Genomic regulatory network of human olfactory neuroepithelial cells infected with novel coronavirus (SARS-COV-2).

Objective To explore the genomic changes of human olfactory neuroepithelial cells after the novel coronavirus (SARS-COV-2) infecting the human body, and establish a protein-protein interaction (PPI) network of differentially expressed genes (DEGs), in order to understand the impact of SARS-COV-2 infection on human olfactory neuroepithelial cells, and provide reference for the prevention and treatment of new coronavirus pneumonia. Methods The public dataset GSE151973 was analyzed by NetworkAnalyst. DEGs were selected by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis. PPI network, DEGs-microRNA regulatory network, transcription factor-DEGs regulatory network, environmental chemicals-DEGs regulatory network, and drug-DEGs regulatory network were created and visualized by using Cytoscape 3.7.2. Results After SAR-COV-2 invading human olfactory neuroepithelial cells, part of the gene expression profile was significantly up-regulated or down-regulated. A total of 568 DEGs were found, including 550 up-regulated genes (96.8%) and 18 down-regulated genes (3.2%). DEGs were mainly involved in biological processes such as endothelial development and angiogenesis of the olfactory epithelium, and the expression of molecular functions such as the binding of the N-terminal myristylation domain. PPI network suggested that RTP1 and RTP2 were core proteins. MAZ was the most influential transcription factor. Hsa-mir-26b-5p had the most obvious interaction with DEGs regulation. Environmental chemical valproic acid and drug ethanol had the most influence on the regulation of DEG. Conclusion The gene expression of olfactory neuroepithelial cells is significantly up-regulated or down-regulated after infection with SAR-COV-2. SARS-CoV-2 may inhibit the proliferation and differentiation of muscle satellite cells by inhibiting the function of PAX7. RTP1 and RTP2 may resist SARS-CoV-2 by promoting the ability of olfactory receptors to coat the membrane and enhancing the ability of olfactory receptors to respond to odorant ligands. MAZ may regulate DEGs by affecting cell growth and proliferation. Micro RNA, environmental chemicals and drugs also play an important role in the anti-SAR-COV-2 infection process of human olfactory neuroepithelial cells.Copyright © 2022 Editorial Department of Journal of Shanghai Second Medical University. All rights reserved.

Inhibition of Human Coronaviruses by Combinations of Host-Targeted and Direct-Acting Antivirals.

Antiviral compounds targeting cellular metabolism are part of the therapeutic arsenal to control the spread of virus infection, either as sole treatment or in combination with direct-acting antivirals (DAA) or vaccines. Here, we describe the effect of two of them, lauryl gallate (LG) and valproic acid (VPA) both exhibiting a wide antiviral spectrum, against infection by coronaviruses such as HCoV-229E, HCoV-OC43, and SARS-CoV-2. A consistent 2 to 4-log-decrease in virus yields was observed in the presence of each antiviral, with an average IC50 value of 1.6 µM for LG and 7.2 mM for VPA. Similar levels of inhibition were observed when adding the drug 1 h before adsorption, at the time of infection or 2 h after infection, supporting a postvirus entry mechanism of action. The specificity of the antiviral effect of LG against SARS-CoV-2, relative to other related compounds such as gallic acid (G) and epicatechin gallate (ECG), predicted to be better inhibitors according to in silico studies, was also demonstrated. The combined addition of LG, VPA, and remdesivir (RDV), a DAA with a proven effect against human coronaviruses, resulted in a robust synergistic effect between LG and VPA, and to a lesser extent between the other drug combinations. These findings reinforce the interest of these wide antiviral spectrum host-targeted compounds as a first line of defense against viral diseases or as a vaccine complement to minimize the gap in antibody-mediated protection evoked by vaccines, either in the case of SARS-CoV-2 or for other possible emerging viruses.

