RESUMEN
Tacrolimus, a calcineurin inhibitor, is a highly effective immunosuppressant used in solid organ transplantation (SOT). However, it is characterized by a narrow therapeutic range and high inter-patient variability in pharmacokinetics. Standard weight-based dosing followed by empiric dose titration is suboptimal in controlling drug concentrations, increasing risk of rejection or toxicity, particularly in the initial months post transplantation. This review explores the potential of combined pre-transplant genotyping and pharmacokinetic (PK) modelling to improve tacrolimus dosing in paediatric SOT recipients. A systematic search of Medline, Embase and Cochrane databases identified studies published between March 2013 and March 2023 that investigated genotype- and PK model-informed tacrolimus dosing in children post-SOT. The Newcastle-Ottawa Scale assessed study quality. Seven studies encompassing paediatric kidney, heart, liver and lung transplants reported using genotype and model-informed dosing. A combination of clinical and genetic factors significantly impacts tacrolimus clearance and thus initial dose recommendation. Body size, transplant organ and co-medications were consistently important, while either time post-transplant or haematocrit emerged in some studies. Several models were identified, however, with limitations evident in some and with absence of evidence for their effectiveness in optimizing initial and subsequent dosing. This review highlights the development of PK models in paediatric SOT that integrate genotype and clinical covariates to personalize early tacrolimus dosing. While promising, prospective studies are needed to validate and confirm their effectiveness in improving time to therapeutic concentrations and reducing under- or overexposure. This approach has the potential to optimize tacrolimus therapy in paediatric SOT, thereby improving outcomes.
RESUMEN
Pharmacogenomics (PGx) investigates the influence of genetics on drug responses, enabling tailored treatments for personalized healthcare. This study assessed the accuracy of genotyping six genes using whole genome sequencing with four different computational tools and various sequencing depths. The effects of using different reference genomes (GRCh38 and GRCh37) and sequence aligners (BWA-MEM and Bowtie2) were also explored. The results showed generally minor variations in tool performance across most genes; however, more notable discrepancies were observed in the analysis of the complex CYP2D6 gene. Cyrius, a CYP2D6-specific tool, demonstrated the most robust performance, achieving the highest concordance rates for CYP2D6 in all instances, comparable to the consensus approach in most cases. There were rather small differences between the samples with 20× coverage depth and those with higher depth, but the decreased performance was more evident at lower depths, particularly at 5×. Additionally, variations in CYP2D6 results were observed when samples were aligned to different reference genomes using the same method, or to the same genome using different aligners, which led to reporting incorrect rare star alleles in several cases. These findings inform the selection of optimal PGx tools and methodologies as well as suggest that employing a consensus approach with two or more tools might be preferable for certain genes and tool combinations, especially at lower sequencing depths, to ensure accurate results. Additionally, we show how the upstream alignment can affect the performance of tools, an important factor to take into account.
Asunto(s)
Benchmarking , Citocromo P-450 CYP2D6 , Farmacogenética , Humanos , Citocromo P-450 CYP2D6/genética , Farmacogenética/normas , Farmacogenética/métodos , Citocromo P-450 CYP2C19/genética , Secuenciación Completa del Genoma/normas , Secuenciación Completa del Genoma/métodos , Técnicas de Genotipaje/métodos , Genotipo , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2A6/genética , Pruebas de Farmacogenómica/normas , Pruebas de Farmacogenómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Vitamina K Epóxido ReductasasRESUMEN
Obesity is characterized by dysregulated adipogenesis that leads to increased number and/or size of adipocytes. Understanding the molecular mechanisms governing adipogenesis is therefore key to designing therapeutic interventions against obesity. In our study, we analyzed 3'-end sequencing data that we generated from human preadipocytes and adipocytes, as well as previously published RNA-seq datasets, to elucidate mechanisms of regulation via long non-coding RNA (lncRNA), alternative splicing (AS) and alternative polyadenylation (APA). We discovered lncRNAs that have not been previously characterized but may be key regulators of white adipogenesis. We also detected 100 AS events and, using motif enrichment analysis, identified RNA binding proteins (RBPs) that could mediate exon skipping-the most prevalent AS event. In addition, we show that usage of alternative poly(A) sites in introns or 3'-UTRs of key adipogenesis genes leads to isoform diversity, which can have significant biological consequences on differentiation efficiency. We also identified RBPs that may modulate APA and defined how 3'-UTR APA can regulate gene expression through gain or loss of specific microRNA binding sites. Taken together, our bioinformatics-based analysis reveals potential therapeutic avenues for obesity through manipulation of lncRNA levels and the profile of mRNA isoforms via alternative splicing and polyadenylation.
