Nontypeable Haemophilus influenzae challenge during gammaherpesvirus infection enhances viral reactivation and latency.

Gammaherpesviruses are ubiquitous, lifelong pathogens associated with multiple cancers that infect over 95% of the adult population. Increases in viral reactivation, due to stress and other unknown factors impacting the immune response, frequently precedes lymphomagenesis. One potential stressor that could promote viral reactivation and increase viral latency would be the myriad of infections from bacterial and viral pathogens that we experience throughout our lives. Using murine gammaherpesvirus 68 (MHV68), a mouse model of gammaherpesvirus infection, we examined the impact of bacterial challenge on gammaherpesvirus infection. We challenged MHV68 infected mice during the establishment of latency with nontypeable Haemophilus influenzae (NTHi) to determine the impact of bacterial infection on viral reactivation and latency. Mice infected with MHV68 and then challenged with NTHi, saw increases in viral reactivation and viral latency. These data support the hypothesis that bacterial challenge can promote gammaherpesvirus reactivation and latency establishment, with possible consequences for viral lymphomagenesis.

Peri-mortem rigidity in a fatal case of severe salicylate poisoning.

INTRODUCTION: There has been a previous case report of peri-arrest muscle rigidity in the setting of severe salicylate poisoning (serum salicylate concentration 1,500 mg/L), described as paratonia or rapid rigor mortis. We present an image of rapid rigor mortis in another fatal salicylate poisoning. CASE SUMMARY: We report a 42-year-old male with severe salicylate poisoning (peak salicylate concentration 1,600 mg/L). During the peri-arrest period, the patient developed isotonic flexion of the upper and lower extremities, the clinical signs of rapid-occurring rigor mortis. Despite resuscitative efforts, the patient died. IMAGE: Our patient is exhibiting peri-arrest rigidity in the upper extremities. DISCUSSION: Peri-mortem rigidity is due to depletion of adenosine triphosphate. Severe salicylate poisoning causes uncoupling of oxidative phosphorylation which prevents the production of adenosine triphosphate, which is required to release myosin from actin to allow the muscle to relax. A limitation of our report is that we did not definitively exclude other uncouplers of oxidative phosphorylation, such as 2,4-dinitrophenol. However, the history of aspirin ingestion was provided by the patient and corroborated by his mother, and it was confirmed by measurement of his salicylate concentration. CONCLUSION: We hypothesize that in our patient, rapid-occurring rigor mortis likely resulted from depletion of adenosine triphosphate. This occurred as a result of uncoupling of oxidative phosphorylation in the mitochondria from severe salicylate poisoning, as adenosine triphosphate is required for muscle relaxation.

Precipitated opioid withdrawal in a patient started on olanzapine/samidorphan.

BACKGROUND: Olanzapine/Samidorphan (Lybalvi®) is a novel oral agent for the treatment of schizophrenia and bipolar I disorder. It was designed to reduce weight gain associated with olanzapine. Samidorphan is an analog of naltrexone, initially intended to treat substance use disorders by antagonizing mu, delta, and kappa opioid receptors. CASE REPORT: We present the case of a 36-year-old who took their first dose of olanzapine/samidorphan shortly before calling for emergency services. The patient took diphenhydramine and an epinephrine autoinjector for what they thought was an allergic reaction but continued to have symptoms. EMS reported involuntary muscle movements thought to be due to dystonia from olanzapine. In the ED, they experienced generalized muscle spasms lasting for several seconds and diaphoresis. Initially, the staff treated for a presumed dystonic reaction to olanzapine and administered diphenhydramine 25 mg IV, diazepam 2 mg IV, midazolam 5 mg IV, and benztropine 1 mg IV without improvement. It was later determined that the patient took 16 mg of buprenorphine SL daily. With this information, precipitated opioid withdrawal was felt to be the likely cause of symptoms. The patient received 16 mg of buprenorphine for an initial Clinical Opiate Withdrawal Scale (COWS) score of 11 with repeat COWS of 6. Why should an emergency physician be aware of this? Initiating olanzapine/samidorphan in the setting of chronic opioid therapy may result in precipitated opioid withdrawal. Additional SL buprenorphine may be a reasonable treatment modality.

