Adverse Events and Outcomes of High-volume Plasma Exchange in 50 Acute Liver Failure Patients: A Monocentric Retrospective Real-world Study.

Background and aims: Acute liver failure (ALF) is a condition that mostly requires Intensive Care Unit (ICU) admission and sometimes necessitates emergency liver transplantation. High-volume plasma exchange (HVPE) may improve transplant-free survival (TFS) in ALF. Our study assessed complications of HVPE therapy and outcome in ALF patients. Methods: We conducted a single-center retrospective study of all patients admitted to the ICU for ALF and who underwent HVPE between June 2016 and June 2021. The plasmapheresis technique used was centrifugation, and the volume exchanged was calculated as 15% of the ideal body weight. Dedicated staff prospectively collected clinical adverse effects, while biological data were retrospectively collected. The primary outcome was the rate of severe adverse effects (SAE, defined as severe manifestations of hypotension, allergy, metabolic disturbances or other life-threatening event) that occurred during HVPE sessions. Factors influencing day-21 TFS were also studied. Results: One hundred twenty sessions were performed in 50 patients. The main etiology for ALF was paracetamol (52% of the patients). During the session, hemoglobin, platelet, transaminases, ammonia and bilirubin decreased, coagulation factors increased, and creatinine and lactate remained unchanged. At least one SAE was reported for 32 out of 120 sessions (26.7% [19%-35.5%], mostly severe alkalosis [24/117], hypotension [4/120] and hypocalcemia [4/119]). Arterial pH ≤ 7.43 following HVPE and paracetamol etiology were negatively and positively associated with day-21 TFS, respectively. Conclusion: Severe adverse effects were frequent during HVPE performed for ALF, mainly severe alkalosis, hypotension and hypocalcemia. Post-HVPE, pH and paracetamol etiology were prognosis markers.

Trends in adverse effects of medical treatment in Paediatric populations in the United States: A global burden of disease study, 2000-2019.

BACKGROUND: Adverse effects of medical treatment (AEMT) pose significant risks to paediatric patients. However, the mortality trends associated with AEMT in this population have been unclear. OBJECTIVE: We aimed to clarify the trends in the incidence, disability-adjusted life years (DALYs) and mortality rates of AEMT for children in the US from 2000 to 2019. METHODS: Data were retrieved from the Global Burden of Disease study 2019. We estimated age-standardized incidence, DALYs and mortality rates of paediatric AEMT per 100,000 children in the US using a Bayesian meta-regression model. We also analysed incidence, DALYs and mortality in different age groups, and employed Joinpoint regression models to assess the age- and sex-specific trends. RESULTS: The number of deaths due to AEMT in children, the number of cases, and DALYs were 105.1, 551,076 and 145,555 in 2019, decreased by 37.5%, 6% and 28% from those in 2000, respectively. Age-standardized mortality rates decreased across all age groups, while the incidence increased across all age groups with an average annual percentage change (AAPC) of 2.2% in those children <1 year and 4.5% in 5-9 years of age. The increases in DALYs over time was higher in children aged 1-4 years (AAPC: 0.51, 95% CI: 0.47, 0.62) and 5-9 years (AAPC: 0.33, 95% CI: 0.15, 0.50), with the 1-4 year age group being the highest. CONCLUSION: The study reveals declining AEMT mortality but rising incidence and DALYs, emphasizing a disproportionate burden in <1, 1-4 and 5-9 years. To develop effective mitigation strategies, future research is warranted to identify the causes of increased AEMT in children, especially young males.

Mostly harmless? Clinical practice guidelines need further consideration of psychotherapy adverse effects.

The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines on mood disorders recommend psychotherapy as foundational care for patients with acute depression with minimal discussion of any potential adverse effects. Randomised controlled trial evidence on psychotherapy adverse effects is limited. This is problematic because clinicians must balance the benefits of treatment against the harms, and clinical decisions become skewed without data on adverse effects. We suggest that clinical practice guidelines should be more guarded about recommending psychotherapy and add consensus statements on adverse effects for informed consent and clinical decision-making.

Parasomnias and sleep-related movement disorders induced by drugs in the adult population: a review about iatrogenic medication effects.

Parasomnias and sleep-related movement disorders (SRMD) are major causes of sleep disorders and may be drug induced. The objective of this study was to conduct a systematic review of the literature to examine the association between drug use and the occurrence of parasomnias and SRMD. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews, we searched PubMed databases between January 2020 and June 2023. The searches retrieved 937 records, of which 174 publications were selected for full-text screening and 73 drugs were identified. The most common drug-induced parasomnias were nightmares and rapid eye movement (REM) sleep behaviour disorders and sleepwalking. In terms of drug-induced SRMD, restless legs syndrome, periodic limb movement disorders (PLMD), and sleep-related bruxism were most frequent. Medications that inhibit noradrenergic, serotonergic, or orexin transmission could induce REM sleep (e.g., nightmares). Regarding sleepwalking, dysregulation of serotoninergic neurone activity is implicated. Antipsychotics are mentioned, as well as medications involved in the gamma-aminobutyric acid (GABA) pathway. A mechanism of desensitisation-autoregulation of GABA receptors on serotoninergic neurones is a hypothesis. SRMD and PLMD could involve medications disrupting the dopamine pathway (e.g., antipsychotics or opioids). Opioids would act on mu receptors and increase dopamine release. The role of adenosine and iron is also hypothesised. Regarding bruxism, the hypotheses raised involve dysregulation of mesocortical pathway or a downregulation of nigrostriatal pathway, related to medications involving dopamine or serotonin. Parasomnias are rarely identified in drug product labels, likely due to the recent classification of their diagnoses. An analysis of pharmacovigilance data could be valuable to supplement existing literature data.

Methadone Conversion Using a 3-Day Switch Strategy in Patients with Cancer on High-Dose Opioids: A Retrospective Study.

INTRODUCTION: Methadone has shown effectiveness in pain control in patients with cancer who are intolerant to other opioids in China. However, the optimal strategy for methadone conversion from previous high doses of opioids in refractory cancer pain remains debatable. This study aimed to describe the efficacy and safety of a 3-day switch (3DS) strategy for methadone conversion in patients with refractory cancer pain on high doses of opioids. METHODS: We retrospectively reviewed 30-day medical records of 70 patients with refractory cancer pain who used a 3DS strategy for methadone conversion from previous high doses of opioids from July 2018 to December 2022. The 3DS strategy indicated that the methadone dose was increased by one third every day for 3 days. Data on the rate of successful conversion, the time to stable analgesia after conversion, the conversion efficiency, the corrected QT (QTc) interval, the actual conversion ratios, adverse events (AEs), and quality of life were analyzed. RESULTS: Seventy patients received 3DS methadone conversion and 64 patients were eligible for analysis. Fifty patients (78%) achieved stable analgesia, and the median time to stable analgesia was 8.14 ± 2.70 (range 6-14) days. The average dose of methadone was 77.94 ± 42.74 mg. The most common AEs (≥ 10%) included constipation, dry mouth, nausea, and cold sweats. The incidence of constipation was reduced post-methadone conversion, and a statistically significant but asymptomatic prolongation of the QTc interval was observed. Additionally, the actual conversion ratios were lower than Ayonrinde's recommended ratios. CONCLUSIONS: The 3DS strategy for methadone conversion is applicable in Chinese patients with refractory cancer pain on high doses of opioids.

Comprehensive understanding of the adverse effects associated with temozolomide: a disproportionate analysis based on the FAERS database.

Background: Temozolomide, which is the standard drug for glioma treatment, has several Adverse events (AEs) in the treatment of gliomas and other tumors that are not yet fully understood. This is due to the pharmacological nature of the alkylating agent. A significant proportion of these effects have not been systematically documented or reported. Methods: We selected data from the United States FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the fourth quarter of 2023. Four algorithms were used for disproportionate analysis, with the objective of assessing the association between temozolomide and related adverse events. Results: In this study, 20,079,906 case reports were collected from the FAERS database, of which 15,152 adverse events related to temozolomide were reported. A total of 352 preferred terms (PTs) and 24 system organ classes (SOCs) that were significantly disproportionally related to the four algorithms were included. The SOCs included blood and lymphatic system disorders (χ2 = 18,220.09, n = 4,325); skin and subcutaneous tissue disorders (χ2 = 408.06, n = 1,347); investigations (χ2 = 639.44, n = 3,925); musculoskeletal and connective tissue disorders (χ2 = 1,317.29, n = 588); and psychiatric disorders (χ2 = 1,098.47, n = 877). PT levels were screened for adverse drug reaction signals consistent with drug inserts, such as anemia, thrombocytopenia, liver function abnormalities, nausea and vomiting, as well as rarely reported adverse drug reactions, such as aplastic anemia, myelodysplastic syndromes, electrolyte disorders, cerebral edema, and high-frequency mutations. Conclusion: The results of our investigation demonstrated both adverse effects that had been reported and a multitude of unreported adverse effects that were serious in nature and lacked a clear cause. These novel findings suggest that more attention should be given to the clinical conditions of patients after treatment to provide a more comprehensive perspective and understanding for further clarifying the safety of temozolomide.

