Catatonia associated with pediatric postoperative cerebellar mutism syndrome.

OBJECTIVE: To ascertain the presence of catatonia in cases of pediatric postoperative cerebellar mutism syndrome (PPCMS). METHOD: A systematic review of PPCMS case reports of patients aged 0-17 years with sufficient clinical information to extract catatonic phenomena was undertaken following PRISMA guidelines. Standardized catatonia rating scales were applied to selected cases retrospectively to ascertain whether diagnostic criteria for catatonia were met. A case known to the authors is also presented. RESULTS: Two hundred twenty-one suitable full-text articles were identified. Following screening and application of inclusion criteria, 51 articles were selected plus seven more from their references, reporting on 119 subjects. All cases met Bush and Francis (BF) diagnostic criteria for catatonia, 92.5% Pediatric Catatonia Rating Scale (PCRS), 52.9% ICD-11, and 44.5% DSM-5. All patients presented with mutism. The next most frequent signs were immobility/stupor (77.3%), withdrawal (35.3%), mannerisms (23.5%), and excitement/agitation (18.5%). Most cases presented with stuporous catatonia (75.6%). Catatonia most frequently occurred following resection of medulloblastoma (64.7%). Preoperative hydrocephalus occurred in 89 patients (74.8%). CONCLUSION: Catatonia was frequent in this PPCMS sample, with a predominant stuporous variant; it should be considered in patients with PPCMS and assessed with reliable and validated instruments for prompt diagnosis and management.

Design, quality and validation of the EU-OPENSCREEN fragment library poised to a high-throughput screening collection.

The EU-OPENSCREEN (EU-OS) European Research Infrastructure Consortium (ERIC) is a multinational, not-for-profit initiative that integrates high-capacity screening platforms and chemistry groups across Europe to facilitate research in chemical biology and early drug discovery. Over the years, the EU-OS has assembled a high-throughput screening compound collection, the European Chemical Biology Library (ECBL), that contains approximately 100 000 commercially available small molecules and a growing number of thousands of academic compounds crowdsourced through our network of European and non-European chemists. As an extension of the ECBL, here we describe the computational design, quality control and use case screenings of the European Fragment Screening Library (EFSL) composed of 1056 mini and small chemical fragments selected from a substructure analysis of the ECBL. Access to the EFSL is open to researchers from both academia and industry. Using EFSL, eight fragment screening campaigns using different structural and biophysical methods have successfully identified fragment hits in the last two years. As one of the highlighted projects for antibiotics, we describe the screening by Bio-Layer Interferometry (BLI) of the EFSL, the identification of a 35 µM fragment hit targeting the beta-ketoacyl-ACP synthase 2 (FabF), its binding confirmation to the protein by X-ray crystallography (PDB 8PJ0), its subsequent rapid exploration of its surrounding chemical space through hit-picking of ECBL compounds that contain the fragment hit as a core substructure, and the final binding confirmation of two follow-up hits by X-ray crystallography (PDB 8R0I and 8R1V).

CIPSI: An open chemical intellectual property service for medicinal chemists.

The availability of patent chemical data offers public access to a chemical space that is not well covered by other sources collecting small molecules from scholarly literature. However, open applications to facilitate the search and analysis of biologically-relevant molecular structures present in patents are still largely missing. We have developed CIPSI, an open Chemical Intellectual Property Service @ IMIM to assist medicinal chemists in searching and analysing molecules in SureChEMBL patents. The current version contains 6,240,500 molecules from 236,689 pharmacological patents, of which 5,949,214 are confidently assigned to core chemical structures reminiscent of the Markush structure in the patent claim. The platform includes some graphical tools to facilitate comparative patent analyses between drugs, chemical substructures, and company assignees. CIPSI is available at https://cipsi.org.

In silico approaches in carcinogenicity hazard assessment: case study of pregabalin, a nongenotoxic mouse carcinogen.