Prolonged venom-induced consumptive coagulopathy following Mangshan pit viper (Protobothrops mangshanensis) envenomation despite Hemato Polyvalent antivenom administration.

This case report summarizes an envenomation by the Mangshan pit viper (Protobothrops mangshanensis), a rare, endangered, venomous snake endemic to Mount Mang of China, and the first reported use of Hemato Polyvalent antivenom (HPAV) for this species. The snakebite occurred in a United States zoo to a 46-year-old male zookeeper. He presented via emergency medical services to a tertiary center after sustaining a single P. mangshanensis bite to the abdomen and was transported with antivenom from the zoo. Within 2 hours of envenomation, he developed oozing of sanguineous fluid and ecchymosis at the puncture site, and about 4 hours post-bite, was treated with HPAV. His coagulation profile fluctuated with the following pertinent peak/nadir laboratory values and corresponding hospital day (HD): undetectable fibrinogen levels, d-dimer 8.89 mg/L and 7.43 mg/L, and INR 2.97 and 1.46 on HD zero and three, respectively. Other peak/nadir values included hemoglobin 9.7 g/dL and creatinine phosphokinase 2410 U/L on HD four and platelets 81 × 109/L on HD seven. The patient received a total of 30 vials of HPAV over 5 days and 1 unit of cryoprecipitate on HD six. Upon discharge on HD eight, laboratory studies were normalizing, except for platelets, and edema stabilized. This case describes an acute, recurrent, and prolonged venom-induced consumptive coagulopathy despite prompt administration and repeated doses of HPAV.

Outcomes of Emergency Department Patients With Opioid Use Disorder Utilizing a Virtual Addiction Bridge Clinic: A Case Series.

OBJECTIVES: Within the last decade, there has been a dramatic increase in the rate of emergency department (ED) visits and death from opioid overdose. Those who present to the ED are at high risk for subsequent morbidity and mortality. Despite effective treatment, many patients do not get rapidly connected to outpatient care. The aim of this investigation was to describe outpatient treatment engagement after ED discharge among patients with opioid use disorder (OUD) enrolled in a virtual Addiction Bridge Clinic (ABC). METHODS: This was a retrospective case series describing an ED-initiated referral for rapid telehealth follow-up among patients with OUD. The primary outcome was addiction treatment engagement among those who completed the initial virtual ABC visit (engaged in ABC) vs. those who did not complete an ABC visit (Not engaged in ABC) at 1 week, 1 month, and 3 and 6 months timepoint intervals after the initial ED presentation. RESULTS: Of the N = 201 patients referred to the ABC between March and December 2021, a majority were Black (71%) and male (77%). Of the 201 referrals, 85 (42%) completed an initial ABC telehealth visit. Subsequent treatment engagement was 26% at 1 week, 26% at 1 month, 22% at 3 months, and 18% at 6 months after the index ED visit. CONCLUSIONS: A telehealth-enabled virtual addiction bridge clinic is one potential approach to reduce barriers to rapid treatment access. Strategies are needed to improve subsequent addiction treatment engagement after a virtual addiction bridge clinic visit.

Phase variable acetylation of lipooligosaccharide modifies antibody production and opsonophagocytic killing of non-typeable Haemophilus influenzae.

Non-typeable Haemophilus influenzae (NTHi) causes millions of infections each year. Though it is primarily known to cause otitis media, recent studies have shown NTHi is emerging as a primary pathogen for invasive infection, prompting the need for new vaccines and treatments. Lipooligosaccharide (LOS) has been identified as a potential vaccine candidate due to its immunogenic nature and outer membrane localization. Yet, phase variable expression of genes involved in LOS synthesis has complicated vaccine development. In this study, we used a chinchilla model of otitis media to investigate how phase variation of oafA, a gene involved in LOS biosynthesis, affects antibody production in response to infection. We found that acetylation of LOS by OafA inhibited production of LOS-specific antibodies during infection and that NTHi expressing acetylated LOS were subsequently better protected against opsonophagocytic killing. These findings highlight the importance of understanding how phase variable modifications might affect vaccine efficacy and success.

