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Context Growth hormone (GH) replacement therapy improves longitudinal growth and adult height in children with GH deficiency (GHD). GH stimulates insulin-like growth factor (IGF)-I release, the biomarker used for monitoring GH activity during treatment. Objective This study aims to provide model-based insights into the dose–IGF-I responses of once-weekly somapacitan, a novel long-acting GH, compared with daily GH in children with GHD. Methods Analyses included dosing information and 1473 pharmacokinetic samples from 210 somapacitan-treated pediatric patients with GHD across 3 trials, including phase 1 (NCT01973244), phase 2 (NCT02616562; REAL 3), and phase 3 (NCT03811535; REAL 4), as well as 1381 IGF-I samples from 186 patients with GHD treated with somapacitan in REAL 3 and REAL 4. Pharmacokinetic/pharmacodynamic modeling to characterize somapacitan dose–IGF-I response and predict the response to dosing day changes. Results Relationships were established between somapacitan dose, exposure, change from baseline IGF-I SD score (SDS), and height velocity (HV). A linear model permitted the development of a tool to calculate estimated average weekly IGF-I exposure from a single IGF-I sample obtained at any time within the somapacitan dosing interval at steady state. In practice, the use of this tool requires knowledge of somapacitan injection timing relative to IGF-I sample collection timing. IGF-I SDS simulations support flexible dosing day changes while maintaining at least 4 days between doses. Conclusion We characterized the dose–IGF-I response of somapacitan in children with GHD. To support physicians in IGF-I monitoring, we present a practical guide about expected weekly average IGF-I concentrations in these patients and provide insights on dosing day flexibility. [ABSTRACT FROM AUTHOR]

Pexidartinib is a colony-stimulating factor-1 receptor inhibitor approved in the United States for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Because of the risk of severe and potentially fatal hepatotoxicity, pexidartinib is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. Pexidartinib pharmacokinetics are influenced by the fat content of meals: compared with the fasted state, consuming a high-fat meal with pexidartinib increases pexidartinib absorption by 100%; a low-fat meal increases absorption by approximately 60%. Pexidartinib was initially authorized to be taken at 800 mg/day on an empty stomach; therefore, if this same dose of pexidartinib is taken with food, there is a risk of overexposure and potential toxicity. To reduce the risk of hepatotoxicity and improve patient compliance, pexidartinib has undergone a revised dosing regimen, from 800 mg/day (400 mg twice daily) fasted to 500 mg/day (250 mg twice daily) with a low-fat meal (approximately 11–14 g of total fat). The objective of this report is to educate clinical and allied health professionals on the revised dosing regimen and the importance of patient compliance with a low-fat meal. Healthcare professionals need to understand the rationale for the switch from pexidartinib dosing on an empty stomach to dosing with a low-fat meal and how meal composition and timing influence pharmacokinetics. Finally, we provide guidance for the healthcare team of prescribing providers, nurses, pharmacists, and dietitians who are caring for patients with TGCT on pexidartinib. It is important for healthcare providers to deliver consistent messaging on the low-fat meal requirement and help patients fit pexidartinib into their regular meal schedules. Consulting a dietitian may be helpful for patients, especially those with complex dietary needs. We provide an overview of the roles and responsibilities of each healthcare professional and outline steps to best support patients, including key questions and answers related to the revised dosing regimen. This report provides the information necessary to guide the multidisciplinary team caring for patients with TGCT and to support them through the pexidartinib dosing regimen change. [ABSTRACT FROM AUTHOR]

