p38 Mitogen-Activated Protein Kinase Signaling Enhances Reovirus Replication by Facilitating Efficient Virus Entry, Capsid Uncoating, and Postuncoating Steps.

Mammalian orthoreovirus serotype 3 Dearing is an oncolytic virus currently undergoing multiple clinical trials as a potential cancer therapy. Previous clinical trials have emphasized the importance of prescreening patients for prognostic markers to improve therapeutic success. However, only generic cancer markers such as epidermal growth factor receptor (EGFR), Hras, Kras, Nras, Braf, and p53 are currently utilized, with limited benefit in predicting therapeutic efficacy. This study aimed to investigate the role of p38 mitogen-activated protein kinase (MAPK) signaling during reovirus infection. Using a panel of specific p38 MAPK inhibitors and an inactive inhibitor analogue, p38 MAPK signaling was found to be essential for establishment of reovirus infection by enhancing reovirus endocytosis, facilitating efficient reovirus uncoating at the endo-lysosomal stage, and augmenting postuncoating replication steps. Using a broad panel of human breast cancer cell lines, susceptibility to reovirus infection corresponded with virus binding and uncoating efficiency, which strongly correlated with status of the p38ß isoform. Together, results suggest p38ß isoform as a potential prognostic marker for early stages of reovirus infection that are crucial to successful reovirus infection. IMPORTANCE The use of Pelareorep (mammalian orthoreovirus) as a therapy for metastatic breast cancer has shown promising results in recent clinical trials. However, the selection of prognostic markers to stratify patients has had limited success due to the fact that these markers are upstream receptors and signaling pathways that are present in a high percentage of cancers. This study demonstrates that the mechanism of action of p38 MAPK signaling plays a key role in establishment of reovirus infection at both early entry and late replication steps. Using a panel of breast cancer cell lines, we found that the expression levels of the MAPK11 (p38ß) isoform are a strong determinant of reovirus uncoating and infection establishment. Our findings suggest that selecting prognostic markers that target key steps in reovirus replication may improve patient stratification during oncolytic reovirus therapy.

Generalized thermomechanical interaction in two-dimensional skin tissue using eigenvalues approach.

The aim of this work is to analytically study the thermo-mechanical response of two-dimensional skin tissues when subjected to instantaneous heating. A complete understanding of the heat transfer process and the associated thermal and mechanical effects on the patient's skin tissues is critical to ensuring the effective applications of thermal therapy techniques and procedures. The surface boundary of the half-space undergoes a heat flux characterized by an exponentially decaying pulse, while maintaining a condition of zero traction. The utilization of Laplace and Fourier transformations is employed, and the resulting formulations are then applied to human tissues undergoing regional hyperthermia treatment for cancer therapy. To perform the inversion process for Laplace and Fourier transforms, a numerical programming method based on Stehfest numerical inverse method is employed. The findings demonstrate that blood perfusion rate and thermal relaxation time significantly influence all the analyzed distributions. Numerical findings suggest that thermo-mechanical waves propagate through skin tissue over finite distances, which helps mitigate the unrealistic predictions made by the Pennes' model.

Development of Masitinib Derivatives with Enhanced Mpro Ligand Efficiency and Reduced Cytotoxicity.

Recently, a high-throughput screen of 1900 clinically used drugs identified masitinib, an orally bioavailable tyrosine kinase inhibitor, as a potential treatment for COVID-19. Masitinib acts as a broad-spectrum inhibitor for human coronaviruses, including SARS-CoV-2 and several of its variants. In this work, we rely on atomistic molecular dynamics simulations with advanced sampling methods to develop a deeper understanding of masitinib's mechanism of Mpro inhibition. To improve the inhibitory efficiency and to increase the ligand selectivity for the viral target, we determined the minimal portion of the molecule (fragment) that is responsible for most of the interactions that arise within the masitinib-Mpro complex. We found that masitinib forms highly stable and specific H-bond interactions with Mpro through its pyridine and aminothiazole rings. Importantly, the interaction with His163 is a key anchoring point of the inhibitor, and its perturbation leads to ligand unbinding within nanoseconds. Based on these observations, a small library of rationally designed masitinib derivatives (M1-M5) was proposed. Our results show increased inhibitory efficiency and highly reduced cytotoxicity for the M3 and M4 derivatives compared to masitinib.