In silico toxicology protocols are meant to support computationally-based assessments using principles that ensure that results can be generated, recorded, communicated, archived, and then evaluated in a uniform, consistent, and reproducible manner. We investigated the availability of in silico models to predict the carcinogenic potential of pregabalin using the ten key characteristics of carcinogens as a framework for organizing mechanistic studies. Pregabalin is a single-species carcinogen producing only one type of tumor, hemangiosarcomas in mice via a nongenotoxic mechanism. The overall goal of this exercise is to test the ability of in silico models to predict nongenotoxic carcinogenicity with pregabalin as a case study. The established mode of action (MOA) of pregabalin is triggered by tissue hypoxia, leading to oxidative stress (KC5), chronic inflammation (KC6), and increased cell proliferation (KC10) of endothelial cells. Of these KCs, in silico models are available only for selected endpoints in KC5, limiting the usefulness of computational tools in prediction of pregabalin carcinogenicity. KC1 (electrophilicity), KC2 (genotoxicity), and KC8 (receptor-mediated effects), for which predictive in silico models exist, do not play a role in this mode of action. Confidence in the overall assessments is considered to be medium to high for KCs 1, 2, 5, 6, 7 (immune system effects), 8, and 10 (cell proliferation), largely due to the high-quality experimental data. In order to move away from dependence on animal data, development of reliable in silico models for prediction of oxidative stress, chronic inflammation, immunosuppression, and cell proliferation will be critical for the ability to predict nongenotoxic compound carcinogenicity.

Impact of the COVID-19 pandemic on the spontaneous reporting and signal detection of adverse drug events.

External factors severely affecting in a short period of time the spontaneous reporting of adverse events (AEs) can significantly impact drug safety signal detection. Coronavirus disease 2019 (COVID-19) represented an enormous challenge for health systems, with over 767 million cases and massive vaccination campaigns involving over 70% of the worldwide population. This study investigates the potential masking effect on certain AEs caused by the substantial increase in reports solely related to COVID-19 vaccines within various spontaneous reporting systems (SRSs). Three SRSs were used to monitor AEs reporting before and during the pandemic, namely, the World Health Organisation (WHO) global individual case safety reports database (VigiBase®), the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER). Findings revealed a sudden over-reporting of 35 AEs (≥ 200%) during the pandemic, with an increment of the RRF value in 2021 of at least double the RRF reported in 2020. This translates into a substantial reduction in signals of disproportionate reporting (SDR) due to the massive inclusion of COVID-19 vaccine reports. To mitigate the masking effect of COVID-19 vaccines in post-marketing SRS analyses, we recommend utilizing COVID-19-corrected versions for a more accurate assessment.

Illuminating the Chemical Space of Untargeted Proteins.

According to the Illuminating the Druggable Genome (IDG) initiative, 90% of the proteins encoded by the human genome still lack an identified active ligand, that is, a small molecule with biologically relevant binding potency or functional activity in an in vitro assay. Under this scenario, there is an urgent need for new approaches to chemically address these yet untargeted proteins. It is widely recognized that the best starting point for generating novel small molecules for proteins is to exploit the expected polypharmacology of known active ligands across phylogenetically related proteins following the paradigm that similar proteins are likely to interact with similar ligands. Here, we introduce a computational strategy to identify privileged structures that, when chemically expanded, are highly probable to contain active small molecules for untargeted proteins. The protocol was first tested on a set of 576 currently targeted proteins having at least one protein family sibling the year before their first active ligand was reported. A privileged structure contained in active ligands that were identified in the following years was correctly anticipated for 214 (37%) of those targeted proteins, a lower-bound recall estimate when considering data completeness issues. When applied to a set of 1184 untargeted potential druggable genes in cancer, the identification of privileged structures from known bioactive ligands of protein family siblings allowed for extracting a priority list of diverse commercially available small molecules for 960 of them. Assuming a minimum success rate of 37%, the chemical library selections should be able to deliver active ligands for at least 355 currently untargeted proteins associated with cancer.

