Maximum Daily Dose Research Articles

Airborne antibiotics, antimicrobial resistance, and bacterial pathogens in a commercial composting facility: Transmission and exposure risk

Multiple elements associated with antimicrobial resistance in compost may escape into the air during the composting process, including antibiotic resistance genes (ARGs), human pathogenic bacteria (HPBs), and even antibiotics. Although antibiotics play a critical role in the evolution of resistance in HPBs, no information is available on airborne antibiotics in composting facilities. In this study, we systematically quantified airborne antibiotics, ARGs, and HPBs in comparison with those in compost. The burden of antibiotics in the air reached 4.17 ± 2.71 × 102 ng/g, significantly higher than that in compost. The concentration of ARGs (102 copies/g) in air also increased compared with that in compost. Concentrations of target contaminants in air were affected by temperature, organic matter, and heavy metals. Co-occurrence network analysis revealed the connectivity and complexity of antibiotics, ARGs, and HPBs were greater in air than in compost. The maximum daily antibiotic intake dose was up to 1.18 × 10−1ng/d/kg, accompanied by considerable inhalation levels of ARGs and HPBs. Our results reveal the severity of airborne antimicrobial resistance (AMR) elements in composting facilities, highlight the non-negligible amount of antibiotics and their co-existence with ARGs and HPBs, and shed light on the potential role of airborne antibiotics in the evolution of environmental AMR.

Variation in Opioid Agonist Dosing in Clinical Trials by Race and Ethnicity

Racial and ethnic disparities in access to treatment and quality of treatment for opioid use disorder (OUD) have been identified in usual care settings. In contrast, disparities in treatment quality within clinical trials are relatively unexamined. To estimate racial and ethnic differences in the dose of opioid agonist treatment for OUD in the first 4 weeks of treatment in clinical trials. This cohort study performed analysis of the methadone and buprenorphine treatment arms of 3 trials conducted by the National Institute on Drug Abuse Clinical Trials Network between May 2006, and January 31, 2017, at multiple Clinical Trials Network sites across the US. Trial participants who were randomized to and initiated buprenorphine or methadone treatment and who identified as Hispanic, non-Hispanic Black, or non-Hispanic White were included in the present study. Data were analyzed from November 1, 2023, to August 5, 2024. Combined race and ethnicity as self-classified by the patient at trial enrollment. The maximum daily dose of buprenorphine or methadone received in each week for the first 4 weeks of treatment. The mean dose and the percentage of patients receiving a higher dose (buprenorphine ≥16 mg and methadone ≥60 mg) were compared across race and ethnicity groups. A total of 1748 patients (1263 who initiated buprenorphine and 485 who initiated methadone treatment) were included in the analysis (1168 [66.8%] male; median age, 33 [IQR, 26-45] years). Of these, 138 patients (7.9%) identified as Black, 273 (15.6%) as Hispanic, and 1337 (76.5%) as White. In week 4, Black patients received buprenorphine doses 2.5 (95% CI -4.6 to -0.5) mg lower and methadone doses 16.7 (95% CI, -30.7 to -2.7) mg lower compared with White patients, after standardizing by age and sex. In week 4, the percentage of patients receiving a higher dose of medication (buprenorphine ≥16 mg; methadone ≥60 mg) was 16.9 (95% CI, -31.9 to -1.9) points lower for Black patients compared with White patients. Hispanic and White patients received similar buprenorphine doses; Hispanic patients received lower methadone doses than White patients. In this cohort study of data from 3 clinical trials, White patients generally received higher doses of medication than Black patients. Future research is needed to understand the mechanisms of and interventions to reduce disparities in OUD treatment quality and how such disparities impact generalizability of trial results.

Exceeding the guideline-recommended maximum daily dose of opioids for long-term treatment of non-cancer pain in Germany – a large retrospective observational study