A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of Coronavirus Disease 2019 (COVID-19). There is a dire need for novel effective antivirals to treat COVID-19, as the only approved direct-acting antiviral to date is remdesivir, targeting the viral polymerase complex. A potential alternate target in the viral life cycle is the main SARS-CoV-2 protease 3CLpro (Mpro). The drug candidate PF-00835231 is the active compound of the first anti-3CLpro regimen in clinical trials. Here, we perform a comparative analysis of PF-00835231, the pre-clinical 3CLpro inhibitor GC-376, and the polymerase inhibitor remdesivir, in alveolar basal epithelial cells modified to express ACE2 (A549+ACE2 cells). We find PF-00835231 with at least similar or higher potency than remdesivir or GC-376. A time-of-drug-addition approach delineates the timing of early SARS-CoV-2 life cycle steps in A549+ACE2 cells and validates PF-00835231's early time of action. In a model of the human polarized airway epithelium, both PF-00835231 and remdesivir potently inhibit SARS-CoV-2 at low micromolar concentrations. Finally, we show that the efflux transporter P-glycoprotein, which was previously suggested to diminish PF-00835231's efficacy based on experiments in monkey kidney Vero E6 cells, does not negatively impact PF-00835231 efficacy in either A549+ACE2 cells or human polarized airway epithelial cultures. Thus, our study provides in vitro evidence for the potential of PF-00835231 as an effective SARS-CoV-2 antiviral and addresses concerns that emerged based on prior studies in non-human in vitro models.Importance:The arsenal of SARS-CoV-2 specific antiviral drugs is extremely limited. Only one direct-acting antiviral drug is currently approved, the viral polymerase inhibitor remdesivir, and it has limited efficacy. Thus, there is a substantial need to develop additional antiviral compounds with minimal side effects and alternate viral targets. One such alternate target is its main protease, 3CLpro (Mpro), an essential component of the SARS-CoV-2 life cycle processing the viral polyprotein into the components of the viral polymerase complex. In this study, we characterize a novel antiviral drug, PF-00835231, which is the active component of the first-in-class 3CLpro-targeting regimen in clinical trials. Using 3D in vitro models of the human airway epithelium, we demonstrate the antiviral potential of PF-00835231 for inhibition of SARS-CoV-2.

Closely related reovirus lab strains induce opposite expression of RIG-I/IFN-dependent versus -independent host genes, via mechanisms of slow replication versus polymorphisms in dsRNA binding σ3 respectively.

The Dearing isolate of Mammalian orthoreovirus (T3D) is a prominent model of virus-host relationships and a candidate oncolytic virotherapy. Closely related laboratory strains of T3D, originating from the same ancestral T3D isolate, were recently found to exhibit significantly different oncolytic properties. Specifically, the T3DPL strain had faster replication kinetics in a panel of cancer cells and improved tumor regression in an in vivo melanoma model, relative to T3DTD. In this study, we discover that T3DPL and T3DTD also differentially activate host signalling pathways and downstream gene transcription. At equivalent infectious dose, T3DTD induces higher IRF3 phosphorylation and expression of type I IFNs and IFN-stimulated genes (ISGs) than T3DPL. Using mono-reassortants with intermediate replication kinetics and pharmacological inhibitors of reovirus replication, IFN responses were found to inversely correlate with kinetics of virus replication. In other words, slow-replicating T3D strains induce more IFN signalling than fast-replicating T3D strains. Paradoxically, during co-infections by T3DPL and T3DTD, there was still high IRF3 phosphorylation indicating a phenodominant effect by the slow-replicating T3DTD. Using silencing and knock-out of RIG-I to impede IFN, we found that IFN induction does not affect the first round of reovirus replication but does prevent cell-cell spread in a paracrine fashion. Accordingly, during co-infections, T3DPL continues to replicate robustly despite activation of IFN by T3DTD. Using gene expression analysis, we discovered that reovirus can also induce a subset of genes in a RIG-I and IFN-independent manner; these genes were induced more by T3DPL than T3DTD. Polymorphisms in reovirus σ3 viral protein were found to control activation of RIG-I/ IFN-independent genes. Altogether, the study reveals that single amino acid polymorphisms in reovirus genomes can have large impact on host gene expression, by both changing replication kinetics and by modifying viral protein activity, such that two closely related T3D strains can induce opposite cytokine landscapes.