Identification of Virulence Factors Involved in a Murine Model of Severe Achromobacter xylosoxidans Infection.

Achromobacter xylosoxidans (Ax) is an opportunistic pathogen and causative agent of numerous infections particularly in immunocompromised individuals with increasing prevalence in cystic fibrosis (CF). To date, investigations have focused on the clinical epidemiology and genomic comparisons of Ax isolates, yet little is known about disease pathology or the role that specific virulence factors play in tissue invasion or damage. Here, we model an acute Ax lung infection in immunocompetent C57BL/6 mice and immunocompromised CF mice, revealing a link between in vitro cytotoxicity and disease in an intact host. Mice were intratracheally challenged with sublethal doses of a cytotoxic (GN050) or invasive (GN008) strain of Ax. Bacterial burden, immune cell populations, and inflammatory markers in bronchoalveolar lavage fluid and lung homogenates were measured at different time points to assess disease severity. CF mice had a similar but delayed immune response toward both Ax strains compared to C57BL/6J mice. GN050 caused more severe disease and higher mortality which correlated with greater bacterial burden and increased proinflammatory responses in both mouse models. In agreement with the cytotoxicity of GN050 toward macrophages in vitro, mice challenged with GN050 had fewer macrophages. Mutants with transposon insertions in predicted virulence factors of GN050 showed that disease severity depended on the type III secretion system, Vi capsule, antisigma-E factor, and partially on the ArtA adhesin. The development of an acute infection model provides an essential tool to better understand the infectivity of diverse Ax isolates and enable improved identification of virulence factors important to bacterial persistence and disease.

Rapid induction onto extended-release injectable buprenorphine following opioid overdose: A case series.

Background: Buprenorphine treatment has been associated with reduced non-prescribed opioid use and opioid related overdose (OD). We evaluated initial outcomes of rapid induction onto extended-release injectable buprenorphine (BUP-XR) within 7 days of emergency department presentation for unintentional OD. Methods: Between February 2019-February 2021, N = 19 patients with opioid use disorder received buprenorphine/naloxone (4/1 mg), followed by BUP-XR (300 mg) at induction and continued BUP-XR outpatient for 6 months. Primary outcomes included adverse events, repeat OD, and death. Results: For patients who received at least one dose of BUP-XR, there were no treatment related serious adverse events or symptoms of precipitated withdrawal. In addition, there were no repeat visits for ODs or deaths within 6 months of the initial OD. Discussion: These preliminary findings support the need for larger controlled clinical trials to examine the safety and efficacy of rapid induction of BUP-XR in patients with opioid use disorder at high risk of opioid OD. Rapid induction onto long-lasting injectable buprenorphine may be a promising and protective treatment approach in the future.

Evaluation of Strontium Interference in Calcium Measurement Procedures and Content in Supplements as Measured by ICP-MS.

BACKGROUND: Bone health supplements containing strontium are available without prescription, however, the effects of strontium interference on clinical laboratory calcium measurement procedures are unknown. METHODS: To evaluate strontium interference on total calcium measurements, plasma pools with exogenously added strontium were measured by 3 total calcium measurement procedures. For ionized calcium measurements, whole blood pools prepared with exogenously added strontium were measured by 2 ionized calcium measurement procedures. An inductively coupled plasma mass spectrometry assay (ICP-MS) was validated for research measurements of strontium content in commercially available supplements. RESULTS: Exogenous strontium addition to plasma caused positive bias for total calcium measurements. Strontium concentrations of 1.0 mg/dL (0.114 mmol/L), 2.5 mg/dL (0.284 mmol/L), and 5.0 mg/Dl (0.568 mmol/L) resulted in mean biases of 1.9% to 3.5%, 4.9% to 9.0%, and 10.8% to 19.2%, respectively, for total calcium measurement procedures. Biases for ionized calcium measurements were less than 4.5% for a strontium concentration of 5.0 mg/dL (0.568 mmol/L). An in-house-developed ICP-MS assay for strontium in commercially available supplements exhibited within-laboratory and within-run coefficients of variation of less than 3%, and a linear response was obtained over the assay analytical measurement range of 10 to 100 000 ng/mL (0.0001 to 1.141 mmol/L). Strontium recovery for the ICP-MS assay was 97.1% to 105.3%. The largest amount of strontium measured in dietary supplements was 395 mg in a 1054 mg tablet. CONCLUSIONS: Some dietary supplements contain larger amounts of strontium than indicated on the product label. High concentrations of strontium may cause significant interference for total calcium measurement procedures, but ionized calcium measurement procedures are not significantly affected.