BackgroundHigh-dose long-term opioid therapy (LTOT) has been associated with increased mortality and hospitalizations. Therefore, the evidence-based German guideline on LTOT for chronic non-cancer pain (CNCP) recommends to only exceed the maximum daily dose (MDD) of opioids in exceptional cases. This study aimed to determine the portion of LTOT patients who exceeded the guideline-recommended MDD and identify predictors of exceeding in administrative claims data.MethodsThe retrospective observational analysis of opioid prescriptions in patients receiving LTOT for CNCP was based on administrative claims by a large German statutory health insurance company. Patients with at least two quarters of opioid prescriptions between January 2018 and June 2019 were included and followed up for two years. Predictors were identified by logistic regression. In addition, the number of patients still in opioid therapy and the extent of exceeded MDDs were analyzed over time.ResultsThe sample consisted of 113,475 patients. Overall, 10.5% of the patients exceeded the guideline-recommended MDD averaged over the observation period. Strong predictors for exceeding the MDD were receiving opioid prescriptions from > 7 physicians (OR = 7.66, p < .001), receiving predominantly strong opioids (OR = 6.79, p < .001) and receiving opioids for at least one year prior to inclusion (OR = 5.35, p < .001). Within the non-exceeding group, 28.1% discontinued opioid therapy. In contrast, 9.9% of patients in the exceeding group discontinued opioid therapy, whereas the vast majority remained on treatment until the end of the observation period. Furthermore, a slight increase in prescribed doses was observed over time.ConclusionsThe results indicate that a moderate proportion of patients exceeded the guideline-recommended MDD. However, certain patient groups were more likely to receive high doses. This applied in particular to those who were already on treatment at the time of inclusion and continued to receive opioids until the end of the observation period. Further research should examine whether the continuous opioid therapy among the patients with exceeding the guideline-recommended MDD might be related to specific indications, a lack of therapeutic options or avoidance of withdrawal.Trial registrationGerman Clinical Trials Register (drks.de/search/en). Identifier: DRKS00024854. Registered 28 April 2021.

Variability of solar UV radiation in the northern mountains of the Czech Republic, 2020–2021

Solar ultraviolet (UV) radiation has a crucial role in many atmospheric processes and a huge impact on living organisms. Its main positive effect is the synthesis of vitamin D, but it also causes problems such as sunburn, skin cancer or eye cataracts. In the mountains, high doses of UV frequently occur due to a specific combination of atmospheric and geographical factors such as a high ground reflection as a consequence of a large number of days with snow cover, or a lower concentration of atmospheric pollutants in comparison to lowland urban regions. This study used measurements of erythemal UV radiation from two high altitude areas: the Hrubý Jeseník Mountains (Vysoká hole meteorological station, 1 464 m a.s.l.) and the Giant Mountains (Luční bouda meteorological station, 1 413 m a.s.l.) in the Czech Republic, during 2020 and 2021. We evaluated the daily and monthly changes in erythemal dose and UV index. The maximum daily dose of 5.0 kJ.m-2 (8.9 of UV index) was measured on 28 June 2020 at Vysoká hole. The maximal UV index of 10.1 was observed at Luční bouda on 5 July 2020, while the maximum daily dose of 4.9 kJ.m-2 occurred on 14 June 2021. The main factors that caused changes in solar UV radiation were the amount of cloud cover as well as the total ozone column.

Features of diagnostics and therapy of familial Mediterranean fever

The purpose of this work is to attempt to provide an overview of current recommendations for the diagnosis and treatment of familial Mediterranean fever, as well as to present our own clinical observation of this pathology. A selective analysis of the literature over the past 5 years (2020-2024) was carried out in the scientometric databases PubMed (https://pubmed.ncbi.nlm.nih.gov) and the Russian Science Citation Index (www.elibrary.ru). Current data on the autoinflammatory disease familial Mediterranean fever are reviewed. It is important to understand the fact that this pathological condition can be combined with a wide range of autoimmune diseases. The lack of therapy is dangerous for the development of serious complications (systemic amyloidosis). Attention is drawn to the use of colchicine, as well as in the case of colchicine resistance and insufficient effectiveness of colchicine – IL-1 inhibitors. We present our own clinical observation of this disease with an emphasis on the features of the course and stages of therapy for this pathology. A young man, Armenian, was treated for 3 years due to acute conditions with an increase in body temperature to febrile levels, severe abdominal pain and moderate arthralgia. The conditions were accompanied by leukocytosis and increased CRP, but no signs of acute surgical disease were detected. After a molecular genetic study, the diagnosis of familial Mediterranean fever was verified. Colchicine was prescribed, which helped stop many manifestations of the disease; she has been taking it regularly for 5 years. Currently, episodes of exacerbations have become significantly less frequent, laboratory markers of acute inflammation have normalized, but the use of colchicine in the maximum daily dose causes abdominal discomfort. Rare episodes of exacerbations during treatment suggest insufficient effectiveness of this drug. An option to achieve results in such a situation is to use a class of genetically engineered biological drugs such as IL-1 inhibitors. Familial Mediterranean fever is a rare pathological condition, but doctors of various clinical specialties should be wary of its detection. Achieving treatment success requires constant monitoring of the patient’s condition, prescribing therapy with colchicine or IL-1 inhibitors from the moment of diagnosis.

Longitudinal Symptom Burden and Pharmacologic Management of Catatonia in Autism with and without Profound Impairment: An Observational Study.