Primary and Community Care Transformation in Post-COVID Era: Nationwide General Practitioner Survey.

Introduction: The health emergency caused by COVID-19 has led to substantial changes in the usual working system of primary healthcare centers and in relations with users. The Catalan Society of Family and Community Medicine designed a survey that aimed to collect the opinions and facilitate the participation of its partners on what the future work model of general practitioners (GPs) should look like post-COVID-19. Methodology: Online survey of Family and Community Medicine members consisting of filiation data, 22 Likert-type multiple-choice questions grouped in five thematic axes, and a free text question. Results: The number of respondents to the questionnaire was 1051 (22.6% of all members): 83.2% said they spent excessive time on bureaucratic tasks; 91.8% were against call center systems; 66% believed that home care is the responsibility of every family doctor; 77.5% supported continuity of care as a fundamental value of patient-centered care; and >90% defended the contracting of complementary tests and first hospital visits from primary healthcare (PHC). Conclusions: The survey responses describe a strong consensus on the identity and competencies of the GP and on the needs of and the threats to the PHC system. The demand for an increase in health resources, greater professional leadership, elimination of bureaucracy, an increase in the number of health professionals, and greater management autonomy, are the axes towards which a new era in PHC should be directed.

Chemoinformatics and artificial intelligence colloquium: progress and challenges in developing bioactive compounds.

We report the main conclusions of the first Chemoinformatics and Artificial Intelligence Colloquium, Mexico City, June 15-17, 2022. Fifteen lectures were presented during a virtual public event with speakers from industry, academia, and non-for-profit organizations. Twelve hundred and ninety students and academics from more than 60 countries. During the meeting, applications, challenges, and opportunities in drug discovery, de novo drug design, ADME-Tox (absorption, distribution, metabolism, excretion and toxicity) property predictions, organic chemistry, peptides, and antibiotic resistance were discussed. The program along with the recordings of all sessions are freely available at https://www.difacquim.com/english/events/2022-colloquium/ .

Fragment-based virtual screening identifies a first-in-class preclinical drug candidate for Huntington's disease.

Currently, there are no therapies available to modify the disease progression of Huntington's disease (HD). Recent clinical trial failures of antisense oligonucleotide candidates in HD have demonstrated the need for new therapeutic approaches. Here, we developed a novel in-silico fragment scanning approach across the surface of mutant huntingtin (mHTT) polyQ and predicted four hit compounds. Two rounds of compound analoging using a strategy of testing structurally similar compounds in an affinity assay rapidly identified GLYN122. In vitro, GLYN122 directly binds and reduces mHTT and induces autophagy in neurons. In vivo, our results confirm that GLYN122 can reduce mHTT in the cortex and striatum of the R/2 mouse model of Huntington's disease and subsequently improve motor symptoms. Thus, the in-vivo pharmacology profile of GLYN122 is a potential new preclinical candidate for the treatment of HD.

Catatonia in older adults: A systematic review.

BACKGROUND: Catatonia is a complex psychomotor syndrome that often goes unrecognized and untreated, even though its classification has evolved in recent years. Prompt and correct identification of catatonia allows for highly effective treatment and prevention of possible complications. The underrecognition of catatonia in older patients is also frequent, and research in this population is scarce. AIM: To conduct a systematic review of the literature on catatonia in older people to ascertain its clinical characteristics across settings. METHODS: Following the PRISMA guidelines, MEDLINE, EMBASE, and PsycINFO databases were searched from inception to December 2021, with a strategy aimed at identifying all articles published on catatonia in older adults. Titles and abstracts were scanned and selected independently by two authors. Papers investigating issues related to catatonia and/or catatonic symptoms in older people, with English abstracts available, were included. References of selected articles were revised to identify other relevant studies. RESULTS: In total, 1355 articles were retrieved. After removing duplicates, 879 remained. Of the 879 identified abstracts, 669 were excluded because they did not meet the inclusion criteria. A total of 210 articles underwent full text review, and 51 were eliminated for various reasons. Fourteen more articles were selected from the references. Overall, 173 articles were reviewed: 108 case reports, 35 case series, 11 prospective cohort studies, 6 case-control studies, 3 retrospective cohort studies and 10 reviews. We found several particular aspects of catatonia in this population. Catatonia in older patients is highly prevalent and tends to have a multifactorial etiology. Older patients, compared to younger patients, have a higher risk of developing catatonia with benzodiazepine (BZD) withdrawal, in bipolar disorder, and in the general hospital. Age, together with other risk factors, was significantly associated with the incidence of deep venous thrombosis, neuroleptic malignant syndrome poor outcome, other complications and mortality. Treatment with BZDs and electroconvulsive therapy is safe and effective. Prompt treatment of its cause is essential to ensure a good prognosis. CONCLUSION: Catatonia in older patients is highly prevalent and tends to have a multifactorial etiology. The risk of developing catatonia in some settings and conditions, as well as of developing complications, is high in this population. Symptomatic treatment is safe and effective, and timely etiologic treatment is fundamental.

Environmental levels of carbaryl impair zebrafish larvae behaviour: The potential role of ADRA2B and HTR2B.

The insecticide carbaryl is commonly found in indirectly exposed freshwater ecosystems at low concentrations considered safe for fish communities. In this study, we showed that after only 24 h of exposure to environmental concentrations of carbaryl (0.066-660 ng/L), zebrafish larvae exhibit impairments in essential behaviours. Interestingly, the observed behavioural effects induced by carbaryl were acetylcholinesterase-independent. To elucidate the molecular initiating event that resulted in the observed behavioural effects, in silico predictions were followed by in vitro validation. We identified two target proteins that potentially interacted with carbaryl, the α2B adrenoceptor (ADRA2B) and the serotonin 2B receptor (HTR2B). Using a pharmacological approach, we then tested the hypothesis that carbaryl had antagonistic interactions with both receptors. Similar to yohimbine and SB204741, which are prototypic antagonists of ADRA2B and HTR2B, respectively, carbaryl increased the heart rate of zebrafish larvae. When we compared the behavioural effects of a 24-h exposure to these pharmacological antagonists with those of carbaryl, a high degree of similarity was found. These results strongly suggest that antagonism of both ADRA2B and HTR2B is the molecular initiating event that leads to adverse outcomes in zebrafish larvae that have undergone 24 h of exposure to environmentally relevant levels of carbaryl.

Infection control and the prevalence, management and outcomes of SARS-CoV-2 infections in mental health wards in London, UK: lessons learned from wave 1 to wave 2.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has high morbidity and mortality in older adults and people with dementia. Infection control and prevention measures potentially reduce transmission within hospitals. AIMS: We aimed to replicate our earlier study of London mental health in-patients to examine changes in clinical guidance and practice and associated COVID-19 prevalence and outcomes between COVID-19 waves 1 and 2 (1 March to 30 April 2020 and 14 December 2020 to 15 February 2021). METHOD: We collected the 2 month period prevalence of wave 2 of COVID-19 in older (≥65 years) in-patients and those with dementia, as well as patients' characteristics, management and outcomes, including vaccinations. We compared these results with those of our wave 1 study. RESULTS: Sites reported that routine testing and personal protective equipment were available, and routine patient isolation on admission occurred throughout wave 2. COVID-19 infection occurred in 91/358 (25%; 95% CI 21-30%) v. 131/344, (38%; 95% CI 33-43%) P < 0.001 in wave 1. Hospitals identified more asymptomatic carriers (26/91; 29% v. 16/130; 12%) and fewer deaths (12/91; 13% v. 19/131; 15%; odds ratio = 0.92; 0.37-1.81) compared with wave 1. The patient vaccination uptake rate was 49/58 (85%). CONCLUSIONS: Patients in psychiatric in-patient settings, mostly admitted without known SARS-CoV-2 infection, had a high risk of infection compared with people in the community but lower than that during wave 1. Availability of infection control measures in line with a policy of parity of esteem between mental and physical health appears to have lowered within-hospital COVID-19 infections and deaths. Cautious management of vulnerable patient groups including mental health patients may reduce the future impact of COVID-19.

Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome.

BACKGROUND: Acquired long QT syndrome (aLQTS) is a serious unpredictable adverse drug reaction. Pharmacogenomic markers may predict risk. METHODS: Among 153 aLQTS patients (mean age 58 years [range, 14-88], 98.7% White, 85.6% symptomatic), computational methods identified proteins interacting most significantly with 216 QT-prolonging drugs. All cases underwent sequencing of 31 candidate genes arising from this analysis or associating with congenital LQTS. Variants were filtered using a minor allele frequency <1% and classified for susceptibility for aLQTS. Gene-burden analyses were then performed comparing the primary cohort to control exomes (n=452) and an independent replication aLQTS exome sequencing cohort. RESULTS: In 25.5% of cases, at least one rare variant was identified: 22.2% of cases carried a rare variant in a gene associated with congenital LQTS, and in 4% of cases that variant was known to be pathogenic or likely pathogenic for congenital LQTS; 7.8% cases carried a cytochrome-P450 (CYP) gene variant. Of 12 identified CYP variants, 11 (92%) were in an enzyme known to metabolize at least one culprit drug to which the subject had been exposed. Drug-drug interactions that affected culprit drug metabolism were found in 19% of cases. More than one congenital LQTS variant, CYP gene variant, or drug interaction was present in 7.8% of cases. Gene-burden analyses of the primary cohort compared to control exomes (n=452), and an independent replication aLQTS exome sequencing cohort (n=67) and drug-tolerant controls (n=148) demonstrated an increased burden of rare (minor allele frequency<0.01) variants in CYP genes but not LQTS genes. CONCLUSIONS: Rare susceptibility variants in CYP genes are emerging as potentially important pharmacogenomic risk markers for aLQTS and could form part of personalized medicine approaches in the future.

A Workflow of Integrated Resources to Catalyze Network Pharmacology Driven COVID-19 Research.

In the event of an outbreak due to an emerging pathogen, time is of the essence to contain or to mitigate the spread of the disease. Drug repositioning is one of the strategies that has the potential to deliver therapeutics relatively quickly. The SARS-CoV-2 pandemic has shown that integrating critical data resources to drive drug-repositioning studies, involving host-host, host-pathogen, and drug-target interactions, remains a time-consuming effort that translates to a delay in the development and delivery of a life-saving therapy. Here, we describe a workflow we designed for a semiautomated integration of rapidly emerging data sets that can be generally adopted in a broad network pharmacology research setting. The workflow was used to construct a COVID-19 focused multimodal network that integrates 487 host-pathogen, 63 278 host-host protein, and 1221 drug-target interactions. The resultant Neo4j graph database named "Neo4COVID19" is made publicly accessible via a web interface and via API calls based on the Bolt protocol. Details for accessing the database are provided on a landing page (https://neo4covid19.ncats.io/). We believe that our Neo4COVID19 database will be a valuable asset to the research community and will catalyze the discovery of therapeutics to fight COVID-19.

Catatonia in pediatric obsessive-compulsive disorder: report of two cases.

Catatonia is a psychomotor syndrome which may occur in a wide variety of medical, neurological, and psychiatric conditions. In pediatrics, this condition is rare and is associated with high morbidity and mortality if not correctly diagnosed and treated. Catatonia in obsessive-compulsive disorder is an infrequent association that has been understudied and underdiagnosed. To add to the knowledge on this unusual clinical presentation, two pediatric patients are reported and discussed together with the other two cases described in the literature. These four cases in total of catatonia associated with OCD confirm that it is a relationship that is infrequently reported, possibly because of lack of awareness in clinicians that catatonia can also be caused by OCD, and because the similarity between some catatonic signs and some compulsive phenomena may compound the identification of the former. Most cases of catatonia in this small series seemed to have responded to the optimization of the treatment for OCD. This highlights the clinical importance of an accurate diagnosis of catatonia when associated with OCD.