Clinical characteristics and outcomes using dexmedetomidine in nonintubated patients: A poison center observational study.

PURPOSE: Dexmedetomidine is a central α2 agonist commonly used on intubated patients. It is increasingly being used off-label in nonintubated agitated patients. We sought to determine the overall clinical course, adverse effects, and need for subsequent mechanical ventilation in toxicology patients after treatment with dexmedetomidine. METHODS: This was a retrospective cohort study conducted by chart review of electronic records from the Virginia Poison Control Center from January 1, 2019 to February 4, 2022. Inclusion criteria consisted of all poison center cases where dexmedetomidine was used. The primary outcome was the presence or absence of clinical improvement following dexmedetomidine use. Secondary outcomes included adverse effects, subsequent intubation, or death. RESULTS: During this study period, there were 220 cases in which dexmedetomidine was used to treat agitation. After exclusions, 70 cases were analyzed. The categories included antimuscarinic (n = 19), polysubstance (n = 16), sedative withdrawal (n = 10), unknown agitation (n = 7), sympathomimetic (n = 5), baclofen withdrawal (n = 3), unknown ingestion (n = 3), sedative/hypnotic (n = 2), antipsychotic (n = 2), hallucinogenic (n = 2), and opioid withdrawal (n = 1). Clinical improvement occurred in 62 of 70 patients (89%). There were no deaths. A total of 4 patients were intubated after starting dexmedetomidine, 2 for refractory agitation and 2 for hypoxia after aspiration. CONCLUSION: Global clinical improvement was observed in the agitated toxicology patients administered dexmedetomidine. There was one case of intubation secondary to oversedation. Dexmedetomidine could be a useful adjunctive treatment for agitated toxicologic patients but should be studied further before routinely used.

Adherence of Nontypeable Haemophilus influenzae to Cells and Substrates of the Airway Is Differentially Regulated by Individual ModA Phasevarions.

Adherence of nontypeable Haemophilus influenzae (NTHi) to the host airway is an essential initial step for asymptomatic colonization of the nasopharynx, as well as development of disease. NTHi relies on strict regulation of multiple adhesins for adherence to host substrates encountered in the airway. NTHi encode a phase-variable cytoplasmic DNA methyltransferase, ModA, that regulates expression of multiple genes; a phasevarion (phase-variable regulon). Multiple modA alleles are present in NTHi, in which different alleles methylate a different DNA target, and each controls a different set of genes. However, the role of ModA phasevarions in regulating adherence of NTHi to the host airway is not well understood. This study therefore sought to investigate the role of four of the most prevalent ModA phasevarions in the regulation of adherence of NTHi to multiple substrates of the airway. Four clinical isolates of NTHi with unique modA alleles were tested in this study. The adherence of NTHi to mucus, middle ear epithelial cells, and vitronectin was regulated in a substrate-specific manner that was dependent on the ModA allele encoded. The adhesins Protein E and P4 were found to contribute to the ModA-regulated adherence of NTHi to distinct substrates. A better understanding of substrate-specific regulation of NTHi adherence by ModA phasevarions will allow identification of NTHi populations present at the site of disease within the airway and facilitate more directed development of vaccines and therapeutics. IMPORTANCE Nontypeable Haemophilus influenzae (NTHi) is a predominant pathogen of the human airway that causes respiratory infections such as otitis media (OM) and exacerbations in the lungs of patients suffering from chronic obstructive pulmonary disease (COPD). Due to the lack of a licensed vaccine against NTHi and the emergence of antibiotic-resistant strains, it is extremely challenging to target NTHi for treatment. NTHi adhesins are considered potential candidates for vaccines or other therapeutic approaches. The ModA phasevarions of NTHi play a role in the rapid adaptation of the pathogen to different environmental stress conditions. This study addressed the role of ModA phasevarions in the regulation of adherence of NTHi to specific host substrates found within the respiratory tract. The findings of this study improve our understanding of regulation of adherence of NTHi to the airway, which may further be used to enhance the potential of adhesins as vaccine antigens and therapeutic targets against NTHi.