Asunto(s)
Adipogénesis , Empalme Alternativo , Perfilación de la Expresión Génica , Poliadenilación , ARN Largo no Codificante , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Adipogénesis/genética , Humanos , Adipocitos/metabolismo , Adipocitos/citología , Regiones no Traducidas 3' , MicroARNs/genética , MicroARNs/metabolismo , Transcriptoma , Regulación de la Expresión Génica , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Biología Computacional/métodosRESUMEN
INTRODUCTION: DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse. METHODS AND ANALYSIS: Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out. ETHICS AND DISSEMINATION: The ethics approval of the trial has been obtained from the Royal Children's Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission. TRIAL REGISTRATION NUMBER: NCT05667766.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Farmacogenética , Humanos , Niño , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Estudios Multicéntricos como Asunto , Medicina de Precisión/economía , Trasplante de Células Madre HematopoyéticasRESUMEN
Point-of-care (POC) glucometry is commonly used in horses; however, measurement error with this method when analysing hypoglycaemic samples (<4â¯mmol/L) is unknown. The objective of this study was to determine the precision and accuracy of glucometry in hypoglycaemic horses in comparison to a laboratory method of glucose measurement (LAB). Repeatability coefficients were 0.47â¯mmol/L for POC and 0.09â¯mmol/L for LAB, and coefficients of variation were 10â¯% and 2.11â¯%, for the POC and LAB methods, respectively. Systemic bias with the POC method was present, with a mean bias of -0.26â¯mmol/L (95â¯% limits of agreement: -0.88 - 0.37) in comparison to LAB, and <70% of measurements were within 20â¯% of paired LAB results. Prior to use of glucometers, assessment of the diagnostic performance of the equipment is necessary, including determination of acceptable criteria and reference ranges for hypoglycaemic samples.
Asunto(s)
Glucemia , Enfermedades de los Caballos , Hipoglucemia , Sistemas de Atención de Punto , Caballos , Animales , Hipoglucemia/veterinaria , Hipoglucemia/diagnóstico , Hipoglucemia/sangre , Enfermedades de los Caballos/diagnóstico , Enfermedades de los Caballos/sangre , Glucemia/análisis , Reproducibilidad de los Resultados , Masculino , FemeninoRESUMEN
PURPOSE: To investigate self-reported individual-, household-, and community-level factors impacting COVID-19 vaccination decision-making among a sample of high school-aged US adolescents. METHODS: We surveyed adolescents ages 15-17 living in the United States during September and October 2022 (n = 454). Univariable and targeted bivariable and multivariable analyses were conducted to examine associations between adolescent characteristics and COVID-19 vaccination status, satisfaction with vaccination status, reasons weighed for and against vaccination, and experience of perceived access barriers. RESULTS: More than three-quarters of high school-aged adolescents in our sample reported satisfaction with their current COVID-19 vaccination status, and respondents were more likely to report satisfaction with their COVID-19 vaccination status when they reported actively participating in the decision. DISCUSSION: Adolescents remain an important age group for targeted public health and policy interventions given that their vaccination rates still lag behind averages for adults. Allowing for minor consent to vaccination, as well as parent-, school-, or peer-based interventions, may prove especially effective for addressing rates among high school-aged students.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Toma de Decisiones , Estudiantes , Humanos , Adolescente , Masculino , Femenino , Estados Unidos , Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Estudiantes/psicología , Estudiantes/estadística & datos numéricos , Encuestas y Cuestionarios , Vacunación/estadística & datos numéricos , Vacunación/psicología , SARS-CoV-2RESUMEN
This study reports on 10 frontline healthcare workers, employed during the COVID-19 pandemic and experiencing symptoms of burnout and PTSD, treated with group ketamine-assisted psychotherapy (KAP) in a private outpatient clinic setting. Participants attended 6 sessions once weekly. These included 1 preparation session, 3 ketamine sessions (2 sublingual, 1 intramuscular), 2 integration sessions. Measures of PTSD (PCL-5), depression (PHQ-9), and anxiety (GAD-7) were administered at baseline and post-treatment. During ketamine sessions, the Emotional Breakthrough Inventory (EBI) and the 30-item Mystical Experience Questionnaire (MEQ-30) were recorded. Participant feedback was gathered 1-month post-treatment. We observed improvements in participants' average PCL-5 (59% reduction), PHQ-9 (58% reduction), and GAD-7 (36% reduction) scores from pre- to post-treatment. At post-treatment, 100% of participants screened negative for PTSD, 90% had minimal/mild depression or clinically significant improvement, and 60% had minimal/mild anxiety or clinically significant improvement. MEQ and EBI scores had large variations among participants at each ketamine session. Ketamine was well tolerated, and no significant adverse events were reported. Participant feedback corroborated findings of improvements observed in mental health symptoms. We found immediate improvements treating 10 frontline healthcare workers experiencing burnout, PTSD, depression, and anxiety using weekly group KAP and integration.
