Cholinergic Toxidrome Research Articles

Tracheal gas insufflation for refractory hypercapnia

A 65 year male patient got admitted to ICU after alleged intake of ~ 250 ml of Chlorpyrifos (Organophosphate insecticides which cause cholinergic toxidrome) and cypermethrin (Synthetic pyrethroid) and presented with cholinergic toxidrome with severe hypercapnia (supercarbia). All conventional and advanced modes of ventilation failed to ventilate the patient because of severe bronchospasm and a prolonged expiratory time constant with high airway pressures and high auto-peep. As a last resort, we resorted to unconventional modes, as the patient could not afford ECMO. Tracheal gas insufflation was done using a coaxial flow of humidified oxygen at 8 lpm with a suction catheter and ventilator parameter were adjusted to match the added gas flows. Tracheal gas insufflation can be delivered by a thin catheter placed through the endotracheal tube (terminating within 1 to 2 cm of the main carina) or via a modified endotracheal tube with channels embedded in the walls of the tube. Tracheal gas insufflation flow can be forward (toward the alveoli) or reversed in direction toward the proximal end of the endotracheal tube. Keywords: TGI, Hypercapnia, organophosphate toxicity

Principal causes of acute poisoning in an emergency service: experience between 2014 and 2021 at a University Hospital in Southwestern Colombia

Acute poisonings are a global public health problem, which implies costs and disease burden for society. In Colombia, there is a significant underreporting of data on acute poisoning and data gaps on the toxicological profile of the population. This study aims to identify the epidemiology of acute poisoning in a high-complexity hospital in southwestern Colombia. A descriptive study with retrospective data collection was performed. The variables were expressed through the measure of central tendency and dispersion. Categorical variables were described in proportions. A total of 406 patients were included. The median age was 31 years (IQR 23–48), 56.2% were male, and only 19.2% had a history of mental illness. Suicidal intent represented 58.8% of the cases, and the most frequent route of exposure was the oral route (81.6%). The most prevalent groups of substances were pesticides (34.2%) and medicines (32%). The most common etiological agent was organophosphates (16.5%). Cholinergic toxidrome was the most common. The average stay in the ICU was 4.5 days (± 4.8), and the mortality was 4.2%. The principal causes of acute poisoning were drugs and pesticides, with a predominant etiology of organophosphates and depressants of the central nervous system. There was a significant predominance of young male patients with suicidal intent, low mental disorders, elevated unemployment rate, and similar mortality reported in other studies. This study improves the knowledge about acute poisoning in southwestern Colombian to carry out multicenter analytic studies.

Lack of cholinergic features in healthcare workers caring for a patient with organophosphate poisoning

Introduction Controversy exists with regard to risk of secondary exposure of health care workers caring for patients who have ingested an organophosphate insecticide. We aim to report clinical effects of staff members caring for an organophosphate poisoned patient. Incident A 76-year-old male presented to the Emergency Department exhibiting a cholinergic toxidrome requiring atropine, intubation and mechanical ventilation. Methods We undertook a retrospective chart review of any Emergency Department presentations for medical assessment in relation to the incident and conducted telephone interviews of any healthcare workers who did not present but were deemed to be closely involved with patient care. We collected data including age, gender, symptoms reported and plasma cholinesterase activity measurement. Results We collected data from 13 individuals, of whom nine presented for medical assessment, including the patient’s spouse. Five additional staff members were interviewed, having been identified via Emergency Department rostering documentation. The 13 healthcare workers comprised five nurses, four paramedics and four doctors. Dizziness and nausea were reported in two and the patient’s spouse reported one episode of vomiting. Of the nine patients who had plasma cholinesterase activity measured, none were below the laboratory reference range, including those who experienced symptoms. Conclusions We found no clinical nor biochemical evidence of toxicity in healthcare workers caring for a critically ill patient with organophosphate ingestion. These findings are consistent with previously published guidelines advocating standard/Level D personal protective equipment. We believe that emergency departments should not be closed as a safety measure.

