Administration Recommendations Research Articles

2022 AAHA Canine Vaccination Guidelines (2024 Update).

Vaccination is a cornerstone of canine preventive healthcare and one of the most cost-effective ways of maintaining a dog's health, longevity, and quality of life. Canine vaccination also serves a public health function by forming a barrier against several zoonotic diseases affecting dogs and humans. Canine vaccines are broadly categorized as containing core and noncore immunizing antigens, with administration recommendations based on assessment of individual patient risk factors. The guidelines include a comprehensive table listing canine core and noncore vaccines and a recommended vaccination and revaccination schedule for each vaccine. The guidelines explain the relevance of different vaccine formulations, including those containing modified-live virus, inactivated, and recombinant immunizing agents. Factors that potentially affect vaccine efficacy are addressed, including the patient's prevaccination immune status and vaccine duration of immunity. Because animal shelters are one of the most challenging environments for prevention and control of infectious diseases, the guidelines also provide recommendations for vaccination of dogs presented at or housed in animal shelters, including the appropriate response to an infectious disease outbreak in the shelter setting. The guidelines explain how practitioners can interpret a patient's serological status, including maternally derived antibody titers, as indicators of immune status and suitability for vaccination. Other topics covered include factors associated with postvaccination adverse events, vaccine storage and handling to preserve product efficacy, interpreting product labeling to ensure proper vaccine use, and using client education and healthcare team training to raise awareness of the importance of vaccinations.

Approach to the patient with thyroid nodules: considering GLP-1 receptor agonists.

Glucagon-like peptide 1 receptor agonists (GLP1RA) have rapidly changed the landscape of diabetes and obesity treatment. Enthusiasm for their use is tempered with concerns regarding their risk for inducing C-cell tumors based on preclinical studies in rodents. A black-box warning from the United States Food and Drug Administration (USFDA) recommends against using GLP1RA in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2), providing clear guidance regarding this cohort of patients. However, emerging data also suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with these agents. Other studies, though, have not confirmed an association between GLP1RA and DTC. With conflicting results concerning thyroid cancer risk, there is no clear consensus regarding the optimal approach to screening patients prior to initiating the medications and/or evaluating for thyroid cancer during GLP1RA treatment. Within the context of patient cases, this review will summarize the existing data, describe ongoing controversies, and outline future areas for research regarding thyroid cancer risk with GLP1RA use.

Post Artesunate Delayed Hemolysis in Pediatric Patients in the United States

Abstract Background Malaria continues to pose a major threat to global public health, causing millions of infections and hundreds of thousands of deaths each year. Intravenous artesunate is the current first line therapy for severe malaria and has substantially reduced its mortality. Some patients develop severe delayed hemolysis after artesunate therapy, a phenomenon termed post artesunate delayed hemolysis (PADH). A recent study of U.S. adults treated with artesunate found that 2.7% of patients experienced PADH and 56% of those patients required blood transfusion. Thus, the U.S. Food and Drug Administration recommends that patients treated with artesunate receive weekly post-treatment monitoring of hemoglobin and hemolytic markers for four weeks after therapy. While PADH in adults frequently requires blood transfusion, the frequency and severity of PADH in pediatric patients in non-endemic countries is not known. Understanding the risk of PADH in pediatric patients is essential to determine appropriate monitoring for this condition. Methods Multicenter Retrospective Chart Review To estimate rates of PADH in pediatric patients (0-18 years of age), we used ICD-10 diagnosis codes to identify patients treated for malaria at seven hospitals (The Children’s Hospital of Philadelphia, Riley Hospital for Children, Texas Children’s Hospital, Seattle Children’s Hospital, UCSF Benioff Children’s Hospital, NYU Langone Medical Center, and Bellevue Hospital), between April 2017 and July 2022. We reviewed post-discharge laboratory values and clinic visits to identify patients with laboratory findings of PADH and determine clinical outcomes. Pediatric Health Information System (PHIS) Database Review To estimate rates of severe PADH requiring repeat emergency room visit or hospitalization, we used ICD-10 diagnosis codes to identify patients who were treated for malaria with artesunate between January 2019 and July 2023 in a database of 49 children’s hospitals (PHIS). We reviewed patient visits within eight weeks of treatment to identify patients with repeat presentations related to anemia or hemolysis. Results In our retrospective chart review, four of seventeen patients (25%) treated with artesunate had laboratory evidence of PADH. None of these patients were symptomatic and none required readmission or medical intervention. Haptoglobin levels remained low in most patients up to four weeks after treatment, regardless of the presence of PADH, and lactate dehydrogenase (LDH) levels slowly declined over this period. We identified 92 patients in the PHIS database who were treated with artesunate. Of these, three patients (3.3%) had a repeat presentation within four weeks with one or more diagnosis suggestive of new onset anemia. Repeat presentations occurred 5-13 days after initial admission for malaria. Conclusion PADH is common in US pediatric patients treated with artesunate for severe malaria. However, severe hemolysis requiring repeat emergency room visit or readmission is rare. We find that haptoglobin and LDH levels were not useful as initial screening labs for PADH in pediatric patients. Together, our findings call into question the utility of weekly laboratory monitoring, as opposed to symptom-based monitoring, to identify pediatric patients at risk of readmission for PADH. Additional studies are necessary to determine which patients would benefit from weekly laboratory monitoring and which can be monitored clinically.

Ultrahigh-Performance Supercritical Fluid Chromatography-Mass Spectrometry in the Clinical Lipidomic Analysis.

Ultrahigh-performance supercritical fluid chromatography-mass spectrometry (UHPSFC/MS) method is optimized for the high-throughput quantitation of lipids in human serum and plasma with an emphasis on robustness and accurate quantitation. Bridged ethylene hybrid (BEH) silica column (100×3mm; 1.7μm) is used for the separation of 17 nonpolar and polar lipid classes in 4.4min using the positive ion electrospray ionization mode. The lipid class separation approach in UHPSFC/MS results in the coelution of all lipid species within one lipid class in one chromatographic peak, including two exogenous internal standards (IS) per lipid class, which provides the optimal conditions for robust quantitation. The method was validated according to European Medicines Agency and Food and Drug Administration recommendations. UHPSFC/MS combined with LipidQuant software allows a semiautomated process to determine lipid concentrations with a total run time of only 8min including column equilibration, which enables the analysis of 160 samples per day.

Breast Implant Rupture Surveillance Practices among Plastic Surgeons in Publicly Funded Healthcare Systems.

The United States Food and Drug Administration (FDA) recommends silicone breast implant rupture surveillance using MRI or ultrasound beginning at 5-6 years post-insertion and every 2-3 years thereafter. No surveillance guidelines exist in Canada or the UK. This study aims to identify surveillance practices and perceived barriers to surveillance among plastic surgeons in Canada and the UK and compare surgeon practices between public and private sectors. All active members of the Canadian Society of Plastic Surgeons (CSPS) and British Association of Plastic, Reconstructive and Aesthetic Surgeons (BAPRAS) with an interest in breast surgery were surveyed. Surgeon demographics, screening practices and perceived barriers to screening were analyzed. Fisher's exact test was used to detect significant associations. The survey response rate was 16%. Most surgeons (68%, n=58/85) were familiar with FDA guidelines; however, only 2.4% (n=2/85) followed them. Surgeons in private practice screened significantly more than surgeons in the public sector [45% (n=13/29) vs 13% (n=7/56), p<0.002]. Among surgeons, ultrasound and high-definition ultrasound were the most common screening modalities and a perceived lack of clinical necessity followed by a perceived lack of satisfactory evidence qualifying these guidelines was the most reported barrier to screening. Despite awareness of FDA guidelines, compliance among surgeons surveyed remains low, reportedly due to a perceived lack of necessity or evidence base. Most public sector surgeons opt not to screen and do not recommend surveillance, even without barriers. While governing bodies should consider current practices to shape guidelines, increasing surgeons' awareness on their evidentiary foundation and potential consequences of silent ruptures is imperative. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Development of a Practical Procedure for Data-Driven Weigh-in-Motion Equipment Calibration Scheduling to Assure Data Accuracy and Consistency over Time

Weigh-in-motion (WIM) technology is a traffic monitoring technology that highway agencies use to obtain information about the weight, axle loading, and configuration of heavy vehicles moving at operational speed. To ensure high-quality WIM data, the Federal Highway Administration (FHWA) recommends regular calibration of WIM equipment. This study addresses the need to optimize the allocation of the limited resources that agencies have for WIM equipment calibration by developing a procedure for data-driven calibration scheduling. This was accomplished through an analysis of WIM measurement errors from test truck data collected during field performance validation and calibration events and an analysis of monthly changes in truck weight and axle loading characteristics, based on WIM data collected between calibration events. The analysis results were used to draw conclusions on the functional performance of different WIM sites. The study also demonstrates how the newly developed National Cooperative Highway Research Program (NCHRP) WIM Data Quality Assurance Analysis Tool can be used to compute truck weight and axle loading parameters and visualize data analysis results using four case studies: two WIM sites with piezo quartz sensors in asphalt pavements and two WIM sites with bending plate sensors in concrete pavements. This paper provides a practical procedure and recommendations that highway agencies can use to develop data-driven WIM calibration schedules that will ensure consistent high-quality WIM data for sites managed by an agency with the aid of the NCHRP WIM Data Quality Assurance Analysis Tool.

Quantification of the Plasma Concentration of Vadadustat by High-Performance Liquid Chromatography with Ultraviolet Detection and Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry.

An inexpensive, simple, and accurate plasma concentration measurement system is needed to actively conduct pharmacokinetic and pharmacodynamic analyses of vadadustat, hypoxia-inducible factor-prolyl hydroxylase inhibitor, in clinical settings. In this study, the authors aimed to develop a method for measuring vadadustat in human plasma that could be applied for therapeutic drug monitoring using high-performance liquid chromatography with ultraviolet detection (HPLC-UV) in a clinical setting. Plasma samples (100 μL) were pretreated with acetonitrile using butyl paraoxybenzoate as an internal standard. Chromatographic separation was performed on a SunShell PFP C18 column (2.6 μm, 4.6 mm × 150 mm). The mobile phase consisted of (A) 20 mM of phosphate buffer (pH 2.4) and (B) acetonitrile (60:40, v/v), delivered isocratically at a flow rate of 1 mL/min. The analytes were detected by UV absorbance at a wavelength of 220 nm, and the column temperature was 40°C. To evaluate the applicability of HPLC-UV in a clinical setting, blood samples were collected at 19 time points from 7 patients who had been taking vadadustat. The calibration curve was linear over the concentration range of 0.2-150 mcg/mL (R2 > 0.99). Intra-assay and interassay accuracy, precision, and stability met the Food and Drug Administration recommendations. The vadadustat plasma concentrations of patients analyzed using the current HPLC-UV method were almost equal to those measured using ultra-performance liquid chromatography-tandem mass spectrometry (mean difference: 0.13 mcg/mL). Large variability in the dose-adjusted plasma concentrations of vadadustat at 12 hours after administration was observed between patients (coefficient of variation = 57.6%). This HPLC-UV method is a simple, accurate quantification method for evaluating plasma concentrations in patients taking vadadustat in a clinical setting.

Restriction of Surgical Options for Pelvic Floor Disorders.

The purpose of this document is to update the 2013 AUGS Position Statement based on subsequent decisions made by the U.S. Food and Drug Administration, published clinical data, and relevant society and national guidelines related to the use of surgical mesh. Urogynecologists specialize in treating pelvic floor disorders, such as pelvic organ prolapse (POP) and urinary incontinence, and have been actively involved and engaged in the national and international discussions and research on the use of surgical mesh in the treatment of POP and stress urinary incontinence. In 2019, the U.S. Food and Drug Administration ordered manufacturers of transvaginally placed mesh kits for prolapse to stop selling and distributing their devices, stating that the data submitted did not provide a reasonable assurance of safety and effectiveness. Evidence supports the use of mesh in synthetic midurethral sling and abdominal sacrocolpopexy. The American Urogynecologic Society (AUGS) remains opposed to any restrictions that ban currently available surgical options performed by qualified and credentialed surgeons on appropriately informed patients with pelvic floor disorders. The AUGS supports the U.S. Food and Drug Administration's recommendations that surgeons thoroughly inform patients seeking treatment for POP about the risks and benefits of all potential treatment options, including nonsurgical options, native tissue vaginal repairs, or abdominally placed mesh. There are certain clinical situations where surgeons may assert that the use and potential benefit of transvaginal mesh for prolapse outweighs the risk of other routes/types of surgery or of not using mesh. The AUGS recommends that surgeons utilize a shared decision-making model in the decision-making process regarding surgical options, including use of transvaginally placed mesh.