Asunto(s)
COVID-19 , Ketamina , Psicoterapia de Grupo , Trastornos por Estrés Postraumático , Humanos , Ketamina/efectos adversos , Trastornos por Estrés Postraumático/epidemiología , Pandemias , Ansiedad , Personal de Salud , Agotamiento Psicológico , DepresiónRESUMEN
The Pcf11 protein is an essential subunit of the large complex that cleaves and polyadenylates eukaryotic mRNA precursor. It has also been functionally linked to gene-looping, termination of RNA Polymerase II (Pol II) transcripts, and mRNA export. We have examined a poorly characterized but conserved domain (amino acids 142-225) of the Saccharomyces cerevisiae Pcf11 and found that while it is not needed for mRNA 3' end processing or termination downstream of the poly(A) sites of protein-coding genes, its presence improves the interaction with Pol II and the use of transcription terminators near gene promoters. Analysis of genome-wide Pol II occupancy in cells with Pcf11 missing this region, as well as Pcf11 mutated in the Pol II CTD Interacting Domain, indicates that systematic changes in mRNA expression are mediated primarily at the level of transcription. Global expression analysis also shows that a general stress response, involving both activation and suppression of specific gene sets known to be regulated in response to a wide variety of stresses, is induced in the two pcf11 mutants, even though cells are grown in optimal conditions. The mutants also cause an unbalanced expression of cell wall-related genes that does not activate the Cell Wall Integrity pathway but is associated with strong caffeine sensitivity. Based on these findings, we propose that Pcf11 can modulate the expression level of specific functional groups of genes in ways that do not involve its well-characterized role in mRNA 3' end processing.
Asunto(s)
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Factores de Escisión y Poliadenilación de ARNm , Factores de Escisión y Poliadenilación de ARNm/genética , Factores de Escisión y Poliadenilación de ARNm/metabolismo , Mutación , ARN Polimerasa II/metabolismo , ARN Mensajero/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Transcripción GenéticaRESUMEN
Pharmacogenomics remains underutilized in clinical practice, despite the existence of internationally recognized, evidence-based guidelines. This systematic review aims to understand enablers and barriers to pharmacogenomics implementation in pediatric oncology by assessing the knowledge, attitudes, and practice of healthcare professionals and consumers. Medline, Embase, Emcare, and PsycINFO database searches identified 146 relevant studies of which only three met the inclusion criteria. These studies reveal that consumers were concerned with pharmacogenomic test costs, insurance discrimination, data sharing, and privacy. Healthcare professionals possessed mostly positive attitudes toward pharmacogenomic testing yet identified lack of experience and training as barriers to implementation. Education emerged as the key enabler, reported in all three studies and both healthcare professionals and consumer groups. However, despite the need for education, no studies utilizing a pediatric oncology consumer or healthcare professional group have reported on the implementation or analysis of a pharmacogenomic education program in pediatric oncology. Increased access to guidelines, expert collaborations and additional guidance interpreting results were further enablers established by healthcare professionals. The themes identified mirror those reported in broader pediatric genetic testing literature. As only a small number of studies met inclusion criteria for this review, further research is warranted to elicit implementation determinants and advance pediatric pharmacogenomics.
Asunto(s)
Neoplasias , Farmacogenética , Humanos , Niño , Conocimientos, Actitudes y Práctica en Salud , Personal de Salud/educación , Oncología Médica , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
Introduction: A comorbid diagnosis of a depressive disorder is a negative prognostic factor for individuals with AN, and novel treatments are needed to target depressive symptoms in this population. One emerging promising treatment for depressive disorders is ketamine, although there is less research investigating the use of ketamine for alleviating depression in people with AN. Case report: This study reports on four patients with a lifetime diagnosis of AN and a comorbid diagnosis of major depressive disorder who received either intramuscular ketamine (n = 2) or intranasal esketamine (n = 2) treatment from a private psychiatric clinic. Depressive symptomatology (PHQ-9) was measured prior to (es)ketamine administration on every dosing session and adverse effects were recorded during and after dosing. All patients reported a subjective decrease in depression, although only those administered intranasal esketamine showed a reduction in PHQ-9 depression scores over time. Number of doses ranged from 3 to 23. All patients tolerated treatment well and no serious adverse effects emerged, however nausea/vomiting was experienced by one patient on one dosing session. Weight remained stable in all cases, although notably across all patients, weight at the beginning of treatment was within a "healthy" range. Discussion: These findings suggest that (es)ketamine may reduce depressive symptoms in people with major depressive disorder and a comorbid diagnosis of AN. Future feasibility and pilot trials are warranted in order to elicit robust data on efficacy, acceptability, safety and tolerability.
RESUMEN
Wildlife translocation is increasingly utilized as a conservation management action, to mitigate the immediate negative effects of habitat loss and fragmentation (e.g. from land clearing or bushfires). Previous research has shown that stress responses can help or hinder survival in translocated wildlife and determine the efficacy of translocation as a conservation action. Yet these translocated animals are only one side of the equation, with translocation also potentially impacting the animals in the recipient population. We measured physiological markers of stress (faecal cortisol metabolite concentrations and neutrophil-lymphocyte ratios) and assessed health condition in a wild koala population one year after a major translocation of bushfire-rescued koalas on Kangaroo Island. We expected to find a high population density at the site (>0.75 koalas per hectare) and that resident koalas would show signs of chronic stress and ill health as a result of territorial conflict over food trees and reproductive opportunities. In contrast, we found that only one-fifth of the population remaining at the site were translocated koalas. The overall population density was also much lower (0.21 koalas per hectare) than anticipated. With no evidence of mass mortality at the site, we suggest that the majority of translocated koalas dispersed away from the site. Our stress marker measurements did not differ between the wild koalas and a sample of captive (non-display) koalas at the nearby Kangaroo Island Wildlife Park and were generally low compared to other studies. Veterinary examinations found that most koalas were in good body condition with very few diagnostic indicators of systemic ill health. Overall, our results suggest that, if there is adequate landscape-scale habitat connectivity and opportunity for dispersal, translocated koalas are likely to disperse from the site of release, with limited impacts on recipient koala populations at translocation release sites.
RESUMEN
Anxiety disorders are the most common group of mental disorders, but they are often underrecognized and undertreated in primary care. Dysfunctional breathing is a hallmark of anxiety disorders; however, mainstays of treatments do not tackle breathing in patients suffering anxiety. This scoping review aims to identify the nature and extent of the available research literature on the efficacy of breathwork interventions for adults with clinically diagnosed anxiety disorders using the DSM-5 classification system. Using the PRISMA extension for scoping reviews, a search of PubMed, Embase, and Scopus was conducted using terms related to anxiety disorders and breathwork interventions. Only clinical studies using breathwork (without the combination of other interventions) and performed on adult patients diagnosed with an anxiety disorder using the DSM-5 classification system were included. From 1081 articles identified across three databases, sixteen were included for the review. A range of breathwork interventions yielded significant improvements in anxiety symptoms in patients clinically diagnosed with anxiety disorders. The results around the role of hyperventilation in treatment of anxiety were contradictory in few of the examined studies. This evidence-based review supports the clinical utility of breathwork interventions and discusses effective treatment options and protocols that are feasible and accessible to patients suffering anxiety. Current gaps in knowledge for future research directions have also been identified.
RESUMEN
Regulation of mRNA polyadenylation is important for response to external signals and differentiation in several cell types, and results in mRNA isoforms that vary in the amount of coding sequence or 3' UTR regulatory elements. However, its role in differentiation of monocytes to macrophages has not been investigated. Macrophages are key effectors of the innate immune system that help control infection and promote tissue-repair. However, overactivity of macrophages contributes to pathogenesis of many diseases. In this study, we show that macrophage differentiation is characterized by shortening and lengthening of mRNAs in relevant cellular pathways. The cleavage/polyadenylation (C/P) proteins increase during differentiation, suggesting a possible mechanism for the observed changes in poly(A) site usage. This was surprising since higher C/P protein levels correlate with higher proliferation rates in other systems, but monocytes stop dividing after induction of differentiation. Depletion of CstF64, a C/P protein and known regulator of polyadenylation efficiency, delayed macrophage marker expression, cell cycle exit, attachment, and acquisition of structural complexity, and impeded shortening of mRNAs with functions relevant to macrophage biology. Conversely, CstF64 overexpression increased use of promoter-proximal poly(A) sites and caused the appearance of differentiated phenotypes in the absence of induction. Our findings indicate that regulation of polyadenylation plays an important role in macrophage differentiation.
Asunto(s)
Poli A , Poliadenilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Poli A/metabolismo , Diferenciación Celular , Macrófagos/metabolismoRESUMEN
We have previously described the role of an essential Saccharomyces cerevisiae gene, important for cleavage and polyadenylation 1 (IPA1), in the regulation of gene expression through its interaction with Ysh1, the endonuclease subunit of the mRNA 3'-end processing complex. Through a similar mechanism, the mammalian homolog ubiquitin protein ligase E3D (UBE3D) promotes the migratory and invasive potential of breast cancer cells, but its role in the regulation of gene expression during normal cellular differentiation has not previously been described. In this study, we show that CRISPR/Cas9-mediated knockout of Ube3d in 3T3-L1 cells blocks their ability to differentiate into mature adipocytes. Consistent with previous studies in other cell types, Ube3d knockout leads to decreased levels of CPSF73 and global changes in cellular mRNAs indicative of a loss of 3'-end processing capacity. Ube3d knockout cells also display decreased expression of known preadipogenic markers. Overexpression of either UBE3D or CPSF73 rescues the differentiation defect and partially restores protein levels of these markers. These results support a model in which UBE3D is necessary for the maintenance of the adipocyte-committed state via its regulation of the mRNA 3'-end processing machinery.
Asunto(s)
Adipocitos , Adipogénesis , Ubiquitina-Proteína Ligasas , Animales , Ratones , Células 3T3-L1 , Adipocitos/metabolismo , Adipogénesis/genética , Adipogénesis/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Mamíferos/genética , Mamíferos/metabolismo , Factores de Escisión y Poliadenilación de ARNm/metabolismo , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Aim: There is limited real-world evidence for patients with treatment-resistant depression (TRD) receiving esketamine nasal spray. Methods: This retrospective cohort study used data collected from a psychiatric clinic's EHR system. Results: A total of 171 TRD patients received esketamine July 2019-June 2021. This predominantly female, white population had several mental health comorbidities and high exposure to psychiatric medications. We observed significant reductions (p < 0.001) in average PHQ-9 and GAD-7 scores from baseline (PHQ-9: mean: 16.7; SD: 5.8; GAD-7: mean: 12.0; SD: 5.8) to last available treatment (PHQ-9: mean: 12.0; SD: 6.4; GAD-7: mean: 8.7; SD: 5.6). There were no reports of serious adverse events. Conclusion: This study found a significant disease burden for patients with TRD. Esketamine appears to be well tolerated and effective in improving depression and anxiety.
Asunto(s)
Antidepresivos , Depresión , Humanos , Femenino , Masculino , Antidepresivos/uso terapéutico , Antidepresivos/efectos adversos , Estudios Retrospectivos , Depresión/tratamiento farmacológico , Administración IntranasalRESUMEN
Acquired hypothyroidism due to iodine deficiency is extremely rare in the United States due to the introduction of table salt iodization in the 1920s (Leung et al., 2012). We present the case of an adolescent male with a history of mild autism spectrum disorder and an extremely restrictive diet who was found to have iodine deficiency as the etiology for his rapidly enlarging goiter and antibody-negative hypothyroidism. Thyroid-stimulating hormone (TSH) was 416 µIU/mL (0.350-5.500 µIU/mL), free thyroxine (T4) was <0.1 ng/dL (0.80-1.80 ng/dL), and triiodothyronine (T3) was 41 ng/dL (82-213 mg/dL) at diagnosis. The patient's 24-hour urinary iodine was undetectable. He was started on iodine supplementation with rapid visible improvement of goiter within two weeks and normalization of thyroid function tests within four weeks. Thorough dietary history and nutritional screening are important in cases of acquired hypothyroidism and/or goiter. Alternatively, diets that are low in iodized salt, dairy, bread, and seafood should raise concern for iodine deficiency, and patients with suspected or proven iodine deficiency should be screened for hypothyroidism.
RESUMEN
BACKGROUND: Ketamine has emerged as a promising pharmacotherapy for depression and other mental illnesses, and the intramuscular (IM) administration of ketamine is now offered at many North American outpatient psychiatric clinics. However, a characterization of the outpatient population receiving IM ketamine treatment and an evaluation of the real-world depression, anxiety, and safety outcomes of long-term psychiatric IM ketamine treatment has not been reported. This study aimed to evaluate the clinical characteristics, treatment patterns, clinical outcomes, and adverse events of patients receiving IM ketamine treatment. METHODS: Patient data from the electronic health records of a private outpatient psychiatric clinic network in the United States were collected and analyzed retrospectively. Adults with any psychiatric diagnosis who received ketamine treatment only by IM administration from January 2018 to June 2021 were included. A total of 452 patients were included in the cohort. RESULTS: Patients receiving IM ketamine treatment had a mean of 2.8 (SD 1.4) psychiatric diagnoses. 420 (93%) patients had a diagnosis of major depressive disorder, 243 (54%) patients had a diagnosis of generalized anxiety disorder, and 126 (28%) patients had a diagnosis of post-traumatic stress disorder. Patients received a median of 4 (range 1-48) IM ketamine treatments. Median depression scores (PHQ-9) improved 38% from 16.0 (IQR 11.3-21.8) at baseline to 10.0 (IQR 6.0-15.0) at last treatment (p < .001). Median anxiety scores (GAD-7) improved 50% from 14.0 (IQR 8.0-17.0) at baseline to 7.0 (IQR 4.3-11.8) at last treatment (p < .001). With maintenance ketamine treatments, average improvements in depression (PHQ-9) and anxiety (GAD-7) scores of at least 4.7 and 4.9 points were maintained for over 7 months. An adverse event occurred during 59 of 2532 treatments (2.3%). CONCLUSIONS: IM ketamine is being utilized to treat psychiatric outpatients with multiple mental illnesses not limited to depression. Average depression and anxiety levels significantly improve throughout IM ketamine treatment and do not regress to baseline during patients' maintenance treatment phase. Prospective studies are recommended to confirm the long-term effectiveness and safety of IM ketamine.
Asunto(s)
Trastorno Depresivo Mayor , Ketamina , Adulto , Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/tratamiento farmacológico , Estudios de Cohortes , Depresión/tratamiento farmacológico , Trastorno Depresivo Mayor/psicología , Humanos , Ketamina/efectos adversos , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Estudios RetrospectivosRESUMEN
Cleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation. Recent work has surprisingly identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers, triggering further studies on understanding CPSF73 regulation and functions in cells. Here, we report that a HECT-like E3 ligase, UBE3D, participates in stabilizing CPFS73 protein by preventing its ubiquitin-mediated degradation by the proteasome. Depletion of UBE3D leads to CPSF73 downregulation, a pre-mRNA cleavage defect, and dysregulated gene expression in cells. UBE3D dysfunction or chemical inactivation of CPSF73 inhibited migration and invasion as well as stem cell renewal phenotypes in vitro in triple-negative breast cancer cells. In addition, genetic overexpression of CPSF73 promoted breast cancer stemness and knocking down CPSF73 inhibited stem cell renewal properties. Together, our findings indicate that targeting the pre-mRNA processing nuclease CPSF73 has potential for breast cancer therapy.
Asunto(s)
Aborto Inducido , Semántica , Femenino , Accesibilidad a los Servicios de Salud , Humanos , EmbarazoRESUMEN
Background/Objective. Thyrotoxicosis, a condition resulting from excessive peripheral thyroid hormone, is typically accompanied by thyroid function tests demonstrating a high free thyroxine (free T4) with appropriate suppression of thyroid-stimulating hormone (TSH). Case report. We describe a 17-year-old female presenting with symptoms of thyrotoxicosis along with suppressed TSH and low free T4, a laboratory pattern concerning for central hypothyroidism. Further history revealed that she was prescribed liothyronine as an adjunct therapy for depression. Discussion. Due to the short half-life of liothyronine, clinical signs and symptoms of thyrotoxicosis may develop before detection by interval lab monitoring. Conclusion. This case highlights the need for close monitoring and caution when treating adolescents with liothyronine and the importance of interpreting atypical laboratory findings within clinical context.