Polymorphisms in the Most Oncolytic Reovirus Strain Confer Enhanced Cell Attachment, Transcription, and Single-Step Replication Kinetics.

Reovirus serotype 3 Dearing (T3D) replicates preferentially in transformed cells and is in clinical trials as a cancer therapy. Laboratory strains of T3D, however, exhibit differences in plaque size on cancer cells and differences in oncolytic activity in vivo This study aimed to determine why the most oncolytic T3D reovirus lab strain, the Patrick Lee laboratory strain (T3DPL), replicates more efficiently in cancer cells than other commonly used laboratory strains, the Kevin Coombs laboratory strain (T3DKC) and Terence Dermody laboratory (T3DTD) strain. In single-step growth curves, T3DPL titers increased at higher rates and produced ∼9-fold higher burst size. Furthermore, the number of reovirus antigen-positive cells increased more rapidly for T3DPL than for T3DTD In conclusion, the most oncolytic T3DPL possesses replication advantages in a single round of infection. Two specific mechanisms for enhanced infection by T3DPL were identified. First, T3DPL exhibited higher cell attachment, which was attributed to a higher proportion of virus particles with insufficient (≤3) σ1 cell attachment proteins. Second, T3DPL transcribed RNA at rates superior to those of the less oncolytic T3D strains, which is attributed to polymorphisms in M1-encoding µ2 protein, as confirmed in an in vitro transcription assay, and which thus demonstrates that T3DPL has an inherent transcription advantage that is cell type independent. Accordingly, T3DPL established rapid onset of viral RNA and protein synthesis, leading to more rapid kinetics of progeny virus production, larger virus burst size, and higher levels of cell death. Together, these results emphasize the importance of paying close attention to genomic divergence between virus laboratory strains and, mechanistically, reveal the importance of the rapid onset of infection for reovirus oncolysis.IMPORTANCE Reovirus serotype 3 Dearing (T3D) is in clinical trials for cancer therapy. Recently, it was discovered that highly related laboratory strains of T3D exhibit large differences in their abilities to replicate in cancer cells in vitro, which correlates with oncolytic activity in a murine model of melanoma. The current study reveals two mechanisms for the enhanced efficiency of T3DPL in cancer cells. Due to polymorphisms in two viral genes, within the first round of reovirus infection, T3DPL binds to cells more efficiency and more rapidly produces viral RNAs; this increased rate of infection relative to that of the less oncolytic strains gives T3DPL a strong inherent advantage that culminates in higher virus production, more cell death, and higher virus spread.

Single Amino Acid Differences between Closely Related Reovirus T3D Lab Strains Alter Oncolytic Potency In Vitro and In Vivo.