Standardization and validation of a high-efficiency liquid chromatography with a diode-array detector (HPLC-DAD) for voriconazole blood level determination.

A specialized service for antifungal blood level determination is not available in Colombia. This service is essential for the proper follow-up of antifungal therapies. To standardize and validate a simple, sensitive, and specific protocol based on high-performance liquid chromatography with a diode array detector for voriconazole blood level quantification. We used an Agilent HPLC™ series-1200 equipment with a UVdiode array detector with an analytical column Eclipse XDB-C18 and pre-column Eclipse- XDB-C18 (Agilent). We used voriconazole as the primary control and posaconazole as an internal control. We performed the validation following the Food and Drug Administration (FDA) recommendations. The best chromatographic conditions were: Column temperature of 25°C, UV variable wavelength detection at 256 nm for voriconazole and 261 nm for posaconazole (internal standard); 50 μl of injection volume, 0,8 ml/min volume flow, 10 minutes of run time, and mobile phase of acetonitrile:water (60:40). Finally, retention times were 3.13 for voriconazole and 5.16 minutes for posaconazole. Quantification range varied from 0.125 μg/ml to 16 μg/ml. The selectivity and chromatographic purity of the obtained signal, the detection limits, and the standardized quantification make this method an excellent tool for the therapeutic monitoring of patients treated with voriconazole.

Assessing Trends in Cytokine-CYP Drug Interactions and Relevance to Drug Dosing.

The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied in vitro and in clinic. Cytokine-mediated suppression of cytochrome P450 (CYP) or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The Food and Drug Administration recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins. To determine the clinical relevance of these drug interactions to dose adjustments, trends in steady-state exposures of CYP-sensitive substrates coadministered with cytokine modulators as reported in the University of Washington Drug Interaction Database were extracted and examined for each of the CYPs. Coadministration of cytochrome P450 family 3 subfamily A (CYP3A) (midazolam/simvastatin), cytochrome P450 subfamily 2C19 (omeprazole), or cytochrome P450 subfamily 1A2 (caffeine/tizanidine) substrates with anti-interleukin-6 and with anti-interleukin-23 therapeutics led to changes in systemic exposures of CYP substrates ranging from ∼ -58% to ∼35%; no significant trends were observed for cytochrome P450 subfamily 2D6 (dextromethorphan) and cytochrome P450 subfamily 2C9 (warfarin) substrates. Although none of these changes in systemic exposures have been reported as clinically meaningful, dose adjustment of midazolam for optimal sedation in acute care settings has been reported. Simulated concentration-time profiles of midazolam under conditions of elevated cytokine levels when coadministered with tocilizumab, suggest a ∼six- to sevenfold increase in midazolam clearance, suggesting potential implications of cytokine-CYP drug interactions on dose adjustments of sensitive CYP3A substrates in acute care settings. Additionally, this article also provides a brief overview of nonclinical and clinical assessments of cytokine-CYP drug interactions in drug discovery and development. SIGNIFICANCE STATEMENT: There has been significant progress in understanding cytokine-mediated drug interactions for CYP-sensitive substrates. This article provides an overview of the progress in this field, including a trend analysis of systemic exposures of CYP-sensitive substrates coadministered with anti-interleukin therapeutics. In addition, the review also provides a perspective of current methods used to assess these drug interactions during drug development and a focus on individualized medicine, particularly in acute care settings.

Efficacy and safety of glecaprevir and pibrentasvir in Saudi patients with chronic hepatitis C virus infection at a major tertiary hospital.