[Display omitted] A cross sectional pan-India study about use of administration devices for paediatric oral and inhalation medicines was conducted with a diverse pool of participants of various age groups. Via 634 respondents from more than 15 states in India, this study has identified the administration devices commonly used by parents/caregivers for children 0 to 18 years and by children over 10 years. It has provided insights on device ease of use, challenges faced and recommendations to facilitate the correct use of administration devices for paediatric oral and inhalation medicines. Ethics approval (DPSRU-BREC/2020/A/008)) was obtained from the Biomedical Research Ethics Committee of Delhi Pharmaceutical Sciences and Research University. The survey was completed by parents only (n = 514) and jointly by both parents and children (n = 120). The mean age of the child was 7.2 ± 4.96 years. 72% of the respondents reported that an oral medicine had been taken recently, 6.3% reported that an inhaled medicine had been taken and the remaining 21.9% reported that both an oral and inhaled medicine had been taken. The use of measuring cup was most prevalent followed by household spoons. The mean of the score for ease of use was found to be highest 4.6 ± 0.50 for oral syringe and lowest (3.8 ± 0.76) for measuring cups. The majority of them found the oral device easy to use. Difficulties were reported mostly for measuring cups and household spoons and were related to a lack of user instructions and measuring difficulties. The respondents who found the device easy to use had mostly received clear instructions from healthcare professionals. Compared to oral devices, there were very limited responses for inhalation devices (n = 175/634). Nebulisers with facemasks were most frequently used followed by manually actuated Metered dose inhalers with and without spacer. The mean of the ease-of-use score for dry powder inhalers was found to be highest (4.2 ± 0.37) followed by mist inhalers (4.0 ± 0) and manually actuated pressurised metered dose inhalers (4.0 ± 0.71). The nebulisers with facemask were reported to be difficult to use by most of the respondents despite receiving clear instructions from healthcare professionals. The study findings add evidence to the understudied area of user experiences and perspectives on administration devices for oral and inhalation medicines in India. It highlights a need for initiatives to improve the usability, availability, and affordability of administration devices for children in India. Awareness on the importance of proper use of devices needs to be raised and sustained about the existence of affordable administration devices. [ABSTRACT FROM AUTHOR]

Aim: Iterative approaches to vancomycin dosing (e.g., dosing when trough concentrations <15–20 mg/L) can be inadequate. Computer‐guided dosing may be superior but has not been evaluated in patients with kidney failure receiving replacement therapy. We evaluated vancomycin concentrations using a hospital protocol and a pharmacokinetic software. We measured vancomycin clearance by the FX8 low‐flux filter because data are absent. Methods: We retrospectively reviewed records of adults with kidney failure requiring replacement therapy receiving vancomycin and dialysed with the FX8 low‐flux filter, and calculated the proportion of pre‐dialysis concentrations that were within, above or below a specified range. One and two‐compartment models in the pharmacokinetic software were assessed by computing mean prediction error (MPE) and root mean square error (RMSE) of observed versus predicted concentrations. Vancomycin extracorporeal clearance was prospectively determined using the extraction method. Results: In 24 patients (34 courses; 139 paired observed and predicted concentrations), 62/139 (45%) pre‐dialysis concentrations were 15–25 mg/L, 29/139 (21%) were above, and 48/139 (35%) were below. MPE for the one‐compartment model was −0.2 mg/L, RMSE 5.3 mg/L. MPE for the two‐compartment model was 2.0 mg/L, RMSE 5.6 mg/L. Excluding the first paired concentrations, the subsequent MPE (n = 105) using one‐compartment model was −0.5 mg/L, RMSE 5.6 mg/L. The MPE for the two‐compartment model was 2.1 mg/L, RMSE 5.8 mg/L. The median extracorporeal clearance was 70.7 mL/min (range: 10.3–130.3; n = 22). Conclusions: Vancomycin dosing was suboptimal and the pharmacokinetic software was not sufficiently predictive. These may improve with a loading dose. The substantial removal of vancomycin by low‐flux filters is not accounted for by the models tested. Summary at a glance: More data are required to inform the prescribing of vancomycin in patients with kidney failure receiving replacement therapy. An iterative approach (dosing in response to a subtherapeutic concentration) achieved a therapeutic concentration in 45% of occasions. Pharmacokinetic software was not sufficiently predictive. Substantial amounts of vancomycin are removed from a low‐flux filter. [ABSTRACT FROM AUTHOR]

Background: Intravenous digoxin loading dose recommendations differ between clinical guidelines and Food and Drug Administration packaging for acute rate control. Objective: The objective of this study was to assess the safety and efficacy of intravenous digoxin loading in patients who received ≤12 µg/kg and >12 µg/kg of digoxin using ideal body weight (IBW). Methods: This single center retrospective cohort study with exempt status from the local Institutional Review Board included patients who received intravenous digoxin and had a serum digoxin concentration (SDC) drawn. Digoxin doses >36 hours after the first dose were excluded. Patients who received a total of >12 µg/kg and ≤12 µg/kg IBW were compared. The primary endpoint was frequency of SDCs ≥1.2 ng/mL, which have been shown to be associated with increased mortality. Results: A total of 244 patients were included (144 receiving >12 µg/kg and 100 receiving ≤12 µg/kg). There were significantly more SDC ≥1.2 ng/mL in the >12 µg/kg group than the ≤12 µg/kg group (50.6% vs. 30.0%; adjusted odds ratio, 3.19; 95% confidence interval [CI]: 1.79-5.84), with no difference in rate control failure. Major limitations of the study include retrospective nature and possible selection bias. Conclusion and Relevance: Compared to patients who received digoxin doses ≤12 µg/kg IBW, patients who received >12 µg/kg IBW had higher rates of SDC ≥1.2 ng/mL. This suggests that appropriate weight-based dosing with 8 to 12 µg/kg IBW has the potential to be a safer approach to digoxin loading, rather than frequently used dosing strategies that result in doses >12 µg/kg. [ABSTRACT FROM AUTHOR]