Low LDL-C: Is It all Good News?

PURPOSE OF REVIEW: This review presents the risks and benefits of very low LDL cholesterol and the safety of using lipid-lowering therapy to achieve these levels. RECENT FINDINGS: A growing body of literature suggests that lower LDL cholesterol levels are associated with a reduced risk of cardiovascular disease. Further, achieving these levels with pharmaceuticals is remarkably safe. Although statins may slightly increase the risk of diabetes mellitus and hemorrhagic stroke, the benefits outweigh the risks. While recommendations from professional societies are increasingly aggressive, additional risk reduction could be achieved by setting more even ambitious LDL cholesterol goals.

Letter to editor: The efects of dabrafenib and/or trametinib treatment in Braf V600­mutant glioma: a systematic review and meta-analysis.

The systematic review and meta-analysis titled "The Effects of Dabrafenib and/or Trametinib Treatment in BRAF V600-Mutant Glioma" provides a critical evaluation of these targeted therapies for a challenging subset of gliomas. This review is notable for its comprehensive data integration, offering a robust assessment of the efficacy and safety of dabrafenib and trametinib. By focusing on BRAF V600 mutations, it contributes valuable insights into personalized treatment strategies. However, limitations include study heterogeneity and a lack of long-term follow-up data, which hinder the generalizability and complete understanding of treatment effects. Additionally, while the review emphasizes therapeutic potential, it requires a thorough evaluation of adverse effects. Future research should address these limitations by providing more consistent data, longer follow-up, and a balanced view of treatment risks and benefits.

Evaluating Cardiovascular Benefits of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) in Type 2 Diabetes Mellitus: A Systematic Review.

Cardiovascular risks and complications remain elevated in patients with type 2 diabetes even after appropriate control of contributing factors like glycemic control, hypertension, and lipid profile. More efficient methods are needed to address this issue in type 2 diabetics. Newer drugs like glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a cardioprotective effect in addition to glycemic control. This systematic review aims to study the latest literature findings on the cardiovascular effects of GLP-1 RAs in patients with type 2 diabetes. We used PubMed, Google Scholar, Science Direct, and Biomed Central databases for our data collection. Our review adheres to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The outcomes evaluated in the review include major adverse cardiovascular events (MACE), heart failure, stroke, all-cause mortality, and effects on cardiovascular risk factors. After careful inspection and quality check, we included 14 articles in the systematic review. GLP-1 RAs were associated with a significant reduction in cardiovascular mortality, all-cause mortality, nonfatal myocardial infarction (MI), and nonfatal stroke, especially in patients with existing cardiovascular risk factors. However, more evidence is required to determine if these benefits extend to those without such risk factors. Limited data suggest that GLP-1 RAs might have a protective effect on arrhythmias, but this area needs further investigation. Despite their potential, several barriers hinder the widespread use of GLP-1 RAs. In conclusion, GLP-1 RAs significantly reduce cardiovascular mortality, all-cause mortality, nonfatal MI, and stroke, with minor effects on hospitalization due to heart failure. Benefits are greater in patients with cardiovascular risk factors. A comprehensive, multilevel approach to policy development and implementation is necessary to optimize the use of these medications in eligible populations.

The relationship between self-reported antipsychotics side effects and depression in Saudi Arabia.