To evaluate the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) in chronic hepatitis C (HCV) patients, and to assess the prescribers' adherence to Food and Drug Administration recommendations on treatment duration. A retrospective cohort study was carried out on chronic HCV patients of ≥18 years, with or without cirrhosis, naive or experienced, and with normal kidney function or chronic kidney disease (including dialysis patients) at Prince Sultan Military Medical City in Riyadh, Saudi Arabia, between February 2020 and March 2021. The primary effectiveness end-point was the number and percentage of patients who achieved a sustained virologic response (SVR12), virologic failure, and non-response. Safety was determined considering both serious and non-serious adverse events. A total of 92 patients were enrolled in this study. Among patients, 52 (56.5%) were female, 84 (91.3%) were naive, and 45 (48.9 %) had HCV genotype 4. The SVR12 was achieved in 91 (98.9%, 95% CI: [94-99.8]) patients. Only one patient (1.1%, 95% CI: [0.2-5.9]) developed virologic non-response and there were missing data on virologic failure. Overall, non-serious adverse events were observed in 26 (28.5%) patients, and none of them had serious adverse events that led to treatment discontinuation. Approximately 75% of the patients received an inappropriate treatment duration (12 weeks vs. the recommended 8 weeks) and most (n=40, 58%; p<0.022) of the exceedingly long treatments were prescribed by registrars. The GLE/PIB was highly effective and safe in chronic HCV Saudi patients.

Current and Upcoming Treatment Strategies After CDK4/6 Inhibitors for Patients With ER+/HER2- Advanced Breast Cancer

This industry symposium took place during the 2023 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain, with a goal of presenting the latest recommendations and upcoming treatment strategies for patients with oestrogen-receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer, who experience disease progression after cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. An expert panel of clinicians explained that most patients will eventually develop resistance to endocrine therapy during the metastatic setting, and there remains a considerable margin for improvement in the second-line (2L) treatment of these patients. Data for current therapeutic options in this patient population were presented, showing that patients who have previously received CDK4/6 inhibitor therapy are often resistant to many of the available 2L therapies, including combination therapies, and that resistance appears during first-line (1L) treatment, becoming particularly significant in tumours harbouring ERS1 mutations. The recent approval of the oral selective oestrogen receptor degrader (SERD), elacestrant, was also discussed. The supporting data for this monotherapy at 2L was presented, along with changes made to the U.S. Food and Drug Administration (FDA) and European Union (EU) best practice recommendations to accommodate this therapeutic option. The panel stressed the importance of testing for ESR1 mutations at each progression during the metastatic treatment course, which is particularly relevant following the approval of elacestrant, for which ESR1 mutation is a predictive factor for efficacy.

Co-Occurrence of Familial Mediterranean Fever and Hematologic Malignancies: Case Report Series

Introduction: Familial Mediterranean Fever (FMF) is an autosomal recessive genetic disorder primarily found among individuals of Mediterranean descent, including Armenians, Italians, Greeks, Arabs, Turks and Jews. In the Armenian population, approximately 90% of FMF cases are associated with three main mutations (M694V, V726A, and M680I) in two alleles of MEFV gene, while more than 300 MEFV variants have been reported worldwide. The homozygous M694V genotype is associated with frequent renal failure due to amyloidosis. Clinical manifestations of FMF include periodic attacks of diffuse serositis with pain and fever that are treated with colchicine or biologic therapy. There is a scarcity of data on patients with FMF and hematologic malignancies. Limited data makes it difficult to generate evidence-based recommendations for the management of these patients, which is mostly based on expert opinions or few case reports. Here we report the case series of patients from Armenia with simultaneous presence of FMF and hematologic malignancies (FMFHM) and evaluate their management challenges. Methods: Data was collected from the Armenian National Registry of Blood Disorders, at the Hematology Center after Prof. R. Yeolyan, and through personal interviews conducted with each patient. Hematology Center is the only institution in Armenia managing hematologic malignancies. We have analyzed 8 patients diagnosed with both FMFHM during 2000-2020, treated in the pediatric (1 patient) and adult (7 patients) hematology departments. Results: 8 patients with FMFHM were identified, from which 4 were diagnosed with myeloproliferative neoplasms (MPN), 2 with acute leukemia (AL), and 2 with non-Hodgkin lymphoma (NHL). The median age of patients was 46, range 20-60 years. Only 5 (62.5%) of patients were regularly taking colchicine for FMF, while the rest refused it. Four MPN patients received treatment only with oral medications (tyrosine kinase inhibitors, hydroxyurea). Autologous hemopoietic stem cell transplantation (auto-HSCT) was performed in 1 NHL patient after indicated 1 st and 2 nd line immuno-chemotherapy. Another 2 AL patients and one NHL patient received protocol-based respective chemotherapy regimens. Moderate gastrointestinal (GI) complications (e.g., epigastric pain, nausea, vomiting, intestinal discomfort) was experienced by 7 (87.5%) patients. Allergic reactions (e.g., moderate skin rash, itching) were seen in 5 patient (62.5%), of which one developed severe anaphylactic shock. A patient with FMF and PMF had ischemic stroke caused by thrombi. Arterial hypertension occurred in 3 (37.5%). Only in one patient reduction of colchicine dosage was performed (1mg/day was reduced to 0.6mg/d), because of interaction with imatinib. The rest of patients received chemotherapy and colchicine treatment as indicated. All 8 patients are alive, 5 of them are in hematologic or molecular remission, two of which received concurrent colchicine treatment. One patient in remission developed renal failure due to FMF (colchicine was refused). Two patients with MPN treated with colchicine experienced disease stabilization. Conclusion: In conclusion, the concurrent appearance of FMFHM may potentially increase the risk of GI side effects, allergic complications, and arterial hypertension, however definitive conclusions require further investigations in larger patient cohorts. While the overall treatment responses were largely positive, the association between MEFV and HM mutations warrants deeper exploration to provide more precise drug administration recommendations for colchicine and cancer medications. Future studies in this area will contribute to a better understanding of the interplay between these conditions and guide optimal treatment strategies.

Treatment Outcomes With Licensed and Unlicensed Stimulant Doses for Adults With Attention-Deficit/Hyperactivity Disorder

Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear. To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses. Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions. Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD. Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses. Change in ADHD symptoms and discontinuations due to adverse events. A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence). Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.

Disease-modifying therapies do not affect sleep quality or daytime sleepiness in a large Australian MS cohort.

Poor sleep is common in multiple sclerosis (MS) and may impact daily functioning. The extent to which disease-modifying therapies (DMTs) contribute to sleep outcomes is under-examined. To compare the effects of DMTs on sleep outcomes in an Australian cohort of people with MS and investigate associations between DMT use and beliefs about sleep problems and daily functioning (social functioning and activity engagement). Sleep outcomes were assessed using the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. DMT use and functioning were self-reported. Of 1,715 participants, 64% used a DMT. No differences in sleep outcomes were detected between participants who did and did not use DMTs, the type of DMT used (lower vs higher efficacy, interferon-β vs other DMTs), the timing of administration, or adherence to standard administration recommendations. Beliefs that DMT use worsened sleep were associated with poorer sleep quality and perceptions that sleep problems interfered with daily functioning. The use of a DMT does not appear to affect self-reported sleep outcomes in people with MS. However, beliefs that DMT use makes sleep worse were associated with poorer sleep quality and increased interference in daily functioning, suggesting a need for education to diminish negative perceptions of DMT use.

"We are in the forgotten corner!" a qualitative study of experiences and challenges among Chinese older women at the onset of acute myocardial infarction.

Acute myocardial infarction (AMI) is a common and serious cardiovascular disease (CVD) that is one of the leading causes of death among women globally and in China. However, there are sex-associated differences and inequalities in the detection and management of AMI, especially in older people. There is little research demonstrating how challenges and barriers affect older women's help-seeking behavior and health-related procedures in China. The objective of this study was to explore the experiences of older women with AMI, focusing on their perception, challenges, and coping strategies at the onset of AMI in Wuhan, China. This study utilized a qualitative research design approach and conducted semi-structured, in-depth, and audio-recorded interviews with 18 women aged 65-84 years, purposively selected from two tertiary hospitals in Wuhan City from November 2021 to April 2022. Interpretative Phenomenological Analysis (IPA) was used in this study to analyze the data on 18 participants and three major themes were generated: disease perception disorder, negative coping strategies, and barriers due to social-environmental contexts. To reduce older women's delay in seeking help, healthcare professionals should provide public health education that emphasizes sex-related disparities, and age-specific knowledge-attitude aspects to high-risk groups. Policy-based and health administration recommendations, including e-health information support, access to care, and social-environmental factors, should be highlighted to promote women's health behavior.

Breast silicone implants' pericapsular impairment: current underdiagnosed status.

Many complications related to silicone implants have been reported recently, from clinical symptoms manifestations to association with some specific types of cancer. During the early 2010s, it was believed that implants were biocompatible and inert to the human body and that gel bleeding/leakage events were rare and without repercussions for the human body. However, at the end of 2010s, several studies pointed out that gel bleeding was more frequent than previously believed, and the pathogenic potential of free silicone should not be ignored. The Food and Drug Administration recommends performing magnetic resonance imaging in asymptomatic patients 5-6 years after implant placement. The descriptors in the Breast Imaging and Reporting Data System lexicon seem outdated for classifying the new generations of implants with cohesive gel, which hinders the diagnosis of device complications. In this review, supported by our research data publications related to silicone implants for 6 years on a prospective study protocol, most of them being original articles, we summarized the main complications observed in clinical practice and discuss the impact of these changes on patients' outcomes focusing on the pericapsular space.

ISSUES OF IMPROVING THE THEORETICAL FOUNDATIONS OF RESOURCE TAXATION

In this article, a proposal has been developed in our republic to calculate taxes on resources, identify existing economic problems in their collection and related organization of tax administration, develop scientific and practical recommendations related to their solutions, and improve them.

Establishing minimally important differences for cardiac MRI end-points in pulmonary arterial hypertension.

Cardiac magnetic resonance (CMR) is the gold standard technique to assess biventricular volumes and function, and is increasingly being considered as an end-point in clinical studies. Currently, with the exception of right ventricular (RV) stroke volume and RV end-diastolic volume, there is only limited data on minimally important differences (MIDs) reported for CMR metrics. Our study aimed to identify MIDs for CMR metrics based on US Food and Drug Administration recommendations for a clinical outcome measure that should reflect how a patient "feels, functions or survives". Consecutive treatment-naïve patients with pulmonary arterial hypertension (PAH) between 2010 and 2022 who had two CMR scans (at baseline prior to treatment and 12 months following treatment) were identified from the ASPIRE registry. All patients were followed up for 1 additional year after the second scan. For both scans, cardiac measurements were obtained from a validated fully automated segmentation tool. The MID in CMR metrics was determined using two distribution-based (0.5sd and minimal detectable change) and two anchor-based (change difference and generalised linear model regression) methods benchmarked to how a patient "feels" (emPHasis-10 quality of life questionnaire), "functions" (incremental shuttle walk test) or "survives" for 1-year mortality to changes in CMR measurements. 254 patients with PAH were included (mean±sd age 53±16 years, 79% female and 66% categorised as intermediate risk based on the 2022 European Society of Cardiology/European Respiratory Society risk score). We identified a 5% absolute increase in RV ejection fraction and a 17 mL decrease in RV end-diastolic or end-systolic volumes as the MIDs for improvement. Conversely, a 5% decrease in RV ejection fraction and a 10 mL increase in RV volumes were associated with worsening. This study establishes clinically relevant CMR MIDs for how a patient "feels, functions or survives" in response to PAH treatment. These findings provide further support for the use of CMR as a clinically relevant clinical outcome measure and will aid trial size calculations for studies using CMR.

High Time to Consider the Role of Thyroid Function in Single Ventricle Heart Disease.

Herein we respond to the controversial United States Food and Drug Administration (FDA) recommendation to perform thyroid function testing in children up to 3years of age within 3weeks of exposure to iodinated contrast media (ICM). Considering the many effects of thyroid hormone on the cardiovascular system, the increased risk of thyroid disease in patients with congenital heart disease, the hemodynamic consequences of the Fontan circulation on the thyroid gland, and the potential clinical significance of subclinical hypothyroidism, we share our perspective that the cardiovascular effects of thyroid hormone may carry more influence for patients with single ventricle heart disease. In our opinion, the FDA statement prompts us to consider routine thyroid hormone surveillance testing in the long-term management of patients with single ventricle heart disease.