Background: Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device that provides life-saving complete respiratory and cardiac support in patients with cardiorespiratory failure. The majority of drugs prescribed to patients on ECMO lack a dosing strategy optimized for ECMO patients. Several studies demonstrated that dosing is different in this population because the ECMO circuit components can adsorb drugs and affect drug exposure substantially. Saturation of ECMO circuit components by drug disposition has been posited but has not been proven. In this study, we have attempted to determine if propofol adsorption is saturable in ex vivo ECMO circuits. Methods: We injected ex vivo ECMO circuits with propofol, a drug that is highly adsorbed to the ECMO circuit components. Propofol was injected as a bolus dose (50 μg/mL) and a continuous infusion dose (6 mg/h) to investigate the saturation of the ECMO circuit. Results: After the bolus dose, only 27% of propofol was recovered after 30 minutes which is as expected. However, >80% propofol was recovered after the infusion dose which persisted even when the infusion dose was discontinued. Conclusion: Our results suggest that if ECMO circuits are dosed directly with propofol, drug adsorption can be eliminated as a cause for altered drug exposure. Field of Research: Artificial Lung/ECMO

Logan D Schneider,1 Anne Marie Morse,2 Michael J Strunc,3 Joyce K Lee-Iannotti,4 Richard K Bogan5 1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA; 2Janet Weis Children’s Hospital, Geisinger Medical Center, Danville, PA, USA; 3The Center for Pediatric Sleep Medicine, Children’s Hospital of The King’s Daughters, Norfolk, VA, USA; 4Department of Neurology, The University of Arizona College of Medicine, Phoenix, AZ, USA; 5Department of Pulmonology, University of South Carolina School of Medicine, Columbia, SC, USACorrespondence: Logan D Schneider, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 450 Broadway St, Pavilion C 2nd Fl MC 5704, Redwood City, CA, 94063, USA, Tel +1 650 723-6601, Fax +1 650 721-3448, Email logands@gmail.comAbstract: Narcolepsy and idiopathic hypersomnia are chronic conditions that negatively affect alertness, mental and physical energy, functioning, and quality of life (QoL). Calcium, magnesium, potassium, and sodium oxybates (low-sodium oxybate; LXB) is an oxybate formulation with 92% less sodium than sodium oxybate (SXB; a treatment for narcolepsy) and the same active moiety. LXB is approved in the US for treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age or older with narcolepsy, and idiopathic hypersomnia in adults. In Phase 3 clinical trials, LXB exhibited a safety profile consistent with that of SXB in narcolepsy. Besides continued efficacy in treating symptoms, potential benefits of long-term LXB treatment include flexible optimization of dosing and regimen, improvement of QoL and functioning, weight loss, and (relative to SXB in narcolepsy) health benefits of reduced sodium content. Dosing of LXB is twice nightly (for narcolepsy) or once or twice nightly (for idiopathic hypersomnia) based on patient characteristics and response, and individualized titration can be leveraged over the long term as a patient’s life circumstances change. Patients with narcolepsy transitioning from SXB initiate LXB at the same dose, and most patients require no further changes to achieve similar efficacy and tolerability. Improvements in functioning and QoL with LXB treatment could have cascading positive effects in multiple domains, particularly in younger patients. In clinical trials, LXB was associated with weight loss in both narcolepsy (in which obesity is a well-established comorbidity) and idiopathic hypersomnia, only occasionally leading participants to be underweight. As both narcolepsy and idiopathic hypersomnia are associated with increased risk of cardiometabolic and cardiovascular comorbidities, limiting medication-related sodium intake with LXB may have significant health benefits, although this has not yet been verified prospectively due to the prolonged follow-up required. LXB is a promising long-term treatment for narcolepsy and idiopathic hypersomnia.Plain Language Summary: Narcolepsy and idiopathic hypersomnia are disorders that make people feel very sleepy. Low-sodium oxybate (LXB) is a medicine for these disorders. Doctors think LXB works on parts of the brain that keep people awake. LXB may quiet those brain parts down at night by reducing their electrical activity, which helps people sleep better. LXB wears off by the morning, so people can wake up normally and feel more alert the next day. LXB has less sodium (which is part of salt) than a medicine called sodium oxybate. Sodium oxybate has been used for narcolepsy for more than 20 years. LXB has several benefits. First, LXB may be healthier than medicines that contain a lot of sodium, such as a high-sodium oxybate. This is because sodium can increase blood pressure and risk of heart disease. Second, LXB can be taken twice each night for narcolepsy, or once or twice each night for idiopathic hypersomnia. This depends on a person’s lifestyle, how well the medicine is working, and side effects. Third, people taking LXB are more able to work and do other activities and have better quality of life. Finally, people taking LXB may lose weight. This can help overweight or obese people.Keywords: cardiovascular, dosing, LXB, hypersomnolence, quality of life, weight loss

Abstract Background Recent systematic reviews and meta-analyses have suggested that low-dose steroids are effective in the treatment of acute respiratory distress syndrome (ARDS). Recent guidelines recommend the use of low-dose steroids instead of high-dose steroids. These systematic reviews were conducted based on the concept that the effect of steroids is constant regardless of their type. We discuss whether the type of steroid used influences the outcomes in patients with ARDS. Main body From a pharmacological standpoint, methylprednisolone has little activity as a mineralocorticoid and may cause pulmonary hypertension. The results of the rank probability of our previous network meta-analysis revealed that low-dose methylprednisolone might be an optimal treatment compared to using other types of steroids or no steroids in terms of ventilator-free days. Similarly, an analysis of individual data from four randomized controlled trials suggested that low-dose methylprednisolone was associated with decreased mortality in patients with ARDS. Dexamethasone has attracted the attention of clinicians as a novel adjunct therapy for ARDS. Conclusion Recent evidence has shown that low-dose methylprednisolone may be an effective treatment option for ARDS. The timing of initiation and duration of low-dose methylprednisolone therapy should be verified in future studies.

Objective: Glioblastomas are the most common primary central nervous system (CNS) tumors. Although modern management strategies have modestly improved overall survival, the prognosis remains dismal, with treatment side effects often impinging on the clinical course. Glioblastomas cause neurological dysfunction by infiltrating CNS tissue and via perifocal oedema formation. The administration of steroids such as dexamethasone is thought to alleviate symptoms by reducing oedema. However, despite its widespread use, the evidence for the administration of dexamethasone is limited and conflicting. Therefore, we aimed to review the current evidence concerning the use and outcomes of dexamethasone in patients with glioblastoma. Methods: We performed a systematic review and meta-analysis according to the PRISMA-P guidelines. We performed a restricted search using the keywords “Dexamethasone” and “Glioblastoma” on PubMed, Web of Science, Cochrane Library, and Academic Search Premier. We included studies reporting on overall survival (OS) and progression-free survival (PFS) in glioblastoma patients receiving higher or lower dexamethasone doses. The risk of bias was assessed using ROBINS-I. We performed a meta-analysis using a random effects model for OS and PFS. Results: Twenty-two retrospective studies were included. Higher doses of dexamethasone were associated with poorer OS (hazard ratio 1.62, confidence interval 1.40–1.88) and PFS (1.49, 1.23–1.81). OS remained worse even when studies corrected for clinical status (1.52, 1.38–1.67). Conclusion: Despite the widespread use of dexamethasone in glioblastoma patients, its use is correlated with worse long-term outcomes. Consequently, Dexamethasone administration should be restricted to selected symptomatic patients. Future prospective studies are crucial to confirm these findings.

Abstract Appropriate antibiotic treatment for critically ill patients with serious Gram-negative infections in the intensive care unit is crucial to minimize morbidity and mortality. Several new antibiotics have shown in vitro activity against carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat resistant Pseudomonas aeruginosa. Cefiderocol is the first approved siderophore beta-lactam antibiotic with potent activity against multidrug-resistant, carbapenem-resistant, difficult-to-treat or extensively drug-resistant Gram-negative pathogens, which have limited treatment options. The spectrum of activity of cefiderocol includes drug-resistant strains of Acinetobacter baumannii, P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp. and Burkholderia spp. and CRE that produce serine- and/or metallo-carbapenemases. Phase 1 studies established that cefiderocol achieves adequate concentration in the epithelial lining fluid in the lung and requires dosing adjustment for renal function, including patients with augmented renal clearance and continuous renal-replacement therapy (CRRT); no clinically significant drug–drug interactions are expected. The non-inferiority of cefiderocol versus high-dose, extended-infusion meropenem in all-cause mortality (ACM) rates at day 14 was demonstrated in the randomized, double-blind APEKS–NP Phase 3 clinical study in patients with nosocomial pneumonia caused by suspected or confirmed Gram-negative bacteria. Furthermore, the efficacy of cefiderocol was investigated in the randomized, open-label, pathogen-focused, descriptive CREDIBLE–CR Phase 3 clinical study in its target patient population with serious carbapenem-resistant Gram-negative infections, including hospitalized patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infections. However, a numerically greater ACM rate with cefiderocol compared with BAT led to the inclusion of a warning in US and European prescribing information. Cefiderocol susceptibility results obtained with commercial tests should be carefully evaluated due to current issues regarding their accuracy and reliability. Since its approval, real-world evidence in patients with multidrug-resistant and carbapenem-resistant Gram-negative bacterial infections suggests that cefiderocol can be efficacious in certain critically ill patient groups, such as those requiring mechanical ventilation for COVID-19 pneumonia with subsequently acquired Gram-negative bacterial superinfection, and patients with CRRT and/or extracorporeal membrane oxygenation. In this article, we review the microbiological spectrum, pharmacokinetics/pharmacodynamics, efficacy and safety profiles and real-world evidence for cefiderocol, and look at future considerations for its role in the treatment of critically ill patients with challenging Gram-negative bacterial infections.

Background The current treatment guidelines of the Infectious Diseases Society of America recommend β-lactam antibiotics as alternative rather than first-line agents for the treatment of uncomplicated urinary tract infection (uUTI). Cephalexin is a commonly prescribed first-generation cephalosporin with excellent bioavailability and urinary penetration; however, little data exist to support optimal dosing for uUTI. Methods This retrospective multicenter cohort study included adult female patients who received 5 to 7 days of cephalexin for symptomatic uUTI with a cefazolin-susceptible urine culture. The primary objective was to compare uUTI treatment failure (eg, continued or recurrent symptoms within 30 days) between patients treated with cephalexin 500 mg twice daily (BID group) and 500 mg 4 times daily (QID group) in the outpatient setting. Secondary outcomes included time to treatment failure, reported adverse events within 7 days of treatment, and occurrence of Clostridioides difficile within 30 days of treatment. Results A total of 261 patients were included (BID, n = 173; QID, n = 88). Baseline characteristics were similar between the groups. Escherichia coli was the most commonly isolated pathogen (85.4%). There was no difference in treatment failure observed between the groups (BID 12.7% vs QID 17%, P =.343), including failure while undergoing therapy (BID 2.3% vs QID 5.7%, P =.438) or recurrence within 30 days (BID 10.4% vs QID 11.3%, P =.438). No differences in reported adverse events (BID 4.6% vs QID 5.6%, P =.103) were observed between groups. Conclusions Twice-daily cephalexin is as effective as 4-times-daily dosing for uUTI. A twice-daily dosing strategy may improve patient adherence. [ABSTRACT FROM AUTHOR]

Traditionally, there has been a common belief that ongoing i.v. antibiotic therapy is superior to an early i.v. to oral switch, especially for severe infections. However, this may be at least partly based on early observations rather than robust, high-quality data and contemporary clinical studies. It is important to examine whether these traditional views align with clinical pharmacological considerations, or conversely, if these considerations may support the broader application of an early i.v. to oral switch under appropriate circumstances. To examine the rationale for an early i.v. to oral antibiotic switch in the context of clinical pharmacokinetic and pharmacodynamic principles and to discuss whether commonly encountered pharmacological barriers are real or simply perceived. We conducted PubMed searches on barriers and clinicians' perceptions about an early i.v. to oral switch, clinical studies comparing switching with i.v.-only dosing, and pharmacological factors affecting oral antimicrobials. We focused on general pharmacological and clinical pharmacokinetic and pharmacodynamic principles and considerations that are relevant when clinicians ponder whether to switch from i.v. to oral antimicrobial dosing. The main focus of this review was on antibiotics. The discussion of the general principles is accompanied by specific examples from the literature. Clinical pharmacological considerations and an imposing and increasing number of clinical studies, including randomized clinical trials, support an early i.v. to oral switch for the treatment of a number of infection types, under appropriate circumstances. We hope that the information provided here will add to calls for a critical examination of the role of i.v. to oral switching for many infections that are currently treated almost exclusively with i.v.-only therapy, and that it will inform health policy and guideline development by infectious diseases organizations. [ABSTRACT FROM AUTHOR]

Study Design: Literature review and meta-analysis. Objectives: Single-center series may be underpowered to detect whether high-dose (HD) tranexamic acid (TXA) confers a higher risk of complications. We sought to determine the safety and efficacy of HD TXA as compared to low-dose (LD) or placebo. Methods: A systematic literature review was performed to find studies where spine surgery patients were given HD TXA (loading dose ≥30 mg/kg). Complication rates were pooled, and meta-analyses performed on outcomes of interest. Articles were evaluated for risk of bias and a strength of evidence assessment was given for each conclusion. Results: Twenty three studies (n = 2331) were included. The pooled medical complication rate was 3.2% in pediatric patients, 8.2% in adults. Using lower dose TXA or placebo as the reference, meta-analysis showed no difference in medical complications (n = 1,723, OR 1.22 [95% CI,.78 to 1.22]; P =.388; I2 = 0%) or thrombotic events (n = 1158 patients, OR 1.27 [95% CI,.71 to 2.63]; P =.528; I2 = 0%). Compared to LD, HD TXA was associated with less intraoperative blood loss (823 patients, WMD = −285 [95% CI, −564 to −5.90]; P =.0454; I2 = 86%), fewer perioperative transfusions (n = 505, OR.28 [95% CI,.082 to.96]; P =.043; I2 = 76%) and lower perioperative transfusion volumes (n = 434, WMD −227.7 mL [95% CI, −377.3 to −78.02]; P =.0029; I2 = 0%). Conclusion: Compared to LD TXA or placebo, there is moderate evidence that HD is not associated with an increased risk of medical complications. Compared to LD, there is moderate evidence that HD reduces transfusion requirements. High-Dose TXA can be safely utilized in healthy patients undergoing major spine surgery. [ABSTRACT FROM AUTHOR]

Objectives: To investigate rates of Surgical Care Improvement Project (SCIP) guideline adherence with regard to intraoperative antibiotic prophylaxis in head and neck surgery with free tissue transfer. Study Design: Retrospective case series. Setting: A single academic center. Methods: All patients who underwent mucosa‐violating head and neck oncologic surgery with free tissue transfer between March 2017 and June 2019 were reviewed. Intraoperative antibiotic data included type, dosage, frequency of administration, and duration. Any deviation from SCIP recommendations was defined as nonadherence. Antibiotic type was categorized as ampicillin‐sulbactam, cefazolin/metronidazole, clindamycin, and others. As a secondary exploratory analysis, postoperative infections were analyzed and stratified by adherent vs nonadherent and by antibiotic type. Results: A total of 129 surgical procedures were included. The mean ± SD number of antibiotic doses during surgery was 3.16 ± 1.2. The mean number of missed doses was 1.86 ± 1.65. Adherence rate with first dosing recommendation was 100%, as compared with 41.7% for dose 2, 23.1% for dose 3, 13.7% for dose 4, 5.26% for dose 5, 2.56% for dose 6, and 0% for dose 7 (P <.001). Ampicillin‐sulbactam (6.4%) had a significantly lower rate of average redosing adherence when compared with cefazolin/metronidazole (73.2%) and clindamycin (63.3%; P <.001). Conclusion: Significant opportunities exist in SCIP guideline adherence rates for intraoperative antibiotic prophylaxis. Cefazolin/metronidazole had a significantly higher rate of appropriate redosing when compared with ampicillin‐sulbactam, which should be considered when choosing a prophylactic antibiotic regimen and performing antibiotic‐based outcomes studies. More attention should be given to intraoperative antibiotic prophylaxis in head and neck surgery with free tissue transfer, as this presents an opportunity for quality improvement and future study heretofore not explored. [ABSTRACT FROM AUTHOR]

Background: The aims of this study were to describe pharmacokinetic/pharmacodynamic target attainment in intensive care unit (ICU) patients treated with continuously infused ß-lactam antibiotics, their associated covariates, and the impact of dosage adjustment. Methods: This prospective, observational, cohort study was performed in three ICUs. Four ß-lactams were continuously infused, and therapeutic drug monitoring (TDM) was performed at days 1, 4, and 7. The primary pharmacokinetic/pharmacodynamic target was an unbound ß-lactam plasma concentration four times above the bacