Sudden Cardiac Death and Myocardial Fibrosis, Determined by Autopsy, in Persons with HIV.

BACKGROUND: The incidence of sudden cardiac death and sudden death caused by arrhythmia, as determined by autopsy, in persons with human immunodeficiency virus (HIV) infection has not been clearly established. METHODS: Between February 1, 2011, and September 16, 2016, we prospectively identified all new deaths due to out-of-hospital cardiac arrest among persons 18 to 90 years of age, with or without known HIV infection, for comprehensive autopsy and toxicologic and histologic testing. We compared the rates of sudden cardiac death and sudden death caused by arrhythmia between groups. RESULTS: Of 109 deaths from out-of-hospital cardiac arrest among 610 unexpected deaths in HIV-positive persons, 48 met World Health Organization criteria for presumed sudden cardiac death; of those, fewer than half (22) had an arrhythmic cause. A total of 505 presumed sudden cardiac deaths occurred between February 1, 2011, and March 1, 2014, in persons without known HIV infection. Observed incidence rates of presumed sudden cardiac death were 53.3 deaths per 100,000 person-years among persons with known HIV infection and 23.7 deaths per 100,000 person-years among persons without known HIV infection (incidence rate ratio, 2.25; 95% confidence interval [CI], 1.37 to 3.70). Observed incidence rates of sudden death caused by arrhythmia were 25.0 and 13.3 deaths per 100,000 person-years, respectively (incidence rate ratio, 1.87; 95% CI, 0.93 to 3.78). Among all presumed sudden cardiac deaths, death due to occult drug overdose was more common in persons with known HIV infection than in persons without known HIV infection (34% vs. 13%). Persons who were HIV-positive had higher histologic levels of interstitial myocardial fibrosis than persons without known HIV infection. CONCLUSIONS: In this postmortem study, the rates of presumed sudden cardiac death and myocardial fibrosis were higher among HIV-positive persons than among those without known HIV infection. One third of apparent sudden cardiac deaths in HIV-positive persons were due to occult drug overdose. (Supported by the National Heart, Lung, and Blood Institute.).

The presence of abdominal pain associated with acetaminophen overdose does not predict severity of liver injury.

AIM: Whilst it is known that abdominal pain is a common symptom in patients with acetaminophen overdose, its association with severity of liver injury has not been clearly defined. This study investigates the association between the symptom of abdominal pain on presentation to hospital and the degree of liver injury post-acetaminophen overdose. METHODS: Admissions with acetaminophen poisoning, requiring treatment with acetylcysteine were identified and reviewed from a search of a large Australian tertiary hospital network from February 20th, 2014, to August 30th, 2018. Parameters such as presence of abdominal pain, time post-ingestion and peak ALT were collected. Single acute ingestions, staggered and repeated supratherapeutic ingestions were analysed. RESULTS: 539 cases were identified in the study period, 79% female, with mean age 25 (17-43) years. Patients presenting to the emergency department with abdominal pain post-acetaminophen overdose had a similar risk of developing hepatotoxicity or acute liver injury compared to patients without abdominal pain regardless of time to presentation. Patients presenting <8-h post-overdose with abdominal pain were as likely to develop hepatotoxicity (1/46, 2.2%) compared to those without abdominal pain (1/54 [1.9%]; OR = 1.18 [0.07 to 19.4]). Those presenting >8-h post-overdose with abdominal pain were as likely to develop hepatotoxicity (13/92, 14.1%) compared to those without abdominal pain (4/35 [11.4%]; OR = 1.28 [0.39 to 4.21]). CONCLUSIONS: The presence of abdominal pain after acetaminophen overdose was not predictive of the development of liver injury in patients receiving acetylcysteine treatment. Further prospective studies are required to confirm this finding. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Psychosocial factors associated with overdose subsequent to Illicit Drug use: a systematic review and narrative synthesis.

BACKGROUND AND AIMS: Psychological and social status, and environmental context, may mediate the likelihood of experiencing overdose subsequent to illicit drug use. The aim of this systematic review was to identify and synthesise psychosocial factors associated with overdose among people who use drugs. METHODS: This review was registered on Prospero (CRD42021242495). Systematic record searches were undertaken in databases of peer-reviewed literature (Medline, Embase, PsycINFO, and Cinahl) and grey literature sources (Google Scholar) for work published up to and including 14 February 2023. Reference lists of selected full-text papers were searched for additional records. Studies were eligible if they included people who use drugs with a focus on relationships between psychosocial factors and overdose subsequent to illicit drug use. Results were tabulated and narratively synthesised. RESULTS: Twenty-six studies were included in the review, with 150,625 participants: of those 3,383-4072 (3%) experienced overdose. Twenty-one (81%) studies were conducted in North America and 23 (89%) reported polydrug use. Psychosocial factors associated with risk of overdose (n = 103) were identified and thematically organised into ten groups. These were: income; housing instability; incarceration; traumatic experiences; overdose risk perception and past experience; healthcare experiences; perception of own drug use and injecting skills; injecting setting; conditions with physical environment; and social network traits. CONCLUSIONS: Global rates of overdose continue to increase, and many guidelines recommend psychosocial interventions for dependent drug use. The factors identified here provide useful targets for practitioners to focus on at the individual level, but many identified will require wider policy changes to affect positive change. Future research should seek to develop and trial interventions targeting factors identified, whilst advocacy for key policy reforms to reduce harm must continue.

"I'm not going to lay back and watch somebody die": a qualitative study of how people who use drugs' naloxone experiences are shaped by rural risk environment and overdose education/naloxone distribution intervention.

BACKGROUND: Overdoses have surged in rural areas in the U.S. and globally for years, but harm reduction interventions have lagged. Overdose education and naloxone distribution (OEND) programs reduce overdose mortality, but little is known about people who use drugs' (PWUD) experience with these interventions in rural areas. Here, we analyze qualitative data with rural PWUD to learn about participants' experiences with an OEND intervention, and about how participants' perceptions of their rural risk environments influenced the interventions' effects. METHODS: Twenty-nine one-on-one, semi-structured qualitative interviews were conducted with rural PWUD engaged in the CARE2HOPE OEND intervention in Appalachian Kentucky. Interviews were conducted via Zoom, audio-recorded, and transcribed verbatim. Thematic analysis was conducted, guided by the Rural Risk Environment Framework. RESULTS: Participants' naloxone experiences were shaped by all domains of their rural risk environments. The OEND intervention transformed participants' roles locally, so they became an essential component of the local rural healthcare environment. The intervention provided access to naloxone and information, thereby increasing PWUDs' confidence in naloxone administration. Through the intervention, over half of participants gained knowledge on naloxone (access points, administration technique) and on the criminal-legal environment as it pertained to naloxone. Most participants opted to accept and carry naloxone, citing factors related to the social environment (responsibility to their community) and physical/healthcare environments (overdose prevalence, suboptimal emergency response systems). Over half of participants described recent experiences administering intervention-provided naloxone. These experiences were shaped by features of the local rural social environment (anticipated negative reaction from recipients, prior naloxone conversations). CONCLUSIONS: By providing naloxone paired with non-stigmatizing health and policy information, the OEND intervention offered support that allowed participants to become a part of the healthcare environment. Findings highlight need for more OEND interventions; outreach to rural PWUD on local policy that impacts them; tailored strategies to help rural PWUD engage in productive dialogue with peers about naloxone and navigate interpersonal conflict associated with overdose reversal; and opportunities for rural PWUD to formally participate in emergency response systems as peer overdose responders. Trial registration The ClinicalTrials.gov ID for the CARE2HOPE intervention is NCT04134767. The registration date was October 19th, 2019.

Differential risks of syringe service program participants in Central Ohio: a latent class analysis.

BACKGROUND: Significant heterogeneity exists among people who use drugs (PWUD). We identify distinct profiles of syringe service program (SSP) clients to (a) evaluate differential risk factors across subgroups and (b) inform harm reduction programming. METHODS: Latent class analysis (LCA) was applied to identify subgroups of participants (N = 3418) in a SSP in Columbus, Ohio, from 2019 to 2021. Demographics (age, sex, race/ethnicity, sexual orientation, housing status) and drug use characteristics (substance[s] used, syringe gauge, needle length, using alone, mixing drugs, sharing supplies, reducing use, self-reported perceptions on the impact of use, and treatment/support resources) were used as indicators to define latent classes. A five-class LCA model was developed, and logistic regression was then employed to compare risk factors at program initiation and at follow-up visits between latent classes. RESULTS: Five latent classes were identified: (1) heterosexual males using opioids/stimulants with housing instability and limited resources for treatment/support (16.1%), (2) heterosexual individuals using opioids with stable housing and resources for treatment/support (33.1%), (3) individuals using methamphetamine (12.4%), (4) young white individuals using opioids/methamphetamine (20.5%), and (5) females using opioids/cocaine (17.9%). Class 2 served as the reference group for logistic regression models, and at the time of entry, class 1 was more likely to report history of substance use treatment, overdose, HCV, sharing supplies, and mixing drugs, with persistently higher odds of sharing supplies and mixing drugs at follow-up. Class 3 was more likely to report history of overdose, sharing supplies, and mixing drugs, but outcomes at follow-up were comparable. Class 4 was the least likely to report history of overdose, HCV, and mixing drugs, but the most likely to report HIV. Class 5 was more likely to report history of substance use treatment, overdose, HCV, sharing supplies, and mixing drugs at entry, and higher reports of accessing substance use treatment and testing positive for HCV persisted at follow-up. CONCLUSIONS: Considerable heterogeneity exists among PWUD, leading to differential risk factors that may persist throughout engagement in harm reduction services. LCA can identify distinct profiles of PWUD accessing services to tailor interventions that address risks, improve outcomes, and mitigate disparities.

Opioid use is associated with increased out-of-hospital cardiac arrest risk among 40 000-cases across two countries.

AIMS: Opioid use has substantially increased in the last decade and is associated with overdose mortality, but also with increased mortality from cardiovascular causes. This finding may partly reflect an association between opioids and out-of-hospital cardiac arrest (OHCA). Therefore, we aimed to investigate OHCA-risk of opioids in the community. METHODS: We conducted 2 population-based case-control studies separately in the Netherlands (2009-2018) and Denmark (2001-2015). Cases were individuals who experienced OHCA of presumed cardiac cause. Each case was matched with up to 5 non-OHCA-controls according to age, sex and OHCA-date. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We included 5473 OHCA-cases matched with 21 866 non-OHCA-controls in the Netherlands, and 35 017 OHCA-cases matched with 175 085 non-OHCA-controls in Denmark. We found that use of opioids (the Netherlands: cases: 5.4%, controls: 1.8%; Denmark: cases: 11.9%, controls: 4.4%) was associated with increased OHCA-risk in both regions (the Netherlands: OR 2.1 [95% CI 1.8-2.5]; Denmark: OR 1.8 [95% CI 1.5-2.1]). The association was observed in both sexes, and in individuals with cardiovascular disease (the Netherlands: OR 1.8 [95% CI 1.5-2.1]; Denmark: OR 1.6 [95% CI 1.5-1.7]) or without (the Netherlands: OR 3.4 [95% CI: 2.4-4.8], Pinteraction  < .0001; Denmark: OR 2.3 [95% CI: 2.0-2.5], Pinteraction  < .0001). CONCLUSION: Use of opioids is associated with increased OHCA-risk in both sexes, independently of concomitant cardiovascular disease. These findings should be considered when evaluating the harms and benefits of treatment with opioids.

Unintentional cetirizine overdose causing anticholinergic syndrome.

The incidence of anticholinergic syndrome due to second generation antihistamines is infrequently reported. Largely due to their decreased affinity for central nervous system (CNS) receptors, second generation antihistamines are rarely associated with anticholinergic symptoms, though toxicity is still possible particularly when taken in excess. We report a case of a six year old boy who presented with agitation, hallucinations, fixed and dilated pupils, tachycardia, and hyperthermia consistent with anticholinergic toxicity several hours after accidental overdose of a second generation antihistamine, cetirizine. Early identification of this rare phenomenon is important not only for appropriate emergency management but also for avoidance of potentially invasive and unnecessary tests which may further increase patient morbidity.

Successful orthotopic liver transplantation in a patient with a positive SARS-CoV2 test and acute liver failure secondary to acetaminophen overdose.

SARS-CoV2, first described in December 2019, was declared a pandemic by the World Health Organization in March 2020. Various surgical and medical societies promptly published guidelines, based on expert opinion, on managing patients with COVID-19, with a consensus to postpone elective surgeries and procedures. We describe the case of an orthotopic liver transplantation (OLT) in a young female who presented with acute liver failure secondary to acetaminophen toxicity to manage abdominal pain and in the setting of a positive SARS-CoV2 test. Despite a positive test, she had no respiratory symptoms at time of presentation. The positive test was thought to be residual viral load. The patient had a very favorable outcome, likely related to multiple factors including her young age, lack of respiratory COVID-19 manifestations and plasma exchange peri-operatively. We recommend a full work-up for OLT in COVID-19 patients with uncomplicated disease according to standard of care, with careful interpretation of COVID-19 testing in patients presenting with conditions requiring urgent or emergent surgery as well as repeat testing even a few days after initial testing, as this could alter management.

Effects of naloxone and diazepam on blood glucose levels in tramadol overdose using generalized estimating equation (GEE) model; (an experimental study).

BACKGROUND: Tramadol is a synthetic opioid and poisoning is increasing around the world day by day. Various treatments are applied for tramadol poisoning. Due to the unknown effects of tramadol poisoning and some of its treatments on blood glucose levels, this study was conducted to investigate the overdose of tramadol and its common treatments (naloxone, diazepam), and their combination on blood glucose levels in male rats. METHODS: This study was conducted in 45 male Wistar rats. The animals were randomly divided into five groups of 9. They received a 75 mg/kg dose of tramadol alone with naloxone, diazepam, and a combination of both of these two drugs. On the last day, animals' tail vein blood glucose levels (BGL) were measured using a glucometer at different times, including before the tramadol injection (baseline) and 1 hour, 3 hours, and 6 hours after wards. The rats were anesthetized and sacrificed 24 h after the last injection. Blood samples were then taken, and the serum obtained was used to verify the fasting glucose concentration. Data were analyzed using SPSS software at a significance level of 0.05 using a one-way analysis of variance (ANOVA) and a generalized estimating equation (GEE). RESULTS: According to the GEE model results, the diazepam-tramadol and naloxone-diazepam-tramadol groups showed blood glucose levels five units higher than the tramadol group (p < 0.05). The diazepam-tramadol group had significantly higher blood glucose levels than the naloxone-tramadol group (p < 0.05). The mean blood glucose levels before the intervention, 3 hours and 6 hours after the injection of tramadol did not differ between the groups, but the blood glucose levels 1 hour after the injection of tramadol in the group of naloxone-tramadol were significantly lower than in the control group (p < 0.05). Blood glucose levels did not differ between the groups 24 h after injection of tramadol. CONCLUSION: The results of the present study showed tramadol overdose does not affect blood glucose levels. The diazepam-tramadol combination and the diazepam-naloxone-tramadol combination caused an increase in blood glucose levels.

Primaquine overdose in a toddler.

Antimalarial medications carry a risk of rare, but serious side effects. Primaquine in particular is known to cause methemoglobinemia and hemolytic anemia. In patients with underlying glucose-6-phosphate dehydrogenase (G6PD) deficiency, these side effects become amplified and can be life-threatening. This can complicate treatment plans as the recommended first-line management of severe methemoglobinemia, methylene blue, may cause or worsen hemolytic anemia in G6PD deficient patients. We present a case of a toddler with an accidental primaquine overdose who had undiagnosed G6PD deficiency. Over the 2 days following his ingestion he developed severe methemoglobinemia and hemolytic anemia toxicity. He was initially treated with a dose of methylene blue prior to learning of his G6PD deficiency. He was subsequently given additional doses of ascorbic acid and a blood transfusion. His condition gradually improved and he was ultimately discharged in good condition. To our knowledge, this case represents a unique presentation of mixed methemoglobinemia and hemolytic toxicity due to an accidental primaquine overdose in a G6PD deficient pediatric patient. Though cases remain relatively rare, pediatric patients represent the vast majority of known primaquine overdoses. Their diagnosis and treatment require maintaining a high index of suspicion and a good working knowledge of antimalarial toxicities and management options.

Guanfacine toxic ingestion with subsequent cardiogenic pulmonary edema.

Guanfacine is a central alpha-2 agonist often prescribed for Attention-deficit hyperactive disorder as well as tic disorder, with a usual dose of 1-4 mg per day. Due to its sympatholytic mechanism of action, Guanfacine can cause autonomic instability and hypotension. It can additionally cause cardiac dysfunction to include symptomatic bradycardias and contractility suppression. The authors present a case of a 17 year-old male with an ingestion of 80 mg of extended release Guanfacine with delayed onset cardiogenic pulmonary edema requiring mechanical ventilation. Previous pediatric ingestions have generated bradycardia, hypotension, and decreased level of consciousness, responsive to intravenous fluids, vasopressors, and occasionally naloxone. However, cardiogenic pulmonary edema from reduced cardiac contractility is a novel consequence of extended release Guanfacine ingestion. With Guanfacine's extended half-life, this unique case underscores the importance of emergency providers' familiarity with this toxidrome as well the necessity for prolonged, close observation following Guanfacine ingestion.

Out-of-hospital cardiac arrests in the young population; a 6-year review of the Irish out-of-hospital cardiac arrest register.

STUDY PURPOSE: Out-of-hospital cardiac arrests (OHCA) in the young population have only been examined in a limited number of regional studies. Hence, we sought to describe OHCA characteristics and predictors of survival to hospital discharge for the young Irish population. STUDY DESIGN: An observational analysis of the national Irish OHCA register for all OHCAs aged ≤35 years between January 2012 and December 2017 was performed. The young population was categorised into three age groups: ≤1 year, 1-15 years and 16-35 years. Multivariable logistic regression was used to determine the independent predictors of survival to hospital discharge. RESULTS: A total of 1295 OHCAs aged ≤35 years (26.9% female, median age 25 (IQR 17-31)) had resuscitation attempted. OHCAs in those aged ≥16 years (n=1005) were more likely to happen outside the home (38.5% vs 22.8%, p<0.001) and be of non-medical aetiology (59% vs 27.6%, p<0.001) compared with those aged <16 years (n=290). Asphyxiation, trauma and drug overdoses accounted for over 90% of the non-medical OHCAs for those 16-35 years. Overall survival to hospital discharge for the cohort was 5.1%; survival was non-significantly higher for those aged 16-35 years compared with those aged 1-15 years (6.0%, vs 2.8% p=0.93). Independent predictors of survival to hospital discharge included bystander witnessed OHCA, a shockable initial rhythm and a bystander defibrillation attempt. CONCLUSIONS: The high prevalence of non-medical OHCAs and the OHCA location need to be considered when developing OHCA care pathways and preventative strategies to reduce the burden of OHCAs in the young population.

Loss of BOK Has a Minor Impact on Acetaminophen Overdose-Induced Liver Damage in Mice.

Acetaminophen (APAP) is one of the most commonly used analgesic and anti-pyretic drugs, and APAP intoxication is one of the main reasons for liver transplantation following liver failure in the Western world. While APAP poisoning ultimately leads to liver necrosis, various programmed cell death modalities have been implicated, including ER stress-triggered apoptosis. The BCL-2 family member BOK (BCL-2-related ovarian killer) has been described to modulate the unfolded protein response and to promote chemical-induced liver injury. We therefore investigated the impact of the loss of BOK following APAP overdosing in mice. Surprisingly, we observed sex-dependent differences in the activation of the unfolded protein response (UPR) in both wildtype (WT) and Bok-/- mice, with increased activation of JNK in females compared with males. Loss of BOK led to a decrease in JNK activation and a reduced percentage of centrilobular necrosis in both sexes after APAP treatment; however, this protection was more pronounced in Bok-/- females. Nevertheless, serum ALT and AST levels of Bok-/- and WT mice were comparable, indicating that there was no major difference in the overall outcome of liver injury. We conclude that after APAP overdosing, loss of BOK affects initiating signaling steps linked to ER stress, but has a more minor impact on the outcome of liver necrosis. Furthermore, we observed sex-dependent differences that might be worthwhile to investigate.

Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. METHODS: Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah-/-/Rag2-/-/Il2rg-/-/NOD (FRGN) mice to create mice with humanized livers. RESULTS: Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. CONCLUSIONS: In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.

Liver Regeneration after Acetaminophen Hepatotoxicity: Mechanisms and Therapeutic Opportunities.

Acetaminophen (N-acetyl-para-aminophenol; APAP) overdose is the most common cause of acute liver failure in the Western world, with limited treatment opportunities. For years, research on APAP overdose has been focused on investigating the mechanisms of hepatotoxicity, with limited success in advancing therapeutic strategies. Acute liver injury after any insult, including APAP overdose, is followed by compensatory liver regeneration, which promotes recovery and is a crucial determinant of the final outcome. Liver regeneration after APAP-induced liver injury is dose dependent and impaired after severe APAP overdose. Although robust regenerative response is associated with spontaneous recovery and survival, impaired regeneration results in faster progression of injury and death after APAP overdose. APAP hepatotoxicity-induced liver regeneration involves a complex time- and dose-dependent interplay of several signaling mediators, including growth factors, cytokines, angiogenic factors, and other mitogenic pathways. Compared with the liver injury, which is established before most patients seek medical attention and has proved difficult to manipulate, liver regeneration can be potentially modulated even in late-stage APAP-induced acute liver failure. Despite recent efforts to study the mechanisms of liver regeneration after APAP-induced liver injury, more comprehensive research in this area is required, especially regarding factors that contribute to impaired regenerative response, to develop novel regenerative therapies for APAP-induced acute liver failure.

Mice deficient in pyruvate dehydrogenase kinase 4 are protected against acetaminophen-induced hepatotoxicity.

Though mitochondrial oxidant stress plays a critical role in the progression of acetaminophen (APAP) overdose-induced liver damage, the influence of mitochondrial bioenergetics on this is not well characterized. This is important, since lifestyle and diet alter hepatic mitochondrial bioenergetics and an understanding of its effects on APAP-induced liver injury is clinically relevant. Pyruvate dehydrogenase (PDH) is critical to mitochondrial bioenergetics, since it controls the rate of generation of reducing equivalents driving respiration, and pyruvate dehydrogenase kinase 4 (PDK4) regulates (inhibits) PDH by phosphorylation. We examined APAP-induced liver injury in PDK4-deficient (PDK4-/-) mice, which would have constitutively active PDH and hence elevated flux through the mitochondrial electron transport chain. PDK4-/- mice showed significant protection against APAP-induced liver injury when compared to wild type (WT) mice as measured by ALT levels and histology. Deficiency of PDK4 did not alter APAP metabolism, with similar APAP-adduct levels in PDK4-/- and WT mice, and no difference in JNK activation and translocation to mitochondria. However, subsequent amplification of mitochondrial dysfunction with release of mitochondrial AIF, peroxynitrite formation and DNA fragmentation were prevented. Interestingly, APAP induced a rapid decline in UCP2 protein levels in PDK4-deficient mice. These data suggest that adaptive changes in mitochondrial bioenergetics induced by enhanced respiratory chain flux in PDK4-/- mice render them highly efficient in handling APAP-induced oxidant stress, probably through modulation of UCP2 levels. Further investigation of these specific adaptive mechanisms would provide better insight into the control exerted by mitochondrial bioenergetics on cellular responses to an APAP overdose.

Atypical presentation of COVID-19; an observational retrospective study.

BACKGROUND: COVID-19 infection may present with atypical signs and symptoms and false negative polymerase chain reaction (PCR) tests predisposing healthy people and health care workers to infection. The aim of the current study is to evaluate the features of atypical presentations in COVID-19 infection in a referral center in Tehran, Iran. METHODS: Hospital database of inpatients admitted to Loghman Hakim hospital between February 20th and May 11th, 2020 was reviewed and all patients with final diagnosis of COVID-19 infection were evaluated for their presenting symptoms. Patients with chief complaints of "fever", "dyspnea", and/or "cough" as typical presentations of COVID-19 were excluded and those with other clinical presentations were included. RESULTS: Nineteen patients were included with a mean age of 51 ± 19 years, of whom, 17 were males (89%). Median [IQR] Glasgow coma scale (GCS) was 14 [13, 15]. Almost 10 had referred with chief complaint of methanol poisoning and overdose on substances of abuse. Only 8 cases (42%) had positive COVID-19 test. Nine (47%) needed invasive mechanical ventilation, of whom, two had positive COVID-19 test results (p = ns). Eight patients (42%) died with three of them having positive PCRs. CONCLUSIONS: In patients referring to emergency departments with chief complaint of poisoning (especially poisonings that can result in dyspnea including substances of abuse and toxic alcohols), gastrointestinal, and constitutional respiratory symptoms, attention should be given not to miss possible cases of COVID-19.

Brief Report: A Case of Tramadol Overdose: Extracorporeal Life Support and Hemoperfusion as Life-Saving Treatment.

We describe the case of a 49-year-old woman with a Tramadol intoxication associated with multiorgan failure. Veno-arterial femoro-femoral extracorporeal life support (VA-ECLS) and hemoperfusion (HP) were used as rescue treatments. The emergency medical service found a woman at home unconscious. Once in the hospital, she was intubated and catecholamines support was immediately started for a severe shock. Brain CT was normal, whereas EEG revealed a metabolic encephalopathy pattern. Toxic levels of Tramadol and Quetiapine were detected. VA-ECLS was implanted due to persistent multiorgan failure, and HP with a charcoal cartridge was set to increase the Tramadol clearance. To quantify the charcoal cartridge's removal efficiency of Tramadol, Tramadol concentration was measured before and after the cartridge and before and after the treatment in the patient's blood. The charcoal cartridge showed good extraction ratio during the treatment and no significant rebound effect. VA-ECLS and HP allowed the patient to be weaned from vasoconstrictors and the resolution of the organ failures. These treatments might be lifesaving in the Tramadol intoxication.

Bromism: An overlooked and elusive toxidrome from chronic dextromethorphan abuse.

A 47 year old woman presented to the emergency department for an intentional overdose of an over the counter cough suppressant. She had been seen multiple times over the last several months with the same presentation. Her work up revealed a significantly elevated chloride level (125 mmol/L, normal 98-107) as well as an anion gap of 1. She denied any other co-ingestions, including other over the counter medications or alcohol, and was otherwise asymptomatic. She was given fluids and supportive care. Ultimately, a significantly elevated bromide level was noted on a send out lab. She was diagnosed with chronic bromide toxicity (bromism) from recurrent over the counter Robitussin HBr use, which was the source of her hyperchloremia and decreased anion gap.

Toxic Optic Neuropathy From Quinine Overdose.

A 45-year-old man presented with longstanding poor vision in both eyes. His medical history was significant for a remote overdose of quinine. After the ingestion, he fell into a coma and on awakening was not able to see light out of both eyes. Several days later, his central vision began to gradually recover and continued to improve over the span of several months. Presently, he had 20/20 visual acuity in both eyes with severely constricted peripheral visual fields. There were bilateral iris transillumination defects, and both optic nerves were diffusely pale with attenuated vasculature and inner retinal thinning on ocular coherence tomography. We present a patient with the stereotypical findings and natural history of quinine toxicity, a rare and not widely known cause of toxic optic neuropathy and retinopathy.