Background: The utilization rate of antipsychotics to treat different mental disorders is rising. However, little is known about their side effects' impact on depression levels. Therefore, the objective of this study was to examine the association between antipsychotic side effects and depression among psychiatric patients treated with antipsychotics. Methods: This is a prospective, single-center, interview-based, cross-sectional study that examined the association between antipsychotic side effects and depression among adult patients (e.g., ≥18 yrs.) with psychiatric illnesses (e.g., depression, schizophrenia, bipolar disorder) visiting outpatient clinics in a university-affiliated tertiary care center. Antipsychotic side effects were assessed using the Arabic version of the Glasgow Antipsychotic Side-effect Scale (GASS), while depression was assessed using the Arabic version of the 9-item Patient Health Questionnaire (PHQ-9). Univariate and multiple linear regressions were conducted to examine the association between the PHQ-9 and GASS scores. Results: One hundred patients met the inclusion criteria and consented to participate. Most of the patients were females (72 %) with a mean age of 38 years. Schizophrenia (37 %) and bipolar disorder (54 %) were the most common mental disorders among the recruited patients. The majority of patients were treated with atypical (e.g., second-generation) antipsychotics (88 %) for at least six months (74 %). Controlling for age, gender, annual family income, education, employment status, marital status, number of comorbidities, duration of treatment with antipsychotics, the type of antipsychotic, and psychiatric illness, higher GASS scores, which indicate more severe antipsychotic side effects, predicted higher PHQ-9 score (e.g., higher levels of depression) (ß = 0.419, 95 % CI=[0.307-0.532], p-value < 0.0001). Conclusion: Early identification and management of antipsychotic side effects among psychiatric patients should enhance patient adherence and improve treatment outcomes. Future studies should verify the findings of this study using more robust study designs.

Serotonergic Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Review of Past Development, Pitfalls and Failures, and a Look to the Future.

Serotonin has been implicated in the neurobiology of attention-deficit/hyperactivity disorder (ADHD) due to its association with impulsivity, attention, and emotional regulation. Many compounds with serotonergic properties have been evaluated in ADHD, but few have been approved by regulatory authorities. Utilizing a search of public databases, we identified interventions studied in ADHD. Prescribing information and peer-reviewed and gray literature helped us to determine which compounds had an underlying mechanism of action associated with changing serotonin levels. Of the 24 compounds that met the search criteria, 16 had either failed clinical studies in an ADHD population or had been discontinued from future development. The available evidence was assessed to identify the developmental history of drugs with serotonergic activity and the outlook for new ADHD drug candidates targeting serotonin. Several treatment candidates floundered due to an inability to balance effectiveness with safety, underscoring the potential importance of potency, and selectivity. Ongoing drug development includes compounds with multimodal mechanisms of action targeting neurotransmission across serotonin, norepinephrine, and dopamine pathways; it appears likely that treatment which balances competing and complementary monoamine effects may provide improved outcomes for patients. It is hoped that continuing research into ADHD treatment will produce new therapeutic options targeting the serotonergic system, which can positively impact a wide range of symptoms, including mood, anxiety, and sleep as well as attention and hyperactivity.

The additional benefit of computed tomography in cancer patients: impacts of sarcopenia and cachexia on quality of life during chemotherapy.

Objective: This study evaluates the effects of sarcopenia and cachexia on the quality of life (QoL) of patients with gastrointestinal cancer during their initial cycle of chemotherapy, emphasizing the significance of computed tomography (CT) in assessing muscle mass. Materials and Methods: In this prospective study, we evaluated 60 adult patients with gastrointestinal cancer who started chemotherapy between January and December of 2017. Sarcopenia was diagnosed on the basis of CT findings, and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Results: The mean age was 60.9 years, and 33 (55.0%) of the patients were men. Of the 60 patients, 33 (55.0%) had cachexia and 14 (23.3%) had sarcopenia. Chemotherapy significantly reduced QoL, particularly in the physical, role functioning, and social domains, with no differences between the cachexia and sarcopenia groups. Conclusion: Among patients with gastrointestinal cancer submitted to chemotherapy, the chemotherapy-induced decline in QoL does not seem to differ significantly between those with cachexia or sarcopenia, as classified by CT-measured muscle mass, and those without. However, CT-based muscle mass evaluation remains crucial for guiding customized intervention strategies. Integrating this evaluation in radiological reports can provide valuable insights for planning specific care, thus improving patient QoL during treatment.