Basic approach to poisoning focusing “Toxidrome”

Background: The term “toxidrome” is derived from the term “toxic syndrome.”A toxidrome is a constellation of signs and symptoms that are seen with particular classes of poisons. Methods: A systematic review of English literature was done with search item naming toxidrome and or basic approach to poisoning. Search engine was multiple leaded by pubmed having mesh term of toxidrome. The journal sites of asiajol and banglajol was also searched for related topics. Personal communication with toxicology related paper was also applied during the process. Results: All of the toxidromes can be identified using the a quick “toxicological physical exam.” No laboratory tests are necessary! The toxicologic physical exam focuses on the following components: Vital Signs, behavior like sleepy, normal, euphoric, agitated ? Pupils whether small, normal, big? Mucus membranes like checking the axillae whether it is dry, normal, wet?Bowel sounds to see whether it is decreased, normal, increased? There are 7 toxidromes that the emergency physician should be able to recognize and treat.These include: The anticholinergic toxidrome, cholinergic toxidrome, opioid toxidrome, opioid withdrawal toxidrome, sedative-hypnotic toxidrome, sedative-hypnotic withdrawal toxidrome, and sympathomimetic toxidrome. Beside these, two additional toxidrome has recently been introduced, one is serotonergic toxidrome and neuroleptic malignant toxidrome. Patients who take several substances may have a mixed toxidrome. For example, a patient who “speedballs” cocaine and heroin may have features of both the opioid and sympathomimetic toxidromes. Conclusion: Like all clinical syndromes, patients almost never exhibit every single feature of a particular toxidrome. When diagnosing a patient with a specific toxidrome you are looking for the one which best fits. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 185-186

1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model.

Organophosphate nerve agent (OPNA) exposure induces acute and long-term neurological deficits. OPNA exposure at sub-lethal concentrations induces irreversible inhibition of acetylcholinesterase and cholinergic toxidrome and develops status epilepticus (SE). Persistent seizures have been associated with increased production of ROS/RNS, neuroinflammation, and neurodegeneration. A total of 1400W is a novel small molecule, which irreversibly inhibits inducible nitric oxide synthase (iNOS) and has been shown to effectively reduce ROS/RNS generation. In this study, we investigated the effects of 1400W treatment for a week or two weeks at 10 mg/kg or 15 mg/kg per day in the rat diisopropylfluorophosphate (DFP) model. 1400W significantly reduced the number of microglia, astroglia, and NeuN+FJB positive cells compared to the vehicle in different regions of the brain. 1400W also significantly reduced nitrooxidative stress markers and proinflammatory cytokines in the serum. However, neither of the two concentrations of 1400W for two weeks of treatment had any significant effect on epileptiform spike rate and spontaneous seizures during the treatment period in mixed sex cohorts, males, or females. No significant sex differences were found in response to DFP exposure or 1400W treatment. In conclusion, 1400W treatment at 15 mg/kg per day for two weeks was more effective in significantly reducing DFP-induced nitrooxidative stress, neuroinflammatory and neurodegenerative changes.

A complete, evidence-based review on novichok poisoning based on epidemiological aspects and clinical management.

Background: The whole world has learned about the existence of a highly toxic neuro-paralytic substance called Novichok. A wide range of neuro-paralytic toxins were used during the wars of decades ago, which also had harmful and irreversible effects. Fortunately, the establishment of conventions prohibiting the use of these weapons prevented the adverse clinical consequences of these compounds. What we did in the present study was to evaluate the clinical features of Novichok, how to manage exposure to it, and to evaluate the prognostic aspects associated with this poisoning agent. Methods: The manuscript especial databases including Medline, Web of knowledge, Google scholar, and Scopus were deeply searched by the two blinded investigators for all eligible studies based on the considered keywords. Initially 98 articles were initially collected by database searching that considering eligibility criteria, 83 articles were finally eligible for the final assessment. There is a lack of clinical trials and case-cohort studies on general population about treatment and side effects when it comes to human nerve agents and most of the data in our search is based on animal studies. Results: In evaluating various clinical, auto physiological and prognostic aspects of exposure to these substances, special attention was necessary to the following points. First, Novichok agents are considered more potent than other toxic agents. Pathophysiologically, these agents irreversibly bind acetylcholinesterase and produce a rapid cholinergic toxidrome which is responsible for the clinical manifestations as well as the potential dangerous and life threatening side effects caused by these agents. Uniquely, these agents are thought to also target every neuron in the central and peripheral nervous system. As a managerial and therapeutic approach, early and timely treatment of its related complication along with prevents massive exposure and decontamination in addition to rapid resuscitation can prohibit debilitating neuropathy and death due to facing it. Conclusion: The present review highlights the importance of recognizing the potential acute toxic effects of Novichok agents, diagnostic and therapeutic approaches (life-saving antidotal therapy) to complications and ultimately the application of guidelines to improve the prognosis of exposure to these agents for both victims and medical community.

Hemoperfusion for Clinically Suspected Organophosphate and Carbamate Poisoning in Critically Ill Patients: A Randomized Trial

Introduction: Organophosphate poisoning occurs frequently, and despite treatment, increased severity and intensive care unit (ICU) admissions have been observed. We hypothesized that early hemoperfusion/hemadsorption (HA) therapy would change the clinical course of the disease. Methods: We performed a prospective, open, randomized controlled study at an academic ICU. Adult patients referred for an acute cholinergic toxidrome were screened. Patients meeting inclusion and exclusion criteria were randomized to standard of care (SoC) or HA therapy plus SoC, which included 2 6-h cycles of HA 12 h apart beginning within the first 24 h of ICU admission. The primary outcome was a comparison of ICU length of stay (LOS). Results: There were no significant baseline differences between the groups. The median ICU LOS was 6.5 days (IQR 4.5–10) in the HA group compared to 8 days (IQR 3.5–17) for the control group, p = 0.58. Among patients with an excess ICU LOS ≥7 days, the median ICU LOS was significantly shorter for the HA group, 10 days (IQR 8–12) compared to 17 days (IQR 14–22) for the control group, p = 0.001, resulting in a cost saving of EUR 7308 per patient. Duration (8 days vs. 13.5 days) and cumulative dosage (316 mg vs. 887 mg) of atropine among patients with excess ICU LOS were significantly lower in the HA group compared to the SoC group, respectively. A similar reduction in the duration of mechanical ventilation (HA = 6 days vs. SoC = 15 days, p = 0.001) was found. The combination of day 28 mortality and severe complications was lower in the HA group (10%, n = 2/20) compared to the SoC group (42%, 14/33) p = 0.01. Conclusion: HA therapy resulted in significant cost savings driven by a reduced LOS among patients with excess ICU LOS ≥7 days. This therapy was also associated with a significant reduction in the combination of day 28 mortality and severe complications including cardiac arrest, organ dysfunction, reintubation, and tracheostomy.

Supplemental treatment to atropine improves the efficacy to reverse nerve agent induced bronchoconstriction

Exposure to highly toxic organophosphorus compounds causes inhibition of the enzyme acetylcholinesterase resulting in a cholinergic toxidrome and innervation of receptors in the neuromuscular junction may cause life-threatening respiratory effects. The involvement of several receptor systems was therefore examined for their impact on bronchoconstriction using an ex vivo rat precision-cut lung slice (PCLS) model. The ability to recover airways with therapeutics following nerve agent exposure was determined by quantitative analyses of muscle contraction.PCLS exposed to nicotine resulted in a dose-dependent bronchoconstriction. The neuromuscular nicotinic antagonist tubocurarine counteracted the nicotine-induced bronchoconstriction but not the ganglion blocker mecamylamine or the common muscarinic antagonist atropine. Correspondingly, atropine demonstrated a significant airway relaxation following ACh-exposure while tubocurarine did not. Atropine, the M3 muscarinic receptor antagonist 4-DAMP, tubocurarine, the β2-adrenergic receptor agonist formoterol, the Na+-channel blocker tetrodotoxin and the K+ATP-channel opener cromakalim all significantly decreased airway contractions induced by electric field stimulation. Following VX-exposure, treatment with atropine and the Ca2+-channel blocker magnesium sulfate resulted in significant airway relaxation. Formoterol, cromakalim and magnesium sulfate administered in combinations with atropine demonstrated an additive effect.In conclusion, the present study demonstrated improved airway function following nerve agent exposure by adjunct treatment to the standard therapy of atropine.

Do mnemonics help healthcare professionals learn and recall cholinergic toxidromes?

Background The U.S. National Library of Medicine and Department of Homeland Security assembled subject matter experts (SMEs) for the Toxic Chemical Syndrome Definitions and Nomenclature Workshop. The SMEs at this meeting identified a lack of research evaluating the effectiveness of field recognition of toxidromes to guide treatment. They suggested that mnemonics may be helpful for remembering and recognizing toxidromes and further, that rapid toxidrome recognition, through use of a mnemonic or otherwise, leads to rapid action and urgent intervention. Objectives (1) Determine if published studies demonstrate HPs can learn and recall hazardous materials (hazmat) toxidromes. (2) Determine if Healthcare Professionals (HPs) can learn mnemonics for muscarinic and nicotinic toxidromes during the Advanced Hazmat Life Support (AHLS) Provider Course (PC) and recall these cholinergic mnemonics when retested years later. Our hypothesis is HPs can learn these mnemonics and recall them up to four years later. Methods We analyzed results of HPs who completed AHLS PC pre-tests and post-tests during their initial AHLS PC between March 1, 2007 and March 1, 2010, and then, within four years, took either an online retest or a pre-test for a second AHLS PC. We compared pre- and post-test answers for questions regarding muscarinic and nicotinic mnemonics to assess if HPs can learn these mnemonics during an initial AHLS PC and then recall these mnemonics later, during retesting. We compared the percentage of HPs who correctly identified each cholinergic mnemonic on the pre-test, post-test, and retest using McNemar’s test for paired, nominal data. We searched six literature databases to see if there were any previous similar studies. Results Our literature search found no similar published studies. The mean time to re-testing was 3.6 years (SD 0.8 year). The percentage of respondents correctly answering the question for the muscarinic toxidrome was 53% on the pre-test, 100% on the post-test, and 75% on the retest. The percentage of respondents correctly answering the nicotinic toxidrome question was 52% on the pre-test, 100% on the post-test, and 77% on the retest. Conclusion All studied healthcare professionals learned the cholinergic toxidrome mnemonics during their initial AHLS PC. Mnemonic recall declined somewhat on retesting; however, recall was evident in 75–77% of retest takers compared to their pre-test results up to four years earlier, a statistically significant difference (p < .001) for both mnemonics. This supports our study hypothesis that HPs can learn these mnemonics and recall them up to 4 years later.

Assessment of hospitalizations of patients after intoxication with organophosphates used in agriculture

Clinical manifestation of organophosphates toxicity may be differentiate and include cholinergic toxidrome, intermediate syndrome, OP-induced delayed polyneuropathy to chronic OP-induced neuropsychiatric disorder (OPIDN). Patients symptoms, along with decrease in cholinesterase serum level, determines the possible diagnosis of organophosphate poisoning.The aim of the study was to present the clinical manifestation and cholinesterase level changes in intoxication with organophosphorus compounds in patients.A data base was created by analysis of the hospital documents of 34 patients hospitalized due to organophosphate intoxication. Statistical analysis involved frequency tables with percentage values, the application of non-parametric Chi-square test and parametric t-Student test (with homogeneity of variance Levine test). The level of static significance was set to p=0.05.In fatal hospitalizations (20.6%), cholinesterase level was significantly lower (265.87 U/l) than in other patients (4254.78 U/l; p<0.05). Similarly, levels of cholinesterase were decreased in group of patients with acute respiratory failure (999.79 U/l vs 4943.86 U/l in other patients; p<0.05), patients with multi-organ dysfunction syndrome (244.13 U/l vs 4914.89 U/l in other patients; p<0.05) and those with cardiac arrest (547 U/l vs 4636.25 U/l in other patients). A statistically significant difference was also observed in cholinesterase level of patients who required mechanical ventilation (548.17 U/l vs 5219.71 U/l in other group). The study revealed that 29.4% of poisonings were suicidal.The management of a patient with organophosphate poisoning remains challenging and requires continuous control. A significant step in the diagnostic process is the assessment changes in both the clinical picture and cholinesterase level.

A Toxidromic based Assessment of Patterns of Poisoning in a Tertiary Hospital in India

Acute poisoning is an important and common medical emergency. Acute poisoning is one of the major healthchallenges both in developing as well as developed countries 2, 3 Aim of the Study-We had conducted a studywith the objective to investigate the pattern of acute poisoning cases by utilizing the toxidromic approach ina tertiary care hospital in Uttar Pradesh. Material &amp; Methods We had done an observational study on acutepoisoning patients presenting in the Emergency, Medicine, and Pediatrics department of Dr RMLIMS fromJanuary 2020 to January 2021.All consenting patients of both sexes with suspected poisoning were studied.Toxidromic approach based on clinical presentation of poisoned patients was utilized in identification ofthe type of poisoning. Observations &amp; Results –total 82 cases were studied, we came across a total of 82poisoning cases seen over a period of 1 year in the emergency, medicine and paediatric wards of RMLIMS.There were 40 males and 42 females, with Cluster A containing 28 males and 27 females, whereas ClusterB had 12 males and 15 females, The relative risk and Odd’s ratio of total cases came out as 0.49 and 0.45respectively. Majority of the cases in Cluster A &amp;B showed features of Cholinergic Toxidrome, followedby corrosives and sympatholytics, anticholinergic toxidromes and medical toxins. Conclusion: we needto develop appropriate medical facilities like extracorporeal membrane oxygenation (ECMO) as a rescuemodality for patients with acute reversible life threatening cardiopulmonary conditions. Poison control centrewith Analytical Toxicology laboratory should be developed to handle and assist in advising the specific andappropriate management of poisoning cases.

Organophosphorus poisoning: the wet opioid toxidrome

In The Lancet, David Steindl and colleagues describe the case of a 44-year-old man who was poisoned by a novichok organophosphorus nerve agent. 1 Steindl D Boehmerle W Körner R et al. Novichok nerve agent poisoning. Lancet. 2020; (published online Dec 22.)https://doi.org/10.1016/S0140-6736(20)32644-1 Summary Full Text Full Text PDF Scopus (7) Google Scholar The man was a passenger on a domestic flight in Russia when he became confused, and vomited and collapsed unconscious; 2 h later, he was hospitalised in Omsk, Russia, and treated for respiratory failure and coma. After transfer by air ambulance to Berlin, Germany, features of the cholinergic toxidrome (ie, small or pinpoint pupils, bradycardia, sweating, and hypersalivation) allowed a diagnosis of organophosphorus poisoning to be made. Assessments done by a doctor from the air ambulance crew before transfer to Germany did not indicate that organophosphorus poisoning had yet been diagnosed or antidotes used. However, atropine was later detected in urine. With administration of antidotes and intensive care at Charité-Universitätsmedizin Berlin, the man made a full recovery. Novichok nerve agent poisoningOn Aug 20, 2020, a 44-year-old man who was previously healthy suddenly became confused and began to sweat heavily on a domestic flight in Russia approximately 10 min after departure; he vomited, collapsed, and lost consciousness. After an emergency landing, the man was admitted to the toxicology unit of a local hospital in Omsk, Russia, approximately 2 h after symptom onset. According to the discharge report, the patient presented comatose with hypersalivation and increased diaphoresis and was diagnosed to have respiratory failure, myoclonic status, disturbed carbohydrate metabolism, electrolyte disorders, and metabolic encephalopathy. Full-Text PDF

General Approach to the Poisoned Patient

Poisoning and ingestions constitute an increasing amount of morbidity and mortality nationwide. According to the American Association of Poison Control Centers (AAPCC), 2.2 million exposures were reported in 2013, and ingestions are currently the leading cause of injury-related death in the United States. Exposures include intentional overdose or suicide attempts, accidental overdose in drug abusers or children, and work-related injuries or acts of terrorism. According to the AAPCC, 50% of exposures are in children less than 5 years old and 80% of exposures are unintentional. When it comes to the unstable undifferentiated and possibly poisoned patient, one must take a stepwise approach similar to that for any critically ill patient, This review covers the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes of poisoning. Figures show The Full Outline of Unresponsiveness (FOUR) scale, a patient with methemoglobinemia, a hand with scaling due to mercury poisoning, an electrocardiogram with examples of QT prolongation and QRS widening, and an electrocardiogram of bidirectional ventricular tachycardia, pathognomonic of digitalis glycoside poisoning. Tables list a stepwise approach to a potentially poisoned patient, a general approach to the poisoned patient, heart rate, toxidromes, anticholinergic toxidrome, cholinergic toxidrome, Glasgow Coma Scale, toxins and associated odors, electrocardiogram findings, causes of anion-gap metabolic acidosis, and antidotes. This review contains 5 highly rendered figures, 13 tables, and 23 references Key words: Poison ingestion, Accidental poisoning, Toxidrome, Accidental overdose

A case report of cholinesterase inhibitor poisoning: cholinesterase activities and analytical methods for diagnosis and clinical decision making

Suicidal ingestion of organophosphorus (OP) or carbamate (CM) compounds challenges health care systems worldwide, particularly in Southeast Asia. The diagnosis and treatment of OP or CM poisoning is traditionally based on the clinical appearance of the typical cholinergic toxidrome, e.g. miosis, salivation and bradycardia. Yet, clinical signs might be inconclusive or even misleading. A current case report highlights the importance of enzymatic assays to provide rapid information and support clinicians in diagnosis and rational clinical decision making. Furthermore, the differentiation between OP and CM poisoning seems important, as an oxime therapy will most probably not provide benefit in CM poisoning, but—as every pharmaceutical product—it might result in adverse effects. The early identification of the causing agent and the amount taken up in the body are helpful in planning of the therapeutic regimen including experimental strategies, e.g. the use of human blood products to facilitate scavenging of the toxic agent. Furthermore, the analysis of biotransformation products and antidote levels provides additional insights into the pathophysiology of OP or CM poisoning. In conclusion, cholinesterase activities and modern analytical methods help to provide a more effective treatment and a thorough understanding of individual cases of OP or CM poisoning.

Novichok agents: a historical, current, and toxicological perspective

The Novichok, or “newcomer” class of nerve agents are lesser characterized, weaponized organophosphate agents. The use of known Novichok agents in warfare is banned under the Chemical Weapons Convention of 1997. Novichok agents are considered more potent than VX gas and can be applied in unitary and binary forms. Like other nerve agents, Novichok agents irreversibly bind acetylcholinesterase and produce a cholinergic toxidrome. Uniquely, these agents are thought to also target neurons in the peripheral nervous system. Delayed treatment or massive exposure may therefore cause a debilitating neuropathy. The recent 2018 assassination attempt of Russian dissident Sergei Skripal and his daughter Yulia in the United Kingdom highlights the importance of recognizing the potential lethal effects of these nerve agents. Treatment of Novichok agent poisoning is similar to management of other nerve agents. Given increasing worldwide incidents attributed to chemical weapons such as Novichok agents, clinicians should know how to rapidly recognize symptoms of acute poisoning and administer life-saving antidotal therapy, when indicated.

Death Following Ingestion of Clitocybe Species Mushroom

Death due to muscarine toxicity after ingestion of wild mushrooms is a rare event. We present a case of a patient that developed a severe cholinergic toxidrome and subsequently died after ingesting Clitocybe mushrooms.

Toxic Interaction Between Fluoxetine And Donepezil: A Case Of Cholinergic Toxidrome

Toxic Interaction Between Fluoxetine And Donepezil: A Case Of Cholinergic Toxidrome

Poisonings Associated With Illegal Use of Aldicarb as a Rodenticide—New York City, 1994-1997

Although rodenticides historically have been among the most toxic substances available to the public and have been implicated as agents in both unintentional and suicidal exposures, the anticoagulant agents currently in use, such as coumadin and their long-acting derivatives (e.g., brodifacoum), are relatively safe. In 1995, most persons who reported exposure to anticoagulant rodenticides did not develop symptoms or require specific therapy. However, during 1994-1997, the New York City Poison Control Center (NYCPCC) was consulted about 25 patients, primarily persons who had emigrated from the Dominican Republic, who had manifestations consistent with the cholinergic toxidrome, which is not characteristic of poisoning by the anticoagulant rodenticides, after ingesting a rodenticide known as Tres Pasitos ("Three Little Steps"). In each case, the product had been purchased at a neighborhood store for use as a household rodenticide. The Environmental Investigation Unit of the New York State Department of Environmental Conservation (NYDEC) investigated the poisoning incidents. Laboratory analysis indicated that the product contained the carbamate pesticide aldicarb (2-methyl-2-(methylthio)-propionaldehyde O-(methylcarbamoyl) oxime), which is not registered for use as a rodenticide in the United States. This report presents a detailed description of two of these cases and a summary of the remaining cases.