Anti-NMDA receptor encephalitis in older adults: A systematic review of case reports.

OBJECTIVE: To ascertain the clinical characteristics of anti-NMDA receptor encephalitis (NMDARE) in older patients. METHOD: A systematic literature review using PubMed and Scopus of all published case reports of NMDARE was undertaken, from database inception to June 2020. From this, cases reporting on patients older than 65 years of age and whose diagnosis was confirmed by the presence of anti-NMDAR antibodies in CSF were selected. RESULTS: 23 case reports fulfilling the study's criteria were found. Median age was 70.1 years (range 65-84), fourteen were female (60.9%), and mostly presented with acute behavioral and cognitive changes (95.7%). Atypical psychosis occurred in eleven patients (47.8%) with a sudden onset and fluctuating clinical pattern of delusions (39.1%), hallucinations (30.4%), and motility disturbances (34.8%) including catatonia (17.4%). Nine patients presented with seizures (39.1%). Pleocytosis in CSF (>5 WBC) was described in twelve cases (52.2%). Eleven cases (47.8%) had abnormal brain magnetic resonance imaging (MRI) scans with limbic inflammatory lesions. Thirteen patients had an abnormal EEG (56.5%). CONCLUSION: NMDARE should be included in the differential diagnosis of older patients who present with new psychiatric episodes, especially when characterized by sudden onset psychotic polymorphic symptomatology, fluctuating course with marked cognitive decline, and with catatonic features.

Congenericity of Claimed Compounds in Patent Applications.

A method is presented to analyze quantitatively the degree of congenericity of claimed compounds in patent applications. The approach successfully differentiates patents exemplified with highly congeneric compounds of a structurally compact and well defined chemical series from patents containing a more diverse set of compounds around a more vaguely described patent claim. An application to 750 common patents available in SureChEMBL, SureChEMBLccs and ChEMBL is presented and the congenericity of patent compounds in those different sources discussed.

Recognition and Management of Antipsychotic-Induced Parkinsonism in Older Adults: A Narrative Review.

BACKGROUND: Parkinsonism is a common side-effect of antipsychotic drugs especially in older adults, who also present with a higher frequency of neurodegenerative disorders like Idiopathic Parkinson's disease (IPD). Distinguishing between antipsychotic-induced parkinsonism (AIP) and IPD is challenging due to clinical similarities. Up to 20% of older adults may suffer from persisting parkinsonism months after discontinuation of antipsychotics, suggesting underlying neurodegeneration. A review of the literature on AIP in older adults is presented, focusing on epidemiology, clinical aspects, and management. METHODS: A literature search was undertaken on EMBASE, MEDLINE and PsycINFO, for articles on parkinsonism induced by antipsychotic drugs or other dopamine 2 receptor antagonists in subjects aged 65 or older. RESULTS: AIP in older adults is the second most common cause of parkinsonism after IPD. Older age, female gender, exposure to high-potency first generation antipsychotics, and antipsychotic dosage are the main risk factors. The clinical presentation of AIP resembles that of IPD, but is more symmetrical, affects upper limbs more, and tends to have associated motor phenomena such as orofacial dyskinesias and akathisia. Presence of olfactory dysfunction in AIP suggests neurodegeneration. Imaging of striatal dopamine transporters is widely used in IPD diagnosis and could help to distinguish it from AIP. There is little evidence base for recommending pharmacological interventions for AIP, the best options being dose-reduction/withdrawal, or switching to a second-generation drug. CONCLUSIONS: AIP is a common occurrence in older adults and it is possible to differentiate it from IPD. Further research is needed into its pathophysiology and on its treatment.