Genomic regulatory network of human olfactory neuroepithelial cells infected with novel coronavirus (SARS-COV-2)

Objective To explore the genomic changes of human olfactory neuroepithelial cells after the novel coronavirus (SARS-COV-2) infecting the human body, and establish a protein-protein interaction (PPI) network of differentially expressed genes (DEGs), in order to understand the impact of SARS-COV-2 infection on human olfactory neuroepithelial cells, and provide reference for the prevention and treatment of new coronavirus pneumonia. Methods The public dataset GSE151973 was analyzed by NetworkAnalyst. DEGs were selected by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis. PPI network, DEGs-microRNA regulatory network, transcription factor-DEGs regulatory network, environmental chemicals-DEGs regulatory network, and drug-DEGs regulatory network were created and visualized by using Cytoscape 3.7.2. Results After SAR-COV-2 invading human olfactory neuroepithelial cells, part of the gene expression profile was significantly up-regulated or down-regulated. A total of 568 DEGs were found, including 550 up-regulated genes (96.8%) and 18 down-regulated genes (3.2%). DEGs were mainly involved in biological processes such as endothelial development and angiogenesis of the olfactory epithelium, and the expression of molecular functions such as the binding of the N-terminal myristylation domain. PPI network suggested that RTP1 and RTP2 were core proteins. MAZ was the most influential transcription factor. Hsa-mir-26b-5p had the most obvious interaction with DEGs regulation. Environmental chemical valproic acid and drug ethanol had the most influence on the regulation of DEG. Conclusion The gene expression of olfactory neuroepithelial cells is significantly up-regulated or down-regulated after infection with SAR-COV-2. SARS-CoV-2 may inhibit the proliferation and differentiation of muscle satellite cells by inhibiting the function of PAX7. RTP1 and RTP2 may resist SARS-CoV-2 by promoting the ability of olfactory receptors to coat the membrane and enhancing the ability of olfactory receptors to respond to odorant ligands. MAZ may regulate DEGs by affecting cell growth and proliferation. Micro RNA, environmental chemicals and drugs also play an important role in the anti-SAR-COV-2 infection process of human olfactory neuroepithelial cells.

Valproate-coenzyme A conjugate blocks opening of receptor binding domains in the spike trimer of SARS-CoV-2 through an allosteric mechanism.

The receptor-binding domains (RBDs) of the SARS-CoV-2 spike trimer exhibit "up" and "down" conformations often targeted by neutralizing antibodies. Only in the "up" configuration can RBDs bind to the ACE2 receptor of the host cell and initiate the process of viral multiplication. Here, we identify a lead compound (3-oxo-valproate-coenzyme A conjugate or Val-CoA) that stabilizes the spike trimer with RBDs in the down conformation. Val-CoA interacts with three R408 residues, one from each RBD, which significantly reduces the inter-subunit R408-R408 distance by ∼ 13 Å and closes the central pore formed by the three RBDs. Experimental evidence is presented that R408 is part of a triggering mechanism that controls the prefusion to postfusion state transition of the spike trimer. By stabilizing the RBDs in the down configuration, this and other related compounds can likely attenuate viral transmission. The reported findings for binding of Val-CoA to the spike trimer suggest a new approach for the design of allosteric antiviral drugs that do not have to compete for specific virus-receptor interactions but instead hinder the conformational motion of viral membrane proteins essential for interaction with the host cell. Here, we introduce an approach to target the spike protein by identifying lead compounds that stabilize the RBDs in the trimeric "down" configuration. When these compounds trimerize monomeric RBD immunogens as co-immunogens, they could also induce new types of non-ACE2 blocking antibodies that prevent local cell-to-cell transmission of the virus, providing a novel approach for inhibition of SARS-CoV-2.

Phase II study of sodium valproate in combination with oral etoposide in platinum-resistant ovarian cancer.

Patients with platinum-resistant ovarian cancer (PROC) have limited therapeutic options and poor survival. There is a need for the development of newer therapies. Sodium valproic acid (VPA) is a short-chain fatty acid histone deacetylase (HDAC) inhibitor with antitumor activity in preclinical models of PROC. Synergism with conventional cytotoxic agents like etoposide has been demonstrated. In this prospective, single-arm, open-label, phase 2 study, we included patients ≥ 18 years with histologically or cytologically confirmed PROC and Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-3. Patients received oral VPA 60 mg/kg/day in three divided doses for 3 days (D1-D3), followed by oral etoposide 50 mg once daily for two consecutive weeks (D4-D17). Serum samples were collected to assess peak VPA drug levels. The primary endpoint was the overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. We sought to show an improvement in response rate from 25% (historically with oral etoposide) to 40% with the addition of VPA. 27 patients were enrolled in the study, and 18 [median age: 52 (45-59) years; serous histology:17 (94%); ECOG-PS 2 or 3: 14 (78%)] were evaluable for the response after 4 months. Nine patients were lost from follow-up before achieving the primary endpoint (mainly due to Covid-related lockdown issues). The median number of prior lines of treatment was 2 (1-3). ORR was 0% according to GCIG criteria. The disease was stable in two patients [clinical benefit rate (CBR) of 11%]. The median OS and PFS were 7 months and 2 months, respectively. Grade ≥ 3 adverse events were reported in 6 (33%) patients. The addition of valproic acid to oral etoposide in patients with PROC and poor general condition was not helpful and failed to improve responses compared to those historically achieved with single-agent etoposide. However, further phase 2 randomized controlled trials with larger sample size can be done to confirm the findings.

A Case of Cotard Syndrome and Neurosyphilis

BACKGROUND: Cotard syndrome is a rare neuropsychiatric condition in which individuals have delusions of being deceased or losing their organs. It is often seen in patients with severe depression and is associated with catatonia.1 Neurosyphilis is a severe sequelae of untreated treponema pallidum infection in which the paretic form of this disorder commonly has a psychiatric presentation. 2 We present a rare case of Cotard syndrome in a patient with neurosyphilis with successful treatment. OBJECTIVE: To understand Cotard syndrome and underlying neuropsychiatric conditions, and characterize the diagnosis and management of psychiatric symptoms in a patient with neurosyphilis. METHODS: Review of a case using electronic medical records and relevant literature. Key terms searched: 'Cotard syndrome,' 'neurosyphilis,' 'COVID-19 infection' using Medscape and Google Scholar. RESULTS: We present a 49-year-old male with a history of alcohol use disorder in remission, depression, and history of COVID-19 (asymptomatic) 6 months prior. The patient presented to the emergency department for recent changes in behavior. He was agitated, threatening, and required chemical and physical restraint. Evaluation was notable for illogical thought processes with somatic delusions. He repeatedly stated, 'I am already dead, my organs have died,' and had an episode of catatonia. All tests including drug screen and COVID-19 were negative. Rapid plasma regain (RPR) titer was 1:64. Neurology and Infectious Disease were consulted. Lumbar puncture revealed positive venereal disease research laboratory (VDRL) titer of 1:4. The patient was diagnosed with neurosyphilis and major depressive disorder with psychosis with Cotard syndrome. He was treated with intravenous (IV) penicillin G and was discharged on oral mirtazapine 30 mg and olanzapine 20 mg nightly at bedtime, oral donepezil 5 mg daily, thiamine, and folate. CONCLUSIONS: Cotard syndrome is often seen in depression with psychotic features.1 Neurosyphilis can present with depression, anxiety, psychosis, and dementia. Early identification is the key for successful treatment. This is a unique case of neurosyphilis with features of Cotard syndrome in a patient with a history of depression with treatment noncompliance. Studies show that quetiapine and risperidone improve psychosis in neurosyphilis.5 In this case, neurosyphilis was successfully treated with IV penicillin G for 2 weeks. The patient was also tried on antipsychotics and mood stabilizers ' specifically aripiprazole, valproic acid, and haloperidol ' and was eventually stabilized on oral olanzapine 20 mg taken nightly at bedtime. Our differential diagnosis also included COVID-19 delirium with Cotard syndrome, which was ruled out due to a negative COVID test. To our knowledge, there are 2 cases of COVID-19 delirium with Cotard syndrome.6 We present this case to inform clinicians of rare manifestations of neurosyphilis in patients with comorbid psychiatric illness and to advance research into treatment options for psychosis in neurosyphilis.

Telepharmacy at Mental Health Services: A new approach to medication therapy management during COVID-19

Service or Program: The number of COVID-19 infections have increased dramatically since March 2020 in Qatar. Measures have been taken to minimize the risk of exposure to COVID-19 including medication home delivery by postal service and by using telemedicine at The Mental Health Service (MHS), a tertiary care hospital in Qatar. In order to continue patients' access to care during the pandemic, the Medication Therapy Management (MTM) clinic at MHS would like to utilize clinical pharmacists to offer patient counseling, medication reviews, and develop medication action plans with the patients via telepharmacy. Justification/Documentation: Patients for whom counseling is essential to ensure positive outcomes of therapy were identified;patients on lithium or clozapine (phase 1), patient on newly prescribed psychotropics or on antipsychotic polypharmacy (phase 2), females on valproate in childbearing age (phase 3). The aim of this quality improvement (QI) project was to improve the number of patients currently receiving MTM service from baseline (90) by 20% by September 2020, 50% by December 2020 and 80% by March 2021. Outcome measure included percentage increase in patients from baseline who are receiving telepharmacy service, process measures included the percentage compliance of filling the Moresky Medication Adherence Scale-4 by the pharmacist, the percentage of referrals to other MHS services, balance measures were patient/caregivers and staff satisfaction. The improvement in outcome measure was successfully achieved in each phase;phase 1 - 28%, phase 2 - 82%, phase 3 - 127%. QI tools were used as appropriate. Adaptability: This service was intended to be provided by clinical pharmacists to adult patients registered under MHS. Similar service can easily be adapted to another setting by clinical pharmacists using comparable strategies and measures. Significance: The lessons learnt from this QI project will help in increasing patients' access to care, promote better utilization of resources, and allow better communication and management of patients.

Conversion of Stuporous Catatonia to Excited Catatonia from Lorazepam Challenge

Background: Catatonia, a motor dysregulation syndrome with behavioral components, has undergone many conceptual changes since its inception as a syndrome by Kahlbaum in 1874. Prevalence of catatonia in consultation-liaison services is approximately 5.5 percent in patients aged 65 and older.1 Stuporous catatonia is most common, but catatonia may present in excited or malignant subtypes. Together, the subtypes have over 40 documented signs and symptoms, making catatonia difficult to diagnose and appropriately treat.2 Catatonia involves hyperactivation of the orbitofrontal cortex (OFC) and ventromedial prefrontal cortex. GABA, NMDA, and dopamine have been implicated. GABA-A agonism by benzodiazepines improve catatonia by normalizing OFC activity.3 Case: A 66-year-old male with schizophrenia was admitted to a medical unit for failure to thrive after not eating for three days. He had not taken his medications for 2 weeks including chlorpromazine, quetiapine, oxcarbazepine, and clonazepam. Upon psychiatric consult, the patient exhibited staring, grimacing, echopraxia, and negativism. He was diagnosed with stuporous catatonia. 30 minutes after lorazepam challenge (2 milligram intravenous lorazepam), the patient was moving, conversing, and eating. After second dose of lorazepam, the patient became difficult to redirect, displaying stereotypy, verbigeration, and hitting. Additional doses of lorazepam were unsuccessful in breaking excited catatonia. History revealed previous catatonic episodes, including nine months prior when the patient was admitted to a gero-psychiatric unit. He initially presented in stuporous state, normalized with lorazepam, then transitioned to excited state. He received 16 milligrams of lorazepam in 24 hours without successful termination of excited catatonia. Lorazepam in combination with carbamazepine, clozapine, or valproic acid was unsuccessful. Catatonia was successfully treated with 10 sessions of electroconvulsive therapy (ECT) with lorazepam, clozapine, and valproic acid. Maintenance ECT was not continued because of the COVID pandemic, and the patient was admitted to a state facility after regression. Discussion: Catatonia is often encountered on consultation-liaison services in general hospital settings. We observed conversion of stuporous catatonia to excited catatonia after administration of lorazepam. This treatment-resistant catatonia ultimately required ECT. No reported cases of stuporous catatonia transitioning to excited catatonia were found on thorough literature review. Recognition of this conversion may be difficult and may require development of a catatonia scale that clearly identifies the presenting subtype. This is a challenge;clinical signs are not mutually exclusive among subtypes. This patient’s clinical course may provide insight into the identification of treatment-resistant catatonia, and accurate identification is necessary to allow for timely escalation of treatment. References: 1. Solmi M, et al. Prevalence of catatonia and its moderators in clinical samples: Results from a meta-analysis and meta-regression analysis. Schizophrenia Bulletin. 2017;44(5):1133–50. 2. Fink M, Taylor MA. The catatonia syndrome. Archives of General Psychiatry. 009;66(11):1173. 3. Ellul P, Choucha W. Neurobiological approach of Catatonia and Treatment Perspectives. Frontiers in Psychiatry. 2015;6.

Evolution of Therapeutic Drug Monitoring requests in a tertiary University Hospital in the last 16 years

Introduction: TDM has been widely used in clinical practice for many years and has application in various groups of drugs,mainly in drugs with pharmacokinetic variability, concentration related therapeutic and adverse effects, narrow therapeutic index, defined therapeutic concentration range and desired therapeutic effect difficult to monitor. Objectives: The aim of this study is to assess the evolution of TDM application throughout the years and its usefulness and necessity nowadays in a tertiary University Hospital. Methods: Data of Therapeutic Drug Monitoring requests were collected for the years 2005, 2010, 2015, 2019, 2020 and 2021 from the records of the Laboratory of Pharmacology General University Hospital of Alexandroupolis. Drugs monitored included digoxin, valproic acid, carbamazepine, phenytoin, phenobarbital, cyclosporine, tacrolimus, amikacin, gentamycin, vancomycin, serum benzodiazepines, methotrexate, cortisol, acetaminophen, salicylate, theophylline, tobramycin and primidone. More specifically, the data collected were the drug's level measurement and the clinic that requested the specific drug order. Results: A total of 1357 drug level measurement records were found for 2005, 1442 for 2010, 766 for 2015, 520 for 2019, 442 for 2020 and 622 for 2021. During these years the most frequent drug requested for TDM was digoxin (2005), cyclosporine (2010, 2019), valproic acid (2015, 2020), and tacrolimus (2021). In regards to the drugs requested, digoxin was predominantly requested by Cardiology and Pathology, cyclosporine and tacrolimus by Nephrology and valproic acid by Psychiatry. Furthermore, the percentage of non optimal therapeutic levels that required dose adjustments were calculated and will be presented. Conclusion: TDM retains a degree of its value as shown by the number of incidents requiring dose modifications. In addition, the presented results obtained from 2005 to 2021 show that there is a notable decrease in the number of requests for TDM per year. This can be imputed to several reasons such as the replacement of specific drugs with new therapeutic regimens and the evolution of therapeutic drug protocols in several diseases. Another major factor was the measures taken against the Covid-19 pandemic in the last two years which resulted to a substantial decrease of routine health examinations and scheduled appointments in the Hospital.

Congresso Nazionale della Societa Italiana di Psicopatologia

The proceedings contain 130 papers. The topics discussed include: suicide risk and suicide risk factors among immigrants in Italy: a bicenter matched sample study;metacognition and dysfunctional beliefs: which role in sleep quality of subjects affected by psychiatric disease?;COVID-19, mental health, and stigma: a way to go against the grain?;telephone counselling in coping with the COVID-19 lockdown consequences: preliminary data;the risk perception during COVID-19 in a psychiatric population: a cross-sectional observational study;impact of COVID-19 pandemic and coping strategies among depressed patients;and intravenous valproic acid (IV VPA) in acute agitation: a pilot study in an acute psychiatric inpatient unit.

Seven days in medicine: 22-28 June 2022

Alcohol pricing Policies could significantly cut health harms, says WHO European countries could significantly reduce health harms from alcohol consumption by introducing minimum pricing for alcoholic beverages, said the World Health Organization. (Full story doi:10.1136/bmj.o1542) Valproate UK regulator looks into possible transgenerational effects The Medicines and Healthcare Products Regulatory Agency is examining animal data showing that the epilepsy drug sodium valproate could trigger genetic changes that are passed on to future generations. Austerity Local spending cuts link to poor health Local government spending cuts are associated with worse multimorbidity and health related quality of life, concluded a longitudinal study of 147 English local authorities published in the Lancet Regional Health—Europe.2 After controlling for other spending a 1% cut in public health expenditure was associated with a 0.15% increase in the prevalence of two or more chronic conditions.

Atypical Presentation of Lance Adams Syndrome in the setting of Clonazepam overdose and SARS-CoV-2 pneumonia

Objective: To report an atypical presentation of Lance-Adams Syndrome presenting from severe respiratory depression rather than cardiac arrest and to highlight the importance of distinguishing it from post hypoxic myoclonic variants. Background: Clinicians often face difficulty distinguishing Lance-Adams Syndrome (LAS) from Myoclonic Status Epilepticus (MSE). Similarities between the two conditions frequently result in confusion when diagnosing, managing and prognosticating for post-hypoxic myoclonus patients. Design/Methods: A 23-year-old male with a history pertinent for Hemophilia B, depression, opiate and alcohol abuse and chronic pain was found down in his home next to an empty bottle of clonazepam. He was hypoxic with oxygen saturation in the 40s and intubated in the field. Upon arrival to the Emergency room, neurological examination revealed intact corneal reflexes but no gag reflex, cough, or purposeful movements of the extremities. The patient exhibited stimulus induced myoclonic jerking which lasted >30 minutes despite being loaded on valproic acid and levetiracetam. Jerking subsequently ceased with propofol drip. Chest X-ray confirmed interstitial opacities and tested positive for SARS-CoV-2. On attempting to wean sedation, patient exhibited full-body myoclonus including face and palate with inability to follow commands and lack of spontaneous movements. As the EEG showed BIPEDS greater than 2.5 HZ, we decided to burst suppress him and treat with targeted temperature management. After 10 days, the patient was successfully weaned from sedation and extubated, but remained on multiple anti-seizure medications. Results: Patient responded well despite his diffuse cerebral anoxic injury. He regained the ability to follow commands upon discharge but had residual moderate expressive aphasia and post-hypoxic action-induced myoclonus, consistent with LAS. Conclusions: The atypical presentation of this case emphasizes the importance of distinguishing LAS from MSE to guide neurologists to aggressively treat LAS to improve outcome, particularly since MSE historically results with a 90-100% mortality rate.

New onset limbic encephalitis and COVID-19 vaccine: a case report

Background: Autoimmune limbic encephalitis (ALE) is an inflammatory disease involving the medial temporal lobes. It is characterized by subacute onset of short-term memory deficits, seizures and psychiatric disorders. Few new cases of ALE associated both with SARS-CoV2 infection and COVID-19 vaccine have recently been described. Case presentation: A 56-year-old woman was admitted to emergency department for persistent fever and acute onset of confusion few days apart the first dose of BNT162b2 COVID-19 vaccine. Neurological examination revealed confusion and short-term memory loss. Blood test showed only leukopenia and mild increase of the PCR. The patient underwent brain CT-scan which excluded organic lesion for the cognitive deficit. During the hospitalization the patient presented tonic clonic seizures and postictal state therefore an EEG was performed and revealed epileptiform abnormalities in the temporal lobes. Since the hypothesis of encephalitis brain MRI and lombar puncture for cerebral spinal fluid (CSF) analysis were performed with evidence of T2 hyperintensity in temporal lobes and normal values of CSF. Despite steroid and antiepileptic therapy with Carbamazepine, Valproate and Perampanel, several epileptic relapses occurred and there was no improvement of neurological manifestation. The patient was finally discharged with need of home care Conclusions: New onset ALE following COVID-19 vaccine or infection has rarely been described. Clinicians should monitor neurological symptoms to ensure appropriate therapy to maximize the likelihood of good outcome.

SARS-CoV-2 Infection, Sex-Related Differences, and a Possible Personalized Treatment Approach with Valproic Acid: A Review.

Sex differences identified in the COVID-19 pandemic are necessary to study. It is essential to investigate the efficacy of the drugs in clinical trials for the treatment of COVID-19, and to analyse the sex-related beneficial and adverse effects. The histone deacetylase inhibitor valproic acid (VPA) is a potential drug that could be adapted to prevent the progression and complications of SARS-CoV-2 infection. VPA has a history of research in the treatment of various viral infections. This article reviews the preclinical data, showing that the pharmacological impact of VPA may apply to COVID-19 pathogenetic mechanisms. VPA inhibits SARS-CoV-2 virus entry, suppresses the pro-inflammatory immune cell and cytokine response to infection, and reduces inflammatory tissue and organ damage by mechanisms that may appear to be sex-related. The antithrombotic, antiplatelet, anti-inflammatory, immunomodulatory, glucose- and testosterone-lowering in blood serum effects of VPA suggest that the drug could be promising for therapy of COVID-19. Sex-related differences in the efficacy of VPA treatment may be significant in developing a personalised treatment strategy for COVID-19.

Mind your language to catalyse the patient revolution

In one damning example, participants in unethical studies of ivermectin were exposed to its side effects without knowing that they were given the drug (doi:10.1136/bmj.o917).1 Covid was also a free pass to tighten, loosen, or avoid public health measures, with little consultation or input from the public. [...]a terminally ill patient might wish for assisted death, but their doctor might disagree (doi:10.1136/bmj.o1014).3 Or a woman might decline the offer of sodium valproate in pregnancy if sufficiently aware of the risk of birth defects (doi:10.1136/bmj.o1013).4 The BMJ has attempted to bridge these gaps in perspective and information by appointing patient editors. Caitríona Cox and Zoë Fritz explain, with examples, how “some commonly used language confers petulance on patients, renders them passive, or blames them for poor outcomes” (doi:10.1136/bmj-2021-066720).7 To most clinicians, phrases such as “presenting complaint” and descriptions of patients “denying chest pain” are empty jargon, holding no more than functional meaning.

A case of acute encephalopathy with biphasic seizures and delayed diffusion changes

Acute encephalopathy with biphasic seizures and delayed diffusion changes (AESD) is an extremely rare syndrome outside Asia. AESD is diagnosed based on clinic-radiological correlation. Influenza or human herpesvirus 6 infection have been most commonly isolated in previously healthy children with AESD and there is possible correlation with genetic abnormalities such as mutations in the SCN1A gene. We report a 2 year old previously fit and well white female who presented febrile status epilepticus at day 3 of an upper respiratory tract infection with subsequent prolonged left facial palsy and left hemiparesis. Brain MRI on day 4 showed swelling and diffusion restriction of the right hippocampus, without any other focal abnormality or signs of ischaemia. On day 6 she presented clusters of focal left sided seizures, non-responding to treatment Levetiracetam and sodium valproate add on. Repeated brain MRI on 7 showed prolonged and diffuse diffusion restriction over the whole right hemisphere, which along with the characteristic clinical presentation led to the diagnosis of AESD. She received high dose IV steroids with taper over 6 weeks starting on day 9. The seizures stopped on day 10 but motor function recovery was slow. CSF analysis showed no signs of infection. Nasopharyngeal swab was positive for Bocavirus and she had positive antibodies for SARS-COV-2 with negative PCR. Genetic investigations were requested and are pending. This case illustrates the importance of repeated brain imaging in abrupt onset refractory seizures with abnormal neurological examination which can lead to early diagnosis and treatment. More studies are needed to investigate the correlation between SARs-COV-2 or Bocavirus and AESD.

A 5-Year Study of Lithium and Valproic Acid Drug Monitoring in Patients with Bipolar Disorders in an Italian Clinical Center.

Therapeutic drug monitoring (TDM) is an effective tool used to improve the pharmacological treatment in clinical practice, especially to detect subtherapeutic drug plasma concentration (Cp) in order to consider a change of dosage during treatment and reach its putative therapeutic range. In this study, we report the Cp values of lithium and valproic acid (VPA), alone and in combination, mostly in bipolar patients admitted to an Italian clinical center of the University of Pisa during the years 2016-2020, which include 12,294 samples of VPA, 7449 of lithium and 1118 of both in combination. Lithium and VPA are the most utilized drugs in treating bipolar disorders, and their TDM is strongly recommended by recent guidelines. In relation to lithium Cp monitoring, several studies have underlined that 0.5-0.8 mmol/L is the optimal range for chronic treatment, and below 0.4 mmol/L, it is unlikely to produce a clinical response. For VPA, the therapeutic range is 50-100 µg/mL and a linear correlation between Cp and clinical efficacy has been proposed, where below 50 µg/mL, the clinical efficacy of VPA has not been proven thus far. Toxic levels of both drugs were rarely found in our study, while a high percentage of patients, about one-third, had sub-therapeutic Cp during their treatments. In addition, in several cases of patients receiving multiple blood sampling, the initial subtherapeutic Cp changed only partially without reaching its therapeutic window. In relation to age, we found a higher percentage of lithium and VPA Cp values in range in the adolescents than in the adults and elderly groups. No differences were reported when analyzing the distribution of Cp values in males and females. In conclusion, this present study suggests that TDM is widely used by many specialists, but there is still a window of improvement for optimizing pharmacological treatments in clinical practice.

P.0177 Partial ornithine-transcarbamylase deficiency, autoimmunity and psychosis – a complex case report

Background: Ornithine-transcarbamylase deficiency (OTC) is the most common type of urea cycle disorder, and it is the only one with X-linked inheritance. The clinical presentations can vary from severe symptoms caused by hyperammonemia in childhood or adolescence to milder cases with late-onset in adulthood (similar to delirium or acute psychosis) [1], in the context of precipitating factors such as pregnancy, high protein intake, acute stress, infections, certain medications (valproate, steroids, haloperidol) [2]. Method: We present a case of a 31-year-old female, with no history of mental disorders, with a personal history of Hashimoto thyroiditis and urticaria, and a family history of OTC deficiency (her two-year-old niece). She was also a heterozygous carrier for the OTC deletion, reporting periods of meat avoidance and anorexia. She was single, lived alone, and complained of work-related stress, mainly as she worked from home during the COVID-19 pandemic as an IT consultant. The patient presented at our clinic in emergency for psychomotor agitation, slurred speech, complex auditory and visual hallucinations, and mystical delusional ideas. Furthermore, one week before her presentation, she started fasting because of her Christian orthodox religious beliefs (before Easter celebration), but she also complained of insomnia, fatigue, and tachycardia. The patient reported being vaccinated with the first dose of Pfizer's SARS-CoV-2 vaccine one week before the presentation. Results: Laboratory tests showed iron-deficient anemia and ketonuria;hepatic function was normal. Thyroid function was also normal, but anti thyroperoxidase antibodies were elevated. Serum ammonia levels were normal, and urinary orotic acid levels were within normal range. The result of head CT was unremarkable. Neurological examination was normal. She was started on 10 mg i.m. Haloperidol per day, but given the possibility of inducing hyperammonemia in urea cycle disorders patients, she was switched to Risperidone 6 mg/day, which was gradually reduced to 3 mg/day. Also, she was started on a protein-restricted diet. On the second and third days of admission, she was partially disoriented and somnolent but showed no signs of metabolic encephalopathy;therefore, metabolic treatment was not initiated. On the sixth day, she was almost completely recovered, with no psychotic symptoms. After the remission of psychotic symptoms, the neuropsychological evaluation showed significant cognitive deficits: executive functions (impaired performance on Tower of London task), deficits of focused and distributed attention, and decreased immediate verbal memory, even though the patient had received higher education, being at the top of her class during her studies. Given that metabolic profiles were normal, we discuss the complex interactions between autoimmune disorders, genetic factors, precipitating factors, and psychosocial factors that could have contributed to the psychotic episode. Conclusion: Clinicians should consider various factors that can influence the psychological state of a patient, paying attention to atypical factors or symptoms. Also, regarding the treatment of psychiatric symptoms in patients with urea cycle disorders with a normal metabolic profile, psychiatrists must avoid certain medications (haloperidol, valproate) that can worsen the patient's status. No conflict of interest