Little is known about how genetic variations in viruses affect their success as therapeutic agents. The type 3 Dearing strain of Mammalian orthoreovirus (T3D) is undergoing clinical trials as an oncolytic virotherapy. Worldwide, studies on reovirus oncolysis use T3D stocks propagated in different laboratories. Here, we report that genetic diversification among T3D stocks from various sources extensively impacts oncolytic activity. The T3D strain from the Patrick Lee laboratory strain (TD3PL) showed significantly stronger oncolytic activities in a murine model of melanoma than the strain from the Terence Dermody laboratory (T3DTD). Overall in vitro replication and cytolytic properties of T3D laboratory strains were assessed by measuring virus plaque size on a panel of human and mouse tumor cells, and results were found to correlate with in vivo oncolytic potency in a melanoma model. T3DPL produced larger plaques than T3DTD and than the T3D strain from the ATCC (T3DATCC) and from the Kevin Coombs laboratory (T3DKC). Reassortant and reverse genetics analyses were used to decipher key genes and polymorphisms that govern enhanced plaque size of T3DPL Five single amino acid changes in the S4, M1, and L3 genome segments of reovirus were each partially correlated with plaque size and when combined were able to fully account for differences between T3DPL and T3DTD Moreover, polymorphisms were discovered in T3DTD that promoted virus replication and spread in tumors, and a new T3DPL/T3DTD hybrid was generated with enhanced plaque size compared to that of T3DPL Altogether, single amino acid changes acquired during laboratory virus propagation can have a large impact on reovirus therapeutic potency and warrant consideration as possible confounding variables between studies.IMPORTANCE The reovirus serotype 3 Dearing (T3D) strain is in clinical trials for cancer therapy. We find that closely related laboratory strains of T3D exhibit large differences in their abilities to replicate in cancer cells in vitro, which correlates with oncolytic activity in a in a murine model of melanoma. The study reveals that five single amino acid changes among three reovirus genes strongly impact reovirus therapeutic potency. In general, the findings suggest that attention should be given to genomic divergence of virus strains during research and optimization for cancer therapy.

The ETS transcription factor ELF1 regulates a broadly antiviral program distinct from the type I interferon response.

Induction of vast transcriptional programs is a central event of innate host responses to viral infections. Here we report a transcriptional program with potent antiviral activity, driven by E74-like ETS transcription factor 1 (ELF1). Using microscopy to quantify viral infection over time, we found that ELF1 inhibits eight diverse RNA and DNA viruses after multi-cycle replication. Elf1 deficiency results in enhanced susceptibility to influenza A virus infections in mice. ELF1 does not feed-forward to induce interferons, and ELF1's antiviral effect is not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNA-seq revealed that the ELF1 transcriptional program is distinct from interferon signatures. Thus, ELF1 provides an additional layer of the innate host response, independent from the action of type I interferons.

Reduction of virion-associated σ1 fibers on oncolytic reovirus variants promotes adaptation toward tumorigenic cells.

UNLABELLED: Wild-type mammalian orthoreovirus serotype 3 Dearing (T3wt) is nonpathogenic in humans but preferentially infects and kills cancer cells in culture and demonstrates promising antitumor activity in vivo. Using forward genetics, we previously isolated two variants of reovirus, T3v1 and T3v2, with increased infectivity toward a panel of cancer cell lines and improved in vivo oncolysis in a murine melanoma model relative to that of T3wt. Our current study explored how mutations in T3v1 and T3v2 promote infectivity. Reovirions contain trimers of σ1, the reovirus cell attachment protein, at icosahedral capsid vertices. Quantitative Western blot analysis showed that purified T3v1 and T3v2 virions had ∼ 2- and 4-fold-lower levels of σ1 fiber than did T3wt virions. Importantly, using RNA interference to reduce σ1 levels during T3wt production, we were able to generate wild-type reovirus with reduced levels of σ1 per virion. As σ1 levels were reduced, virion infectivity increased by 2- to 5-fold per cell-bound particle, demonstrating a causal relationship between virion σ1 levels and the infectivity of incoming virions. During infection of tumorigenic L929 cells, T3wt, T3v1, and T3v2 uncoated the outer capsid proteins σ3 and µ1C at similar rates. However, having started with fewer σ1 molecules, a complete loss of σ1 was achieved sooner for T3v1 and T3v2. Distinct from intracellular uncoating, chymotrypsin digestion, as a mimic of natural enteric infection, resulted in more rapid σ3 and µ1C removal, unique disassembly intermediates, and a rapid loss of infectivity for T3v1 and T3v2 compared to T3wt. Optimal infectivity toward natural versus therapeutic niches may therefore require distinct reovirus structures and σ1 levels. IMPORTANCE: Wild-type reovirus is currently in clinical trials as a potential cancer therapy. Our molecular studies on variants of reovirus with enhanced oncolytic activity in vitro and in vivo now show that distinct reovirus structures promote adaptation toward cancer cells and away from conditions that mimic natural routes of infection. Specifically, we found that reovirus particles with fewer molecules of the cell attachment protein σ1 became more infectious toward transformed cells. Reduced σ1 levels conferred a benefit to incoming particles only, resulting in an earlier depletion of σ1 and a higher probability of establishing productive infection. Conversely, reovirus variants with fewer σ1 molecules showed reduced stability and infectivity and distinct disassembly when exposed to conditions that mimic natural intestinal proteolysis. These findings support a model where the mode of infection dictates the precise optimum of reovirus structure and provide a molecular rationale for considering alternative reovirus structures during oncolytic therapy.

Exploring the epigenetic landscape: The role of 5-hydroxymethylcytosine in neurodevelopmental disorders.

Recent advances in genetic and epigenetic research have underscored the significance of 5-hydroxymethylcytosine (5hmC) in neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and intellectual disability (ID), revealing its potential as both a biomarker for early detection and a target for novel therapeutic strategies. This review article provides a comprehensive analysis of the role of 5hmC in NDDs by examining both animal models and human studies. By examining mouse models, studies have demonstrated that prenatal environmental challenges, such as maternal infection and food allergies, lead to significant epigenetic alterations in 5hmC levels, which were associated with NDDs in offspring, impacting social behavior, cognitive abilities and increasing ASD-like symptoms. In human studies, researchers have linked alterations in 5hmC levels NDDs through studies in individuals with ASD, fragile X syndrome, TET3 deficiency and ID, specifically identifying significant epigenetic modifications in genes such as GAD1, RELN, FMR1 and EN-2, suggesting that dysregulation of 5hmC played a critical role in the pathogenesis of these disorders and highlighted the potential for targeted therapeutic interventions. Moreover, we explore the implications of these findings for the development of epigenetic therapies aimed at modulating 5hmC levels. The review concludes with a discussion on future directions for research in this field, such as machine learning, emphasizing the need for further studies to elucidate the complex mechanisms underlying NDDs and to translate these findings into clinical practice. This paper not only advances our understanding of the epigenetic landscape of NDDs but also opens up new avenues for diagnosis and treatment, offering hope for individuals affected by these conditions.

Infective endocarditis surgery timing.

BACKGROUND: The optimum timing of surgical intervention in complicated left-sided infective endocarditis is not well established. Guidelines from various professional societies are not consistent regarding this. Data concerning this remains limited with conflicting results. METHODS: The national inpatient database (NIS) was used to identify patients hospitalized from the year 2016 to 2020 for infective endocarditis and who underwent surgical intervention for complicated left-sided endocarditis. Primary and secondary outcomes were analyzed in patients who had surgical intervention within 7 days (early surgery group) and after 7 days (late surgery group) of the index hospitalization. RESULTS: Primary outcome [composite of all-cause death, acute cerebrovascular accident (CVA), peripheral septic emboli, intracranial or intraspinal abscess, and cardiac arrest] was better in the early surgery group compared to the late surgery group 32.6 % vs 45.1 % [adjusted Odds ratio (aOR) = 0.59, 95 % Confidence interval (CI) = 0.52-0.67, P value â‰ª 0.001]. This was mainly due to better incidence of acute CVA (15.7 %vs 24 %, aOR = 0.59, CI = 0.50-0.69, P value â‰ª 0.001), peripheral septic emboli (18.5 % vs 27.3 %, aOR = 0.60, CI = 0.52-0.70, P value â‰ª 0.001) and intracranial/intraspinal abscess (1.2 % vs 4.74 %, aOR = 0.24, CI = 0.14-0.38, P value â‰ª 0.001). There is no difference in the incidence of all-cause in-hospital death (7.57 % vs 7.75 % aOR = 0.97, CI = 0.77-1.23, P value = 0.82) or cardiac arrest (3.4 % vs 3.54 %, aOR = 0.96, CI = 0.68-1.35, P value = 0.80). CONCLUSION: Surgical intervention within 7 days of index hospitalization is associated with a better incidence of acute CVA, peripheral septic emboli, and intracranial or intraspinal abscess but not with a better incidence of all-cause in-hospital death.

Analysis of Primary and Secondary Metabolites, Physical Properties, Antioxidant and Antidiabetic Activities, and Chemical Composition of Rosmarinus officinalis Essential Oils under Differential Water Stress Conditions.

This study investigated the effects of varying water stress levels on Rosmarinus officinalis essential oils (EO). Three samples (S1, S2, and S3) were cultivated under different stress levels (40, 60, and 80%). Increased water stress led to changes in primary and secondary metabolites, EO contents, and physical properties. Antioxidant activity varied, with S2 exhibiting the highest IC50 value. In terms of antidiabetic activity, S2 showed robust α-amylase inhibition, while S3 displayed a commendable influence. For α-galactosidase inhibition, S3 had a moderate effect, and S2 stood out with increased efficacy. Gas chromatography-mass spectrometry analysis revealed stress-induced changes in major compounds. The study enhances the understanding of plant responses to water stress, with potential applications in antioxidant therapy and diabetes management. The findings emphasize the importance of sustainable water management for optimizing the EO quality in its various uses.

Reovirus variants with mutations in genome segments S1 and L2 exhibit enhanced virion infectivity and superior oncolysis.

Reovirus preferentially replicates in transformed cells and is being explored as a cancer therapy. Immunological and physical barriers to virotherapy inspired a quest for reovirus variants with enhanced oncolytic potency. Using a classical genetics approach, we isolated two reovirus variants (T3v1 and T3v2) with superior replication relative to wild-type reovirus serotype 3 Dearing (T3wt) on various human and mouse tumorigenic cell lines. Unique mutations in reovirus λ2 vertex protein and σ1 cell attachment protein were associated with the large plaque-forming phenotype of T3v1 and T3v2, respectively. Both T3v1 and T3v2 exhibited higher infectivity (i.e., a higher PFU-to-particle ratio) than T3wt. A detailed analysis of virus replication revealed that virus cell binding and uncoating were equivalent for variant and wild-type reoviruses. However, T3v1 and T3v2 were significantly more efficient than T3wt in initiating productive infection. Thus, when cells were infected with equivalent input virus particles, T3v1 and T3v2 produced significantly higher levels of early viral RNAs relative to T3wt. Subsequent steps of virus replication (viral RNA and protein synthesis, virus assembly, and cell death) were equivalent for all three viruses. In a syngeneic mouse model of melanoma, both T3v1 and T3v2 prolonged mouse survival compared to wild-type reovirus. Our studies reveal that oncolytic potency of reovirus can be improved through distinct mutations that increase the infectivity of reovirus particles.

SSRI withdrawal syndrome in children and adolescents: a narrative literature review.

INTRODUCTION: While there is considerable published evidence regarding the nature and severity of Selective Serotonin Reuptake Inhibitor (SSRI) discontinuation symptoms in the adult population, information relating to the child and adolescent population remains scarce. This narrative review examined the published literature on SSRI withdrawal symptoms in the under-18-year-old age group. MEDLINE and PsycINFO were comprehensively searched from inception to 5 May 2023. AREAS COVERED: This review highlights the importance of recognizing SSRI withdrawal in children and adolescents and summarizes available literature and guidelines for safe discontinuation. EXPERT OPINION: Evidence of the presence of SSRI withdrawal phenomenon in children and adolescents mainly originates from case reports and extrapolated adult data. Existing data on SSRI withdrawal syndrome in children and adolescents is therefore limited, and there is a need for formal research in this specific population to establish with more certainty the nature and extent of SSRI withdrawal syndrome. Nevertheless, there is currently enough evidence available for prescribing clinicians to provide psychoeducation to patients and families about the possibility of withdrawal symptoms when SSRI treatment is considered. The need for gradual and planned discontinuation should also be discussed for safe withdrawal.

The shared genetic risk factors between Tourette syndrome and obsessive-compulsive disorder.

Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) are two neuropsychiatric disorders that frequently co-occur. Previous evidence suggests a shared genetic diathesis underlying the comorbidity of TS and OCD. This review aims to comprehensively summarize the current literature on the genetic factors linked with TS and its comorbidities, with a focus on OCD. Family studies, linkage analysis, cytogenetic studies, and genome-wide association studies (GWAS) have played a pivotal role in identifying common and rare genetic variants connected with TS and OCD. Although the genetic framework of TS and OCD is complex and multifactorial, several susceptibility loci and candidate genes have been identified that might play a crucial role in the pathogenesis of both disorders. Additionally, post-infectious environmental elements have also been proposed to contribute to the development of TS-OCD, although the dynamics between genetic and environmental factors is not yet fully understood. International collaborations and studies with well-defined phenotypes will be crucial in the future to further elucidate the genetic basis of TS and OCD and to develop targeted therapeutic strategies for individuals suffering from these debilitating conditions.

The Impact of Multisource Feedback on Continuing Medical Education, Clinical Performance and Patient Experience: Innovation in a Child and Adolescent Mental Health Service.

This paper reiterates the importance of the role of multisource feedback (MSF) in continuing medical education/continuing professional development (CME/CPD) and its impact on doctors' performance and patient experience globally. It summarises a unique initiative of robust utilisation of internationally recognised multisource feedback tools in an outpatient child and adolescent mental health service (CAMHS) in Qatar. The process involved the effective adoption and administering of the General Medical Council's (GMC) self-assessment questionnaire (SQ), patient questionnaire (PQ), and colleague questionnaire (CQ) followed by the successful incorporation of these tools in CME/CPD. The original version of the PQ questionnaire and the instructions to the patient document were translated into Arabic through the blind back-translation technique. This initiative of introducing gold-standard MSF tools and processes into clinical practice, among other quality-improvement projects, has contributed to the improvement of service standards and doctors' clinical practice. Patient satisfaction was measured through the annual patient experience analysis using the Experience of Service Questionnaire (ESQ) whereas changes in doctors' performance were evaluated by comparing annual appraisal scores before and after implementation of this initiative. We have demonstrated that when MSF is obtained impartially and transparently using recognised and valid tools, it can improve patient experience and enhance doctors' performance.

TAVR vs balloon aortic valvotomy for severe aortic stenosis and cardiogenic shock: An insight from the National Inpatient Sample database.