Objetivo: Este estudo avalia os efeitos da sarcopenia e da caquexia na qualidade de vida de pacientes com câncer gastrointestinal durante o ciclo inicial de quimioterapia, enfatizando a importância da tomografia computadorizada (TC) na avaliação da massa muscular. Materiais e Métodos: Estudo prospectivo com 60 pacientes adultos com câncer gastrointestinal que iniciaram quimioterapia de janeiro a dezembro de 2017. A TC foi utilizada para o diagnóstico de sarcopenia e o Quality of Life Questionnaire Core 30 da European Organization for Research and Treatment of Cancer foi utilizado para avaliar a qualidade de vida. Resultados: A média de idade dos pacientes foi 60,9 anos e 33 (55%) eram homens. Entre os pacientes, 33 (55%) eram caquéticos e 14 (24%) eram sarcopênicos. A quimioterapia reduziu significativamente a qualidade de vida, especialmente nos domínios físico, de desempenho de papéis e social, sem diferenças entre os grupos caquéticos e sarcopênicos. Conclusão: A diminuição da qualidade de vida não difere significativamente entre pacientes caquéticos/sarcopênicos e não caquéticos/não sarcopênicos com câncer gastrointestinal submetidos a quimioterapia, conforme classificado pela massa muscular medida por TC. No entanto, a avaliação da massa muscular por TC continua crucial para orientar estratégias de intervenção personalizadas. A integração dessa avaliação nos laudos radiológicos pode fornecer informações valiosas para o planejamento de cuidados específicos, melhorando a qualidade de vida dos pacientes durante o tratamento.

The direct targets of metformin in diabetes and beyond.

Metformin, an oral antihyperglycemic drug that has been in use for over 60 years, remains a first-line therapy for type 2 diabetes (T2D). Numerous studies have suggested that metformin promotes health benefits beyond T2D management, including weight loss, cancer prevention and treatment, and anti-aging, through several proposed mechanistic targets. Here we discuss the established effects of metformin and the progress made in identifying its direct targets. Additionally, we emphasize the importance of elucidating the structural bases of the drug and its direct targets. Ultimately, this review aims to highlight the current state of knowledge regarding metformin and its related emerging discoveries, while also outlining critical future research directions.

Reflection on the RANZCP position on the adverse effects of psychotherapy.

OBJECTIVE: In this perspective, we investigate how the Royal Australian and New Zealand College of Psychiatrists' (RANZCP) position statement on psychotherapy takes the potential for adverse effects into account. CONCLUSIONS: Psychotherapy has two critical outcomes - efficacy and adverse effects. Evidence-based psychotherapy is significantly more effective than care-as-usual for about one in 10 psychotherapy patients. However, a similar proportion also reports adverse effects. Despite this, the RANZCP position statement on psychotherapy focuses on efficacy with minimal discussion of the adverse effects. This is an oversight because psychiatrists have legal and ethical obligations to consider the adverse effects as well as the benefits of any treatment. We therefore reflect on the RANZCP's six recommendations in light of the adverse effects of psychotherapy.

Tobacco and Nicotine Products Adverse Health Events: Findings From the FDA Safety Reporting Portal.

Introduction: The FDA oversees regulatory aspects of all U.S. tobacco products. Understanding the impact of emerging health trends and incidents associated with various tobacco and nicotine products is vital for public health. This study utilizes the FDA's Tobacco Product Problem Reports (TPPRs) to characterize and track adverse health events (AHEs) associated with tobacco and nicotine products over time, considering the impact of EVALI and the COVID-19 pandemic. Methods: FDA TPPRs from 2017-2022 provided information on AHEs related to various tobacco products. After data cleaning, 839 reports were categorized by two independent coders based on affected health category, frequency of AHEs reports, and proportion of AHEs per each health category. Additionally, variations in AHEs over time were assessed, considering major health events like EVALI and the COVID-19 pandemic. Results: Among the 839 reports, electronic cigarettes (e-cigarettes) were the primary product of concern, comprising 90.6% (n = 760) of all reports, surpassing traditional cigarettes (5.1%; n = 43) and other products. Notably, 45.6% of reports (n = 383) identified the neurological system as the most frequently mentioned health category, each reporting at least one AHE. This was followed by the respiratory (39.1%; n = 328) and digestive (10.7%; n = 90) systems. Among all reported AHEs, respiratory system issues were most frequent (25.9%; n = 512), closely followed by neurological (25.2%; n = 499) and digestive (6.6%; n = 131) concerns. Most reports occurred in 2019 (65.7%; n = 551), coinciding with the EVALI outbreak, with a subsequent decline post-Q3 2019, highlighting the potential impact of specific health crises on reporting trends. Conclusion: E-cigarettes dominated adverse health reports, particularly affecting the neurological and respiratory systems, with a peak in 2019. Our findings provide insights to regulatory entities and future research, enhancing understanding of AHEs in lesser-explored bodily systems, such as the neurological and digestive systems. This study emphasizes the need for ongoing and improved surveillance of emerging tobacco products to protect public health.