Retained bullets and lead toxicity: a systematic review.

INTRODUCTION: Lead toxicity secondary to retained bullet(s) (RB) after a penetrating gunshot wound is a rare but likely underdiagnosed condition, given the substantial number of firearm injuries in the United States. There is currently no consensus on the indications for surveillance, chelation, or surgical intervention. OBJECTIVE: The purpose of our review is to summarize the literature on systemic lead toxicity secondary to RBs to help guide clinicians in the management of these patients. METHODOLOGY: The primary literature search was conducted in Medline (PubMed), EMBASE, Cochrane, and CENTRAL using the following MESH terms: "chelation" and "lead poisoning" or "lead toxicity" or "lead" and "bullet" or "missile" or "gunshot", or "bullet". RESULTS: The search identified 1,082 articles. After exclusions, a total of 142 articles were included in our final review, the majority of which were case reports. Several factors appear to increase the risk of developing lead toxicity including the location of the RB, the presence of a fracture or recent trauma, number of fragments, hypermetabolic states, and bullet retention duration. Particularly, RBs located within a body fluid compartment like an intra-articular space appear to be at a substantially higher risk of developing lead toxicity. Even though patients with lead toxicity from RBs will have similar symptoms to patients with lead toxicity from other sources, the diagnosis of lead poisoning may occur months or years after a gunshot wound. Symptomatic patients with high blood lead levels (BLLs) tended to improve with a combination of chelation and surgical removal of RBs. CONCLUSIONS: We suggest surveillance with serial BLLs should be performed. Patients with intra-articular RBs appear to be at increased risk of lead toxicity and if possible, early surgical removal of the RBs is warranted, especially given that signs of toxicity are vague, and patients may not have access to follow-up. Long-term chelation should not be used as a surgical alternative and management should be multidisciplinary.

Social determinants of health and emergency department utilization among adults receiving buprenorphine for opioid use disorder.

Background: Individuals with opioid use disorder (OUD) use the emergency department (ED) at high rates. Medication treatment for OUD (MOUD) is associated with reduced ED utilization. However, individuals receiving MOUD still utilize ED services at higher rates than the general population. The objective of this study is to compare the psychosocial and clinical characteristics of those who do and do not utilize ED services based on the Healthy People 2030 framework regarding social determinants of health (SDoH) among a sample of individuals receiving MOUD. Methods: Participants receiving buprenorphine for OUD at an outpatient addiction clinic completed a cross-sectional survey between July and September 2019. A 6-month prospective medical record review was conducted. The primary outcome was ED visit (yes/no) during the 6-month study period. Demographic, psychosocial, and clinical characteristics were gathered from survey measures and chart abstraction. Chi square and T-tests tested differences by ED utilization. Results: Participants (n=142) were 54.9% female and 68.8% Black, with an average age of 43.2 years (SD=12.5). Of the participants, 38.7% visited the ED in the study period, primarily for infectious or musculoskeletal causes. Participants with an ED visit were more likely to be Black (p=.011), have less social support (p=.030), more medical comorbidities (p=.008) including chronic pain (p=.045), and more visits with an addiction provider in the study period (p=.009). Conclusions: Factors associated with ED utilization among individuals receiving buprenorphine for OUD include low social support and medical comorbidities, including chronic pain. More research is needed on modifiable SDoH that influence ED utilization.

Systemic toxicity from subcutaneous brimonidine injection successfully treated with naloxone.