BACKGROUND: Severe Aortic stenosis (AS) complicated by cardiogenic shock (CS) represents a grave clinical condition with limited treatment options. Evidence from small observation studies favors that Transcatheter Aortic Valve Replacement (TAVR) might be a feasible option in these patients in contrast to emergent Balloon Aortic Valvuloplasty (BAV) which is associated with very high short and long-term mortality. METHODS: 11,405 hospitalizations with severe AS complicated by CS between 2016 and 2020 were identified using the National Inpatient Sample (NIS) Database, and patients were then stratified according to whether they received TAVR or BAV. Propensity-score matching was used to account for differences in the baseline characteristics. Primary and secondary outcomes were then compared between 3485 hospitalizations in direct TAVR group and with 3485 matched hospitalizations in the BAV group. The primary outcome was a composite of all-cause in-hospital death, acute cerebrovascular accident (CVA), and myocardial infarction (MI). Secondary outcomes and safety outcomes were also compared between the two groups. RESULTS: TAVR was associated with fewer primary outcomes events as compared to BAV {36.8 % vs 56.8 %, aOR (95%CI) = 0.38(0.30-0.47)}, due to fewer all-cause in-hospital deaths {17.8 % vs 38.9 %, aOR (95%CI) =0.34 (0.26-0.43)} and MI {12.3 % vs 32.4 %, aOR (95%CI) = 0.29 (0.22-0.39)}. TAVR was associated with higher rates of acute CVA {6.17 % vs 3.44 %, aOR (95%CI) = 1.84 (1.08-3.21)} and pacemaker implantation post procedure {11.9 % vs 6.03 %, aOR (95%CI) = 2.10 (1.41-3.18)}. CONCLUSION: Direct TAVR in shock and severe Aortic stenosis is a better strategy than rescue Balloon aortic valvotomy.

Multinational perspectives on changes to psychiatric care during the COVID-19 pandemic: a survey of practicing psychiatrists.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in significant upheaval in psychiatric care. Despite survey data collected from psychiatric patients and broad samples of individuals in single countries, there is little quantitative or qualitative data on changes to psychiatric care from the perspective of mental health providers themselves across developing countries. METHODS: To address this gap, we surveyed 27 practicing psychiatrists from Central and Eastern Europe, as well as Africa, the Middle East, and Latin America. RESULTS: Respondents observed a marked increase in anxiety in their patients, with increased (though less prominent) symptoms of depression, somatization, and addiction. They reported largescale changes in the structure of psychiatric treatment, chiefly a decline in psychiatric admissions and closing/repurposing of psychiatric beds. Results supported strong "buy in" from clinicians regarding the use of telehealth, though some clinicians perceived a reduction in the ability to connect with, and build alliances with, their patients. Finally, clinicians described an improvement in the image and meaning of psychiatry in society, increased awareness of mental illness, and greater value placed on mental health in the general population. CONCLUSIONS: These changes warrant further empirical study as to their potential long-term ramifications, particularly as the COVID-19 pandemic persists and new waves of infection occur periodically throughout the world. The increased psychiatric burden on the population coupled with the apparent salience of mental health and well-being in the public consciousness represents a global opportunity for psychiatry to advocate for further treatment, research, and education.

Evaluating COVID-19 vaccination intentions and vaccine hesitancy among parents of children with autism spectrum disorder.

As the global vaccination mass campaign against COVID-19 extended to children aged 5 to 11 years, some parents remained hesitant about their children being administered the vaccine despite data supporting its safety. Parent vaccine hesitancy (PVH) may have predisposed certain groups of children, particularly those with autism spectrum disorder (ASD), to COVID-19 when other neurotypical children would have been vaccinated. We investigated the current PVH in 243 parents of children with ASD and 245 controls using the Parent Attitudes about Childhood Vaccines (PACV) scale. The study was conducted in Qatar from May to October 2022. Overall, 15.0% [95% CI 11.7%; 18.3%] of parents were vaccine-hesitant, with no difference (p = 0.054) between groups (ASD children [18.2%] vs. controls [11.7%]). The only sociodemographic factor associated with higher vaccine hesitancy was being a mother (as compared to being a father). The COVID-19 vaccine receipt rate at the time of the study did not differ between ASD (24.3%) and non-ASD groups (27.8%). Around two-thirds of parents of children with ASD refused or were unsure about vaccinating their children against COVID-19. We found that the intent to vaccinate against COVID-19 was higher in parents who were married and in those with a lower PACV total score. Continued public health efforts are needed to address vaccine hesitancy among parents.