Catatonia is a highly morbid psychomotor and affective disorder which can affect autistic individuals with and without profound impairment. Catatonic symptoms are treatable with pharmacotherapy and electroconvulsive therapy, but the longitudinal effectiveness of these treatments has not been described. We conducted a prospective observational cohort study of patients with autism and co-morbid catatonia who received outpatient care in a specialized outpatient clinic from July 1st, 2021 to May 31st, 2024. Data investigating pharmacologic interventions, and clinical measures including the Bush Francis Catatonia Rating Scale (BFCRS), Kanner Catatonia Severity Scale (KCS), Kanner Catatonia Examination (KCE), and Clinical Global Impression - Improvement (CGI-I) were collected. Forty-five patients were identified with 39 (86.7%) meeting criteria for profound autism. All patients received pharmacotherapy. 44 (97.8%) were treated with benzodiazepines with a mean maximal daily dose of 17.4 mg (SD=15.8) lorazepam equivalents. Thirty-five patients (77.8%) required more than one medication class for treatment. Fourteen patients (31.1%) attempted to taper off benzodiazepines during the study period; of these, 5 patients (11.1%) were successfully tapered off, and the remaining 9 (17.8%) discontinued the taper due to a return of catatonic symptoms. Statistically significant improvement was observed across all clinical domains except the KCS. However, the majority remained symptomatic over the study period. Despite clinical improvements while receiving the gold standard for psychopharmacologic management of catatonia, chronic symptoms remained for the majority of catatonia patients over the study period, and few were able to taper and discontinue benzodiazepine treatment.

Identification and simultaneous quantification of potential genotoxic impurities in first-line HIV drug dolutegravir sodium using fast ultrasonication-assisted extraction method coupled with GC–MS and in-silico toxicity assessment

Dolutegravir (DLG) has become a distinctive first-line antiretroviral therapy for the treatment of HIV in most countries due to its affordability, high efficacy, and low drug-drug interactions. However, the evaluation of genotoxic impurities (GTIs) in DLG and their toxicity assessment has not been explored thoroughly. Thus, in this study, a simple, fast, and selective analytical methodology was developed for the identification and determination of 7 GTIs in the comprehensive, explicit route of synthesis for the dolutegravir sodium (DLG-Na) drug. A facile, fast ultrasonication-assisted liquid–liquid extraction procedure was adapted to isolate the GTIs in DLG-Na and then analyzed using the gas chromatography (GC)-electron impact (EI)/mass spectrometer (MS) quantification (using selective ion monitoring mode) technique. This EI-GC/MS method was validated as per the current requirements of ICH Q2 (R1) guidelines. Under optimal method conditions, excellent linearities were achieved with R between 0.9959 and 0.9995, and high sensitivity was obtained in terms of detection limits (LOD) between 0.15 to 0.63 µg/g, and quantification limits (LOQ) between 0.45 to 1.66 µg/g for the seven GTIs in DLG. The obtained recoveries ranged from 98.2 to 104.3 % at LOQ, 15 µg/g, and 18 µg/g concentration levels (maximum daily dose of 100 mg). This developed and validated method is rapid, easy to adopt, specific, sensitive, and accurate in estimating the seven GTIs in a relatively complex sodium matrix of the DLG-Na drug moiety. As a method application, two different manufactured samples of DLG-Na drug substances were analyzed for the fate of the GTIs and drug safety for the intended dosage applications. Moreover, an in-silico QSAR toxicity prediction assessment was carried out to prove scientifically the potential GTI nature of each impurity from the alerting functional groups.

P-605 Effectiveness of follitropin delta in patients with potential poor response: A post hoc analysis from the ESTHER-1 trial