Brimonidine is a topical ophthalmic alpha-2 adrenergic agonist solution used to treat glaucoma. The toxidrome includes drowsiness, lethargy, hypotension, bradycardia, and respiratory depression when ingested in infants. We report a case of intentional subcutaneous injection of brimonidine in an elderly patient resulting in hypotension and CNS depression that responded to naloxone. A 73-year-old female with a past medical history significant for glaucoma, hypertension, and indwelling pacemaker presented to the emergency department after injecting her brimonidine tartrate ophthalmic solution subcutaneously (SQ). The patient was not taking any antihypertensive medications or opioids. Initial presentation consisted of lethargy, a paced rhythm of 60 bpm, and blood pressure of 91/24 mmHg with a MAP of 46. Due to central nervous system depression, 3 mg of intranasal naloxone was administered. The patient was treated with intravenous fluids and escalating doses of naloxone and required a continuous infusion. Mental status and vital signs subsequently improved. The patient was admitted to the ICU and naloxone was subsequently weaned over 12 h. Systemic central alpha-2 adrenergic agonist toxicity resulted from SQ brimonidine injection. Central alpha-2 adrenergic agonist overdoses present as sympatholytic effects including CNS depression, bradycardia, hypotension, and may mimic the opioid toxidrome. Brimonidine SQ injection has not previously been reported and this case has similar findings to other central alpha-2 adrenergic agonist poisonings. Naloxone has previously shown variable reversal of CNS depression in central alpha-2 overdose. In this case, high-dose naloxone was useful for reversing CNS depression and hemodynamic instability.

Pressure Necrosis Requiring Fasciotomy After Kratom Overdose.

INTRODUCTION: Kratom (Mitragyna speciosa) is a popular plant-based extract that has dose-dependent stimulatory and sedative effects. It has been used for self-treatment of opioid withdrawal and can result in seizures, hepatotoxicity, and infectious complications from bacterial contamination. Reports of morbidity and mortality associated with Kratom may be confounded by coingestants. We report a case of severe rhabdomyolysis and pressure necrosis leading to fasciotomy in a patient who was using Kratom. CASE REPORT: A 31-year-old male with substance use presented to the emergency department after loss of consciousness for 6 hours after smoking Kratom. He was found to have rhabdomyolysis, acute renal and hepatic injury, and electrolyte disturbances. No ethanol was detected, and urine drug screen was negative. Over the next 3 hours, the patient developed signs of compartment syndrome and he was transferred to the operating room for fasciotomy. He required continuous renal replacement therapy for 48 hours and his labs and clinical status improved. He was discharged 18 days later. A serum and urine sample from the first day of presentation were analyzed for mitragynine and 7-hydroxymitragynine using an Ultra Performance Liquid Chromatography-Tandem Mass Spectrometer (UPLC-MSMS) method. The serum mitragynine was 5 ng/mL and the urine mitragynine 6 ng/mL. CONCLUSIONS: Although there are numerous reports of opioids resulting in prolonged periods of immobilization and rhabdomyolysis, this is not commonly reported in Kratom overdoses.This case report highlights the profound sedative effect of Kratom and the potential of pressure necrosis injury resulting in rhabdomyolysis and compartment syndrome requiring fasciotomy.

Skin Necrosis Following Inadvertent Dermal Injection of Extended-release Buprenorphine.

INTRODUCTION: Extended-release subcutaneous buprenorphine injection is a relatively new formulation and clinicians are still gaining experience with its use. There is sparse literature available on adverse events. We describe a case of skin necrosis associated with the injection site of extended-release buprenorphine. CASE REPORT: A 35-year-old reported immediate swelling and eventual skin breakdown near his buprenorphine injection site. He was found to have ulceration down to the subcutis with no evidence of infection. The patient followed up with dermatology and underwent debridement of the site. The injection site healed with scar formation. DISCUSSION: Although mild to moderate adverse events related to the injection site have been reported in Phase 3 studies of extended-release buprenorphine injection, this is a rare case of skin necrosis requiring surgical intervention and excision of the depot. CONCLUSIONS: This case highlights the potential complication of skin necrosis after inadvertent dermal of extended-release buprenorphine and reviews proper administration techniques.

Erratum to 'Social determinants of health and emergency department utilization among adults receiving buprenorphine for opioid use disorder' [Drug and Alcohol Dependence Reports 3 (2022) 100062].

[This corrects the article PMC9248991.].