS: During this time, 643 women underwent ECS. Of these 643 women, 462 were heterozygotes and 326 of 462 had undergone counseling. Two hundred twenty-two of 462 partners obtained testing, with a median of 32 days from patient to partner result. Approximately 21 couples were heterozygous for the same pathogenic variant. One patient pursued diagnostic testing. CONCLUSION: ECS offers useful information; however, this study highlights significant barriers to completion. There was suboptimal patient follow-up and low partner screening, perhaps from insufficient time to educate and counsel. Future directions include implementing quality measures to ensure optimal completion.

Transient elastography and controlled attenuation parameter to evaluate hepatic steatosis and liver stiffness in postpartum patients.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) affects 30% of adults in the United States. Transient elastography (TE) (Fibroscan, Echosens, Paris, France) with controlled attenuation parameter (CAP) is a noninvasive way to evaluate liver steatosis and liver stiffness. The primary objective of this study was to assess prevalence of elevated liver stiffness and steatosis immediately postpartum. Furthermore, we sought to evaluate whether there were differences in rates of metabolic disorders of pregnancy (gestational diabetes mellitus (GDM), gestational hypertension, and preeclampsia) and pre-pregnancy conditions (type 2 diabetes mellitus (DM), chronic hypertension, and obesity) in those with elevated postpartum liver steatosis/liver stiffness. METHODS: IRB approved prospective cross-sectional study in which TE and liver function tests were performed 1-2 days postpartum. CAP ≥300 dB/m was classified as significant steatosis. Increased liver stiffness was defined as ≥7 kPa. Prevalence was determined by proportion of individuals undergoing TE/CAP who met criteria. Chi-square analysis was used to compare differences between groups. RESULTS: Eighty-nine patients were included: 20 (22%) had GDM, 13 (15%) had gestational hypertension, and 15 (17%) had preeclampsia. Women with kPa ≥7 were more likely to have ALT ≥25, type 2 diabetes, and preeclampsia (p < .05). Pre-gravid BMI, BMI at delivery, and GDM were not associated with increased kPa. Pregravid BMI ≥25 and chronic hypertension were associated with CAP ≥ 300 dB/m (p < .05). GDM, preeclampsia, and gestational hypertension were not associated with CAP ≥300 dB/m. CONCLUSIONS: Patients with preeclampsia, type 2 diabetes, and elevated ALT were more likely to have elevated postpartum liver stiffness. Pregravid BMI ≥25 and ≥30 were associated with increased liver steatosis, although did not impact liver stiffness. GDM was not associated with increased liver stiffness or steatosis. Consideration should be made for screening pregnant patients with preeclampsia, type 2 DM and overweight or obese BMI for liver disease in the postpartum period with potential for lifestyle intervention.

Opening Pandora's box: abnormal genetic carrier screening and need for lifetime follow-up.

OBJECTIVE: Expanded carrier screening (ECS) is rising in popularity because of its application in a diverse population, its decreasing cost, and efficiency.1 However, it has traditionally been used to assess fetal risk. The next generation sequencing ECS panel offered at our academic medical center consists of 283 genes associated with hereditary disorders. Of those, 20 (7.1%) are autosomal recessive conditions, notable for variable expression of the clinical phenotype in heterozygous carriers, which may increase maternal risk for malignancy, bleeding, cardiovascular, or rheumatologic disease. Another 21 (7.4%) are X-linked conditions. We aimed to evaluate the prevalence of variants that have a potential for maternal phenotypic expression and whether identification of specific variants prompted patients to pursue further care in our health system, namely comprehensive genetic counseling and further healthcare consults when recommended. STUDY DESIGN: An institutional review board-approved descriptive retrospective cohort study was performed in a New York City academic medical center at which reproductive aged women were offered universal ECS from 2018 to 2021 by their provider, inclusive of obstetrician-gynecologists, maternal-fetal medicine physicians, and genetic counselors. Pretest counseling was performed by the ordering provider. Patients found to carry mutations with the potential for maternal phenotypic expression were contacted by genetic counselors regarding their clinical risks. In addition, patients who were carriers for factor XI deficiency, Bernard Soulier syndrome, ataxia telangectesia, fumarase deficiency, Nijmegen breakage syndrome, Duchenne muscular dystrophy, and familial hypercholesterolemia were advised to seek specialized healthcare pertaining to their clinical risk. The genetic counseling summary was placed in the electronic medical records (EMRs) so that the primary provider could view the findings. Through our EMRs, we evaluated the rates of healthcare uptake among these patients for at least 1 year after delivery. RESULTS: In total, 168 of 1184 (14.2%) patients were identified as carriers of mutations with a potential for maternal phenotypic expression. Of these, 156 (93%) were pregnant and 12 (7%) were preconception. Of those patients, 143 (85%) were carriers of autosomal recessive traits (Figure 1), whereas 22 of 168 (13%) patients were carriers of X-linked conditions (Figure 2) and 3 of 168 (2%) patients carried both autosomal recessive traits and X-linked conditions. Of these carriers, 132 of 168 (78.6%) patients underwent genetic counseling. The most common heterozygous mutations were sickle cell trait (25.6%), thalassemia (alpha and/or beta) trait (14.2%), factor XI deficiency (4.7%), dystrophic epidermolysis bullosa (4.2%), and Alport syndrome (4.1%). Two patients were diagnosed as homozygous carriers of nonclassical congenital adrenal hyperplasia. During the study period, 23 of 168 (13.6%) patients were heterozygous for specific pathogenic variants (inclusive of factor XI, Bernard Soulier syndrome, ataxia telangectesia, fumarase deficiency, Nijmegen breakage syndrome, Duchenne muscular dystrophy, and familial hypercholesterolemia) and were advised to seek specialized healthcare pertaining to these findings. Of these, 20 (87.0%) received genetic counseling with standardized recommendations, however, only 4 of 23 (17%) patients pursued the recommended referrals during our study period. CONCLUSION: This study described the follow-up rates among patients identified as carriers of conditions with the potential for maternal phenotypic expression using ECS. We observed that 14.2% of patients who underwent ECS were identified as carriers of genetic mutations with the potential for maternal phenotypic expression, and of the 23 who were recommended specific care because a pathogenic variant was identified, only 17.4% of patients followed the recommendations. We believe that as ECS implementation becomes widespread, more maternal carriers with clinical risk to themselves will be identified. Therefore, as we open this Pandora's box, the burden of counseling and follow-up must be addressed.

COVID-19 Vaccination in Palestine/Israel: Citizenship, Capitalism, and the Logic of Elimination.

Despite Israel's responsibility under international law to combat the spread of contagious diseases and epidemics in its occupied territories, Israeli officials have refused to distribute COVID-19 vaccines to Palestinians in the West Bank and Gaza Strip. Through a critical discourse analysis of Israeli officials' statements regarding Israel's COVID-19 vaccination campaign, this paper explores how Israel evades this responsibility while presenting itself as committed to public health and human rights. We find that Israeli officials strategically present Palestinians as an autonomous nation when discussing COVID-19 vaccinations, despite Israel's ongoing attempts to prevent the creation of a Palestinian state. Relatedly, Israel justifies its refusal to vaccinate Palestinians on the grounds of the Palestinian Authority's economic independence, thereby obscuring Israel's control over the Palestinian economy. In this way, Israel relies on citizenship and economic inequality, as internationally sanctioned forms of exclusion, to deny Palestinians their right to health. Drawing on theorists such as Michel Foucault, Achille Mbembe, and Jasbir Puar, we argue that withholding vaccines from Palestinians reveals the ways that Israel furthers its settler-colonial aims under the guise of liberal humanitarianism and economic growth. Instead of directing these conclusions toward Israel as an exceptional case, we contend that these processes reveal how settler-colonial societies use liberal frameworks of citizenship and capitalism to carry out their racialized projects of elimination.

In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer.