Abstract Study question What is the effectiveness of individualised follitropin delta dosing compared to conventional follitropin alfa dosing in patients with potential poor response undergoing ovarian stimulation? Summary answer Individualised follitropin delta dosing provides a favourable efficacy and safety balance and is as good as follitropin alfa in patients with potential poor ovarian response. What is known already Poor ovarian response to controlled ovarian stimulation constitutes a challenge in in-vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) treatment. The dosing algorithm of follitropin delta incorporates the prediction of ovarian response based on anti-Müllerian hormone (AMH), an accurate marker of ovarian reserve, and body weight, for an individualised dosing. In the general IVF/ICSI population and potential high responders, individualised follitropin delta reduces the risk of ovarian hyperstimulation syndrome (OHSS) and/or preventive interventions for OHSS, with sustained efficacy compared to conventional follitropin alfa. However, the performance of follitropin delta in the subpopulation of patients with potential poor response has not been evaluated. Study design, size, duration Post hoc analysis of 332 patients with potential poor response from the ESTHER-1 trial (determined by AMH level at screening &amp;lt;9 pmol/L). Patients received the maximum daily dose of 12 µg follitropin delta (fixed dosing throughout stimulation) as stipulated by the dosing algorithm for patients with AMH &amp;lt;15 pmol/l, or follitropin alfa at a starting dose of 150 IU, with potential dose adjustments from stimulation day 6 and onwards (maximum daily dose of 450 IU). Participants/materials, setting, methods Participants were women, 18–40 years, undergoing their first IVF/ICSI cycle in a GnRH antagonist protocol, including triggering with human chorionic gonadotrophin, IVF/ICSI insemination, and single or double blastocyst transfer on Day 5. Ultrasound was performed 10–11 weeks after transfer to confirm ongoing pregnancy. All pregnancies were followed until birth. Study outcomes include number of oocytes retrieved and number of good quality blastocysts, ongoing pregnancy and live birth rates, cycle cancellation and OHSS rates. Main results and the role of chance A total of 332 patients (25.0% of the overall ESTHER-1 population) had serum AMH at screening of &amp;lt; 9 pmol/l and were included in the analysis: 168 were treated with follitropin delta and 164 were treated with follitropin alfa. Baseline characteristics were similar between the treatment groups, with a mean age of 34.8 years, a median AMH of 5.7 pmol/l and a mean weight of 64.5 kg. With follitropin delta, the mean daily dose was 12.0 µg and with follitropin alfa 12.4 µg, resulting in mean total doses of 104.6 µg and 112.3 µg, respectively. The mean number of oocytes retrieved was 5.8 ± 3.5 with follitropin delta and 5.5 ± 3.6 with follitropin alfa and the mean number of good-quality blastocysts was 1.2 ± 1.4 with both treatments. The ongoing pregnancy rate was 29.8% with follitropin delta and 29.3% with follitropin alfa and the live birth rates were 29.2% and 28.7%, respectively. Thirteen patients (7.7%) treated with follitropin delta and 14 (8.5%) treated with follitropin alfa had their cycles cancelled due to poor response. One case of OHSS (0.6%) was observed in the follitropin delta group, and 3 cases (1.8%) were observed in the follitropin alfa group. Limitations, reasons for caution The main limitation of the study is its post hoc nature. Furthermore, the study is based on a relatively small number of patients. Wider implications of the findings This subgroup analysis, alongside the normoresponder and the potential hyperresponder subgroup of the ESTHER-1 trial, adds evidence for the effectiveness of follitropin delta across all ovarian reserve subgroups of the infertile population. Trial registration number NCT01956110

Large-scale, prospective observational study of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors in a real-world clinical setting.

Regorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting. Patients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1-3 of each 4-week cycle (dose could be modified at investigator's discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS. Between August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators' assessments. Median OS was 17.4 months (95% CI 14.24-23.68). Median TTF was 5.3 (95% CI 4.0-6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. The outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified. https://clinicaltrials.gov, identifier NCT01933958.

Vericiguat Use in Patients with Heart Failure in Real-World Settings during the First Year after the Drug Authorization in Japan.

Background: Vericiguat was developed to treat patients with heart failure (HF). Currently, limited data are available to characterize vericiguat-treated patients in real-world clinical settings. Methods: This retrospective cohort study was done using a Japanese hospital administrative database to describe the use of vericiguat in patients with HF in real-world settings. Adult patients diagnosed with HF prescribed vericiguat between 1 July 2021 and 30 September 2022 were included. Patient characteristics at the initiation of vericiguat treatment, patterns of HF medication use, and vericiguat dose titrations were assessed within the first 90 days of treatment. Results: The study included 829 patients who were initiated on vericiguat therapy. The mean age was 75.5 years and 69.0% were male. Hypertension, coronary artery disease, and diabetes mellitus were present in 91.7, 71.3, and 60.1% of patients, respectively. Most patients had previously received HF medications, with high percentages using angiotensin-receptor blocker neprilysin inhibitors (ARNI; 43.9%) and sodium-glucose cotransporter-2 inhibitors (54.4%). During the first 90 days of vericiguat treatment, 65.8% of the patients were uptitrated from their starting dose, and 32.3% had reached the maximal daily dose. The median time to reach the maximal daily dose was 34 days. The multivariable model identified that initiating vericiguat treatment in an outpatient setting and using ARNI before initiating vericiguat treatment were factors significantly associated with reaching the maximal daily dose of vericiguat at any given time, whereas older age, chronic kidney disease, hyperkalemia, and anemia were not associated. Conclusions: These findings provide early insights into the use of vericiguat, which aid in optimizing the combinations and/or sequences of HF treatment incorporating vericiguat therapy.