The immune system can eliminate tumors, but checkpoints enable immune escape. Here, we identify immune evasion mechanisms using genome-scale in vivo CRISPR screens across cancer models treated with immune checkpoint blockade (ICB). We identify immune evasion genes and important immune inhibitory checkpoints conserved across cancers, including the non-classical major histocompatibility complex class I (MHC class I) molecule Qa-1b/HLA-E. Surprisingly, loss of tumor interferon-γ (IFNγ) signaling sensitizes many models to immunity. The immune inhibitory effects of tumor IFN sensing are mediated through two mechanisms. First, tumor upregulation of classical MHC class I inhibits natural killer cells. Second, IFN-induced expression of Qa-1b inhibits CD8+ T cells via the NKG2A/CD94 receptor, which is induced by ICB. Finally, we show that strong IFN signatures are associated with poor response to ICB in individuals with renal cell carcinoma or melanoma. This study reveals that IFN-mediated upregulation of classical and non-classical MHC class I inhibitory checkpoints can facilitate immune escape.

Identification of novel γ-globin inducers among all potential erythroid druggable targets.

Human γ-globin is predominantly expressed in fetal liver erythroid cells during gestation from 2 nearly identical genes, HBG1 and HBG2, that are both perinatally silenced. Reactivation of these fetal genes in adult red blood cells can ameliorate many symptoms associated with the inherited ß-globinopathies, sickle cell disease, and Cooley anemia. Although promising genetic strategies to reactivate the γ-globin genes to treat these diseases have been explored, there are significant barriers to their effective implementation worldwide; alternatively, pharmacological induction of γ-globin synthesis could readily reach the majority of affected individuals. In this study, we generated a CRISPR knockout library that targeted all erythroid genes for which prospective or actual therapeutic compounds already exist. By probing this library for genes that repress fetal hemoglobin (HbF), we identified several novel, potentially druggable, γ-globin repressors, including VHL and PTEN. We demonstrate that deletion of VHL induces HbF through activation of the HIF1α pathway and that deletion of PTEN induces HbF through AKT pathway stimulation. Finally, we show that small-molecule inhibitors of PTEN and EZH induce HbF in both healthy and ß-thalassemic human primary erythroid cells.

Rapid Assessment and Containment of Candida auris Transmission in Postacute Care Settings-Orange County, California, 2019.

BACKGROUND: Candida auris, a multidrug-resistant yeast, can spread rapidly in ventilator-capable skilled-nursing facilities (vSNFs) and long-term acute care hospitals (LTACHs). In 2018, a laboratory serving LTACHs in southern California began identifying species of Candida that were detected in urine specimens to enhance surveillance of C auris, and C auris was identified in February 2019 in a patient in an Orange County (OC), California, LTACH. Further investigation identified C auris at 3 associated facilities. OBJECTIVE: To assess the prevalence of C auris and infection prevention and control (IPC) practices in LTACHs and vSNFs in OC. DESIGN: Point prevalence surveys (PPSs), postdischarge testing for C auris detection, and assessments of IPC were done from March to October 2019. SETTING: All LTACHs (n = 3) and vSNFs (n = 14) serving adult patients in OC. PARTICIPANTS: Current or recent patients in LTACHs and vSNFs in OC. INTERVENTION: In facilities where C auris was detected, PPSs were repeated every 2 weeks. Ongoing IPC support was provided. MEASUREMENTS: Antifungal susceptibility testing and whole-genome sequencing to assess isolate relatedness. RESULTS: Initial PPSs at 17 facilities identified 44 additional patients with C auris in 3 (100%) LTACHs and 6 (43%) vSNFs, with the first bloodstream infection reported in May 2019. By October 2019, a total of 182 patients with C auris were identified by serial PPSs and discharge testing. Of 81 isolates that were sequenced, all were clade III and highly related. Assessments of IPC identified gaps in hand hygiene, transmission-based precautions, and environmental cleaning. The outbreak was contained to 2 facilities by October 2019. LIMITATION: Acute care hospitals were not assessed, and IPC improvements over time could not be rigorously evaluated. CONCLUSION: Enhanced laboratory surveillance and prompt investigation with IPC support enabled swift identification and containment of C auris. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

A new murine Rpl5 (uL18) mutation provides a unique model of variably penetrant Diamond-Blackfan anemia.

Ribosome dysfunction is implicated in multiple abnormal developmental and disease states in humans. Heterozygous germline mutations in genes encoding ribosomal proteins are found in most individuals with Diamond-Blackfan anemia (DBA), whereas somatic mutations have been implicated in a variety of cancers and other disorders. Ribosomal protein-deficient animal models show variable phenotypes and penetrance, similar to human patients with DBA. In this study, we characterized a novel ENU mouse mutant (Skax23m1Jus) with growth and skeletal defects, cardiac malformations, and increased mortality. After genetic mapping and whole-exome sequencing, we identified an intronic Rpl5 mutation, which segregated with all affected mice. This mutation was associated with decreased ribosome generation, consistent with Rpl5 haploinsufficiency. Rpl5Skax23-Jus/+ animals had a profound delay in erythroid maturation and increased mortality at embryonic day (E) 12.5, which improved by E14.5. Surviving mutant animals had macrocytic anemia at birth, as well as evidence of ventricular septal defect (VSD). Surviving adult and aged mice exhibited no hematopoietic defect or VSD. We propose that this novel Rpl5Skax23-Jus/+ mutant mouse will be useful in studying the factors influencing the variable penetrance that is observed in DBA.

An erythroid-to-myeloid cell fate conversion is elicited by LSD1 inactivation.

Histone H3 lysine 4 methylation (H3K4Me) is most often associated with chromatin activation, and removing H3K4 methyl groups has been shown to be coincident with gene repression. H3K4Me demethylase KDM1a/LSD1 is a therapeutic target for multiple diseases, including for the potential treatment of ß-globinopathies (sickle cell disease and ß-thalassemia), because it is a component of γ-globin repressor complexes, and LSD1 inactivation leads to robust induction of the fetal globin genes. The effects of LSD1 inhibition in definitive erythropoiesis are not well characterized, so we examined the consequences of conditional inactivation of Lsd1 in adult red blood cells using a new Gata1creERT2 bacterial artificial chromosome transgene. Erythroid-specific loss of Lsd1 activity in mice led to a block in erythroid progenitor differentiation and to the expansion of granulocyte-monocyte progenitor-like cells, converting hematopoietic differentiation potential from an erythroid fate to a myeloid fate. The analogous phenotype was also observed in human hematopoietic stem and progenitor cells, coincident with the induction of myeloid transcription factors (eg, PU.1 and CEBPα). Finally, blocking the activity of the transcription factor PU.1 or RUNX1 at the same time as LSD1 inhibition rescued myeloid lineage conversion to an erythroid phenotype. These data show that LSD1 promotes erythropoiesis by repressing myeloid cell fate in adult erythroid progenitors and that inhibition of the myeloid-differentiation pathway reverses the lineage switch induced by LSD1 inactivation.

Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.

Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape1,2. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape3-5. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.

Management of Intravenous Infiltration Injuries.

BACKGROUND: Intravenous (IV) lines are ubiquitous in hospital settings. These lines can malfunction, leaking noxious contents into subcutaneous tissue. Existing literature describes invasive intervention and complex treatment protocols. These persist despite significant changes in the composition and administration of IV agents. The purpose of this study is to examine the consequences of IV infiltrations at a tertiary medical center to update protocols and treatment algorithms. MATERIALS AND METHODS: This study is an observational, retrospective chart review performed at a tertiary care medical center. All inpatient plastic surgery consultations for IV infiltration were reviewed from 2011 to 2017. Patients were included if IV infiltration was suspected or documented. Data were collected for each injury regarding patient demographics, substance, and intervention. RESULTS: The plastic surgery service evaluated 381 IV infiltration injuries from 2011 to 2017, with 363 meeting the criteria. Injuries per year progressively increased, with 32 consultations in 2011 and 102 consultations in 2017. The vast majority of injuries identified (91%) were treated with only elevation and observation. The minority consisted of wound care (7%) performed by nursing or any form of incision, aspiration, or antidote injection (2%) performed by the physician. Of the 363 injuries, the most common infiltrates were noncytotoxic (35%), radiographic contrast (27%), and known vesicants (18%). Interestingly, a large portion of consultations were requested by other surgical services (32%). CONCLUSIONS: Although there is an increase in expert involvement for cases of IV infiltration injuries, the vast majority of these injuries are managed with minimal intervention. This is most likely owing to recent changes that have decreased the potential for harmful infiltration. Contrary to existing literature, invasive intervention is almost never indicated.

Egocentric social networks and smoking among adults with serious mental illness.

Evidence-based smoking cessation treatment is safe and effective for smokers with serious mental illness (SMI); however, quit rates remain low in this population. We explored how social networks influence smoking outcomes among people with SMI who participated in smoking cessation treatment at community mental health centers. We conducted egocentric social network interviews with 41 individuals with SMI who participated in a statewide Medicaid demonstration project of smoking cessation treatment. We estimated the proportions of current smokers, former smokers, and never smokers in participants' (i.e., egos') networks and examined support for quitting from alters, defined as family, friends, peers, or significant others. We used logistic regression and mixed-effect logistic regression to explore the relationship between social network variables and ego's smoking status following cessation treatment. Egos reported an average of 5.9 ± 2.2 alters; 52% of alters were current smokers; 18% were former smokers; and 30% never smoked. The majority (57%) of alters helped an ego quit smoking. The presence of former smokers in the network was associated with decreased odds that the ego was smoking post-treatment. Egos whose friends were highly interconnected were less likely to smoke after treatment. Former smokers in the network may be a valuable resource for quitting particularly for vulnerable groups where there is a high prevalence and acceptability of smoking. Our initial findings suggest that a highly interconnected friendship network structure may be beneficial for people with SMI who are trying to quit smoking.

Nitrous oxide for pain management during in-office hysteroscopic sterilization: a randomized controlled trial.

OBJECTIVES: To evaluate whether inhaled nitrous oxide with oxygen (N2O/O2) is associated with less pain compared to oral sedation for pain management during in-office hysteroscopic sterilization. STUDY DESIGN: This double blinded randomized controlled trial enrolled women undergoing in-office hysteroscopic sterilization. All participants received pre-procedure intramuscular ketorolac and a standardized paracervical block. The intervention group also received N2O/O2 via a nasal mask titrated to a maximum 70%:30% mixture by a nurse during the procedure and placebo pills pre-procedure and the active control group received inhaled O2 during the procedure and 5/325 mg hydrocodone/acetaminophen and 1 mg lorazepam pre-procedure. The primary outcome was maximum procedure pain on a 100 mm Visual Analog Scale (VAS with anchors at 0=no pain and 100=worst imaginable pain) assessed 3-5 min post procedure. Thirty women per treatment arm were required to detect a clinically significant pain difference of 20 mm. RESULTS: Seventy-two women, 36 per study arm, were randomized. Mean age of participants was 34.1±5.7 years and mean BMI was 30.1±6.6kg/m2. Mean maximum procedure pain scores were 22.8±27.6 mm and 54.5±32.7 mm for intervention and control groups, respectively (p<.001). Most study participants (97%) stated N2O/O2 should be offered for gynecologic office procedures and 86% would pay for it if not a covered benefit. CONCLUSIONS: N2O/O2 decreased pain with in-office hysteroscopic sterilization compared to oral sedation and is an effective pain management option for this procedure. IMPLICATIONS: Given its safety and favorable side effect profile, N2O/O2 can be used for pain management for in-office hysteroscopic sterilization and adds a safe, easily administered option to currently available strategies.

A randomized controlled trial of nitrous oxide for intrauterine device insertion in nulliparous women.

OBJECTIVE: To evaluate the effectiveness of inhaled nitrous oxide for pain management among nulliparous women undergoing intrauterine device (IUD) insertion. METHODS: A double-blind, randomized controlled trial was conducted among nulliparous women aged 13-45years who underwent IUD insertion at a US center between October 1, 2013, and August 31, 2014. Using a computer-generated randomization sequence, participants were randomly assigned to inhale either oxygen (O2) or a mixture of 50% nitrous oxide and 50% oxygen (N2O/O2) through a nasal mask for 2minutes before insertion. Only the person administering the inhalation agent was aware of group assignment. The primary outcome was maximum pain assessed 2minutes after insertion via a 100-mm visual analog scale. Analyses were by intention to treat. RESULTS: Forty women were assigned to each group. Mean maximum pain score at the time of insertion was 54.3±24.8mm for the N2O/O2 group and 55.3±20.9mm for the O2 group (P=0.86). Adverse effects were reported for 6 (15%) women in the N2O/O2 group and 7 (18%) in the O2 group (P=0.32). CONCLUSION: N2O/O2 did not reduce the pain of IUD insertion among nulliparous women. ClinicalTrials.gov: NCT02391714.