#88 Establishment of machine learning-based risk prediction model for acute kidney injury after acute myocardial infarction

Abstract Background and Aims Acute kidney injury (AKI) is a common complication of acute myocardial infarction (AMI) with high morbidity, mortality and lack of effective treatment, so prevention is particularly important. This study intends to use machine learning to establish a precise prediction model for AKI after AMI. Method AMI patients were consecutively collected from July 2011 to December 2016 in Beijing Anzhen Hospital, Capital Medical University. First, SelectFromModel and Lasso regression model were used to select features. A predictive model (Model A) was then created using a multivariate logistic regression model in the training set and validated in the test set. At the same time, the prediction model (Model B) is created by machine learning algorithm in the training set. The process of model construction and evaluation is implemented by Python. The algorithm includes MLP, SVM, KNN and SimpleRNN, from which the model with the largest area under the ROC curve (Model B) is selected and verified in the test set. DeLong method was used to compare the model B with model A to compare whether the area under the ROC curve was better than multivariate logistic regression model and select the best model. Results A total of 6014 AMI patients were included in this study, 70% were randomly selected as the training set, and the remaining 30% were used as the test set. Males comprised 80.5% of the total population with a mean age of 58.4 ± 11.7 years. The incidence of AKI in the overall population was 11.2% (674/6014) (Fig. 1). A total of 12 important characteristics were included in the model, including the number of myocardial infarctions, ST-segment elevation myocardial infarction, ventricular tachycardia, third-degree atrioventricular block, decompensated heart failure at admission, admission serum creatinine value, admission urea nitrogen value, admission CK-MB peak value, whether diuretics were used, maximum daily dose of diuretics, days of diuretic use, and whether statins were used. Logistic regression analysis resulted in an area under the ROC curve of 0.80 (95% CI, 0.76-0.84) in the test set (Fig. 2). The models were constructed by MLP, SVM, KNN and SimpleRNN algorithms, respectively, and validated in the test set to calculate the area under the ROC curve of each model in the test set (Fig. 3), and finally the model constructed by MLP algorithm was selected as model B, and its area under the ROC curve was 0.82 (95% CI, 0.78–0.85). The area under the ROC curve of the two models was compared at p=0.363, but the machine learning algorithm constructed models with higher absolute values (Fig. 4). Conclusion The prediction model of AKI risk after AMI constructed based on machine learning is similar to that constructed by logistic regression analysis in terms of prediction ability, but the model constructed by machine learning algorithm has a better trend, indicating that the machine learning algorithm may improve the prediction ability of prediction model and provide an effective tool for early identification of these high-risk patients in clinical practice, early preventive measures, and reduction of morbidity.

Safety evaluation of 8 drug degradants present in over-the-counter cough and cold medications

Although the United States Food & Drug Administration (FDA) has provided guidance on the control of drug degradants for prescription drugs, there is less guidance on how to set degradant specifications for FDA OTC monograph drugs. Given that extensive impurity testing was not part of the safety paradigm in original OTC monographs, a weight of evidence (WOE) approach to qualify OTC degradants is proposed. This approach relies on in silico tools and read-across approaches alongside standard toxicity testing to determine safety. Using several drugs marketed under 21 CFR 341 as case studies, this research demonstrates the utility of a WOE approach across data-rich and data-poor degradants. Based on degradant levels ranging from 1 to 4% of the maximum daily doses of each case study drug and 10th percentile body weight data for each patient group, children were recognized as having the highest potential exposure relative to adults per body mass. Depending on data availability and relationship to the parent API, margins of safety (MOS) or exposure margins were calculated for each degradant. The findings supported safe use, and indicated that this contemporary WOE approach could be utilized to assess OTC degradants. This approach is valuable to establish specifications for degradants in OTCs.

Nitrosamine Contamination in Pharmaceuticals: Regulatory Perspectives and Control Strategies of USFDA, EMA &amp; HC

Various regulatory authorities were notified the presence of nitrosamine impurities in human medicines including angiotensin II receptor blockers (ARBs), ranitidine, nizatidine and metformin in 2018. The presence of nitrosamines led manufacturers to assessed their products by any means that might inadvertently lead to nitrosamine content and taking steps to mitigate these risks after issuance of safety alerts, recall and withdraw certain batches of these drugs. Importantly, global cooperation by regulatory authorities triggered the investigation of synthetic route, rapid development of analytical procedures and publication of guidelines. This article highlights mainly on risk assessment and control strategies adopted by United States Food and Drug Administration (USFDA) and the European Medicines Agency (EMA), and Health Canada (HC) regulatory bodies. Additionally, compare the acceptable intake (AI) values recommended by these regulatory authorities which will help the manufacturer to either limit or eliminate nitrosamines impurities in their medicines because nitrosamines are probable or possible human carcinogens, hence, it is recommended that the potential causes of nitrosamine formation as well as any other pathways observed and evaluate the risk for nitrosamine contamination or formation in their APIs and drug products. Manufacturers should prioritize evaluation of APIs and drug products based on factors such as maximum daily dose, duration of treatment, therapeutic indication, and number of patients treated for the products which are under pre approval stage and already marketed products.&#x0D; Conclusion: &#x0D; As nitrosamine contamination affects patients worldwide, in case the levels of nitrosamines exceed acceptable limits, or more than one nitrosamine is observed, such products should not be commercialized. All the international regulatory agencies continuing to work with to propose various analytical methodologies to determining nitrosamine content in the API or FPP, risk assessment evaluation and control strategies, extrapolation of toxicological data and various confirmatory test for mutagenicity detection. Due to this rapid action taken by global authorities will help manufacturer to design their manufacturing process to be more robust so that they will timely register their products and reduce the additional cost require for its complete analysis by taking care of consumer’s safety as well.

A Comprehensive Review of COVID-19-Infection- and Steroid-Treatment-Associated Bone Avascular Necrosis: A Multi-Study Analysis

Background: The COVID-19 pandemic has presented numerous challenges to the global healthcare system and emerging evidence suggests a potential link between COVID-19 treatment, specifically steroid therapy, and the development of avascular necrosis (AVN) of the hip. This review aims to provide a comprehensive overview of recent studies and case reports investigating the relationship between COVID-19, corticosteroid therapy, and the development of AVN. Understanding the nuances of AVN in the context of COVID-19 is crucial for healthcare professionals to navigate treatment decisions and mitigate potential complications. Materials and Methods: The Preferred Reporting Items for Systematic Reviews and a Meta-Analysis (PRISMA) were used in the systematic review until 1 September 2023. The full texts of the remaining twenty-three (n = 23) articles were independently reviewed by the authors of this review. Conclusions: The association between steroid therapy for COVID-19 and the development of hip AVN is a noteworthy concern even though no relationship is evident between the duration of treatment, cumulative dosage of medication, maximum daily dosage received, and presence of AVN. Further research with larger cohorts and long-term follow up is needed to better understand the causative relationship and optimal management strategies for hip AVN in the context of COVID-19 and steroid therapy.

Patterns of corticosteroid use among remdesivir and matched patients and associated clinical outcomes in hospitalized COVID-19 patients

ABSTRACT Introduction We aimed to investigate patterns of corticosteroid use and their relationship with remdesivir use and clinical outcomes in a large real-life cohort of COVID-19 patients treated in a tertiary-level institution. Methods We retrospectively analyzed a total of 1558 severe and critical COVID-19 patients, including 779 patients treated with remdesivir and 779 matched control patients. Results A total of 167 (10.7%) patients received none, 710 (45.6%) low, 539 (34.6%) high, and 142 (9.1%) very high corticosteroid doses. Patients treated with remdesivir had significantly longer exposure to corticosteroids, received higher average and maximal daily doses, and cumulative corticosteroid doses. In the multivariate analysis remdesivir use, lower cumulative comorbidity burden, higher severity of COVID-19 symptoms, and mechanical ventilation were recognized as mutually independent predictors of the use of higher corticosteroid doses. Higher corticosteroid doses were associated with significantly increased mortality. Among non-remdesivir treated patients, there was a U-shaped relationship between maximal daily corticosteroid dose and mortality. Among remdesivir treated patients gradual increase in mortality with increasing corticosteroid doses was observed. Conclusion Patterns of corticosteroid use differ regarding the use of remdesivir and may moderate its association with survival among severe and critical COVID-19 patients.

DAIR in treating chronic PJI after total knee arthroplasty using continuous local antibiotic perfusion therapy: a case series study

BackgroundAntimicrobial agents are administered via intramedullary antibiotic perfusion (iMAP)/intrasoft tissue antibiotic perfusion (iSAP) to infected lesions to control osteoarticular and soft tissue infections. Continuous local antibiotic perfusion (CLAP) has been reported to be useful. This study aimed to investigate the outcomes of DAIR combined with CLAP for chronic PJI after total knee arthroplasty performed at our hospital.Subjects and methodsSix patients (male; one case, female; five cases, mean age 79.5 years (70–94)) underwent CLAP for chronic PJI after TKA at our hospital between July 2020 and June 2022. They were followable for at least one year after surgery. Seven months (17–219), with a mean follow-up of 24.3 months (12–36). In addition to direct debridement and insert exchange, systemic antimicrobial treatment, and CLAP with gentamicin were performed using NPWT. We investigated the organisms causing the inflammation, the duration of iMAP/iSAP implantation, the maximum daily dose of GM, the maximum GM blood concentration, and the presence or absence of GM-induced adverse events.ResultTwo of six patients had a recurrence of infection at five weeks and five months after initial CLAP and required repeat CLAP treatment, but all patients could preserve their components. The organisms responsible for the flare-ups were MSSA in three cases: ESBL-producing E. coli, mixed MSSA and streptococcal infection, Klebsiella pneumonia in one case each, and unknown pathogens in one case. CLAP therapy for all patients was administered eight times in 6 cases: iMAP, mean: 10.0 days (5–16); iSAP, mean: 19.3 days (15–28); GM dose, mean: 162.5 mg/day (80–240); and GM blood concentration, mean: 1.4 µg/mL (0.2-5.0). Adverse events included one case of reversible acute kidney injury during CLAP in a patient with recurrent infection.SummaryDAIR with CLAP for chronic post-TKA infection can be a useful treatment option to preserve components and allow the infection to subside, provided the implant is not markedly loosened.

Efficacy and tolerability of rufinamide in the treatment of Lennox–Gastaut syndrome (experience of the Svt. Luka’s Association of Medical Institutions)

Background. Lennox–Gastaut syndrome (LGS) is a classic developmental and epileptic encephalopathy with a debut in childhood, characterized by resistance to therapy, a severe course, and an unfavorable prognosis. Due to the existing difficulties in treatment of LGS, hopes are pinned on development of new antiepileptic drugs with fundamentally different mechanisms of action, aimed specifically at the treatment of this severe form of epilepsy.Rufinamide (Inovelon®) is a new antiepileptic drug registered in the Russian Federation for use in the adjunctive therapy of LGS in patients older than 1 year. The main mechanism of action of rufinamide is the restriction of neuronal discharges associated with the blocking effect on sodium channels (regulation of sodium channels activity by increasing duration of their inactive state), and stabilization of neuronal membranes. The drug has a number of advantages concernung pharmacokinetic parameters and efficacy (including a wide spectrum of antiepileptic activity, good oral absorption, absence of active metabolites, urinary excretion, low affinity for plasma proteins, biotransformation without cytochrome P450 isoenzymes, low risk of drug interactions) and fairly good tolerability. The daily dose of rufinamide varies from 600 mg (with simultaneous administration of valproate) to 1000 mg (if the patient does not take valproate) in children over 4 years of age with a body weight of less than 30 kg and up to 2200–3200 mg in children over 4 years of age with a body weight of more than 30 kg and in adults; in children under 4 years of age, the maximum daily dose in combination with valproate is 30 mg/kg, and without valproic acid – 45 mg/kg.Aim. To analyze the efficacy and tolerability of rufinamide in the treatment of epilepsy based on the long-term experience of using the drug in the Svt. Luka’s Association of Medical Institutions.Materials and methods. We observed 64 patients aged from 1.5 to 26 years (44 men, 20 women) treated with rufinamide (Inovelon®). Among them, the structural etiology LGS was diagnosed in 36 patients, the genetic and presumably genetic etiology LGS – in 28. In all cases, rufinamide was used in accordance with approved indications as an additional antiepileptic drug, more often in combination with valproate, topiramate, levetiracetam or lamotrigine. Titration of the drug was carried out according to the recommendations in the instructions for use, up to a therapeutic dose that ranged from 200 to 1600 mg/day (in most cases from 400 to 1200 mg/day), depending on age and concomitant therapy.Results and conclusion. Remission of all types of seizures was registered in 17 (26.6 %) patients, and a decrease in the incidence of seizures by more than 50 % was recorded in 28 (43.8 %) patients. Of them, 13 patients demonstrated reduction in seizures frequency by more than 75–90 % and remission of one of several types of seizures. In general, the therapeutic effect (reduction of seizures frequency by at least 50 %) was achieved in 45 (70.3 %) of 64 patients. A decrease in seizures frequency of by at least 50 % was observed in 8 (12.5 %) patients; in 10 (15.6 %) patients, rufinamide therapy was not effective; in 1 (1.56 %) case an aggravation of bilateral convulsive seizures was noted when rufinamide was administered.In most cases, rufinamide is well tolerated. Our patients had side effects in 10 (15.6 %) cases. Only in 2 (3.1 %) cases, rufinamide was withdrawn directly due to side effects (the reason for withdrawal in these cases was an allergic reaction and psychosis).The retention rate for therapy lasting 1 year or more is 65.6 % (42 of 64 patients).Thus, our data have demonstrated efficacy and good tolerability of rufinamide in treating epileptic seizures associated with LGS, confirming numerous literature data. However, in our analysis, a higher rate of seizure remission was obtained, although we have included patients with mainly resistant forms of epilepsy in the analysis.

1830. Social determinants of cardiovascular disease risk factor control among people living with HIV

Abstract Background HIV is associated with an elevated risk of cardiovascular disease, yet hypertension and high cholesterol are often sub-optimally treated in people with HIV. The role of racial disparities and social determinants of health in the management of these cardiovascular risk factors is poorly understood. Average systolic blood pressures vs TIS score (hypertension treatment intensity), by Black race TIS (therapeutic intensity score) was calculated by dividing the patient’s antihypertensive medication dosage by the maximum daily dosage approved by the US Food and Drug Administration, then summing this proportion for each antihypertensive medication prescribed. For example, if a patient was prescribed two antihypertensive medications each at 75% of the maximum approved dosage, the TIS score would be calculated as 1.5 (0.75 + 0.75). Methods We performed a cross-sectional analysis of adult patients with HIV among three academic medical centers in the United States. We considered various social determinants of health including race, sex, measures of economic stability, education level, health insurance, health literacy, social deprivation index by zip code, and measures of psychosocial stress. We examined a hybridized outcome of risk factor control (poor or good) and treatment intensity (minimal or maximal) for two key cardiovascular risk factors, hypertension and hyperlipidemia. Multinomial logistic regressions were performed to identify factors associated with cardiovascular risk factor control and intensity, with “good control, maximal treatment” used as the reference group. Results Overall, 371 persons were included in the analysis. Participants were 23.5% female, 59.6% Black, 7.3% Hispanic/Latino, with a median age of 59 (interquartile range 53-64). Among study participants with hypertension, Black participants were more likely to have poor control despite maximal treatment (relative risk ratio [RRR] 2.95, 95% CI: 1.30-6.66). In our hyperlipidemia analysis, having the highest quartile of perceived stress was more common among participants with poor than good cholesterol control (27.0% vs 15.9%, p=0.032). Compared to participants with good control and maximal treatment of high cholesterol, participants with the highest quartile of perceived stress were more likely to have poor control with minimal (RRR: 2.80, 95% CI: 1.02-7.63) or maximal (RRR: 3.64, 95% CI: 1.20-11.1) treatment. Conclusion Race and social determinants of health, including perceived stress, appear to influence cardiovascular disease risk factors among persons with HIV. Disclosures Nwora Lance Okeke, MD MPH, Gilead Sciences: Advisor/Consultant

Efficacy and safety of zuranolone in major depressive disorder: a meta-analysis of factor effect and dose-response analyses

Zuranolone is recognised as a promising antidepressant agent. Our study aimed to investigate the efficacy and safety of zuranolone in treating major depressive disorder (MDD). A systematic review was conducted by searching major databases from inception to August 20, 2023 (INPLASY: 202360087). A meta-analysis was performed by using a random-effects model to calculate effect sizes, expressed as standardised mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs). The primary outcome was improvement in depressive symptoms, while secondary outcomes included response and remission rates of depression, improvement in anxiety symptoms, incidence of dropouts, and any side effects. We conducted subgroup analyses for general MDD and postpartum-onset MDD and a dose-response meta-analysis to estimate the relationship between zuranolone dose and outcomes. The study included seven randomised control trials involving 1789 patients. Zuranolone reduced depressive symptoms (SMD=-0.37, 95% CIs=-0.51 to-0.23), increased response rate (OR=2.06, 95% CIs=1.48-2.85) and remission rate (OR=2.04, 95% CIs=1.38-3.02), and reduced anxiety symptoms (SMD=-0.26, 95% CIs=-0.39 to-0.14). Furthermore, zuranolone-treated patients experienced more side effects than those in the control group (OR=1.40, 95% CIs=1.10-1.78), although dropout rate did not significantly differ between the two groups (OR=1.13, 95% CIs=0.85-1.49). According to the dose-response meta-analysis, zuranolone could effectively improve depression and anxiety at increasing doses up to a maximum daily dose of 30mg; however, side effects increased with doses exceeding 30mg. Based on subgroup analyses, zuranolone showed greater efficacy in treatment of postpartum-onset MDD than general MDD, but the difference did not reach statistical significance. Our findings suggested that zuranolone is effective in alleviating depression and anxiety. Nevertheless, there is a potential risk of adverse effects. Given its therapeutic efficacy and risk of side effects, a daily dose of 30mg appears to be the optimal choice. Chang Gung Medical Foundation.

Safety evaluation of INFAT® PLUS: Acute, genetic, teratogenic, and subchronic (90-day) toxicity studies

INFAT®PLUS, is a sn-2 palmitate enriched fat ingredient intended for infant formula. A battery of toxicological studies was conducted in accordance with the Food Safety Toxicological Assessment GB-15193 (China), to confirm the safety of INFAT®PLUS. In the acute oral toxicity test, the LD50 of INFAT® PLUS was higher than 53.4 g /kg BW and 26.7 g/kg BW for ICR mice and SD rats, respectively. In a subchronic study, INFAT® PLUS was administered by oral gavage to SD rats with maximal daily dose of 8.90 g/kg BW for 90 days. No treatment-related clinical signs or mortalities were observed. The no-observed-adverse-effect level (NOAEL) was set at 8.90 g/kg BW. Similarly, no evidence of genotoxicity effect was noted in several in vitro and in vivo tests, including bacterial reverse mutation (Ames) test, mouse erythrocyte micronucleus test, and chromosome aberration test of mouse spermatogonia/spermatocyte. For the teratogenic evaluations, no toxicological signs were observed in both pregnant SD rat and fetuses, and the NOAEL of INFAT® PLUS was determined to be 8.90 g/kg BW. Based on the obtained results we concluded that INFAT® PLUS was found non-toxic under the experimental conditions, and the totality of the safety data supports its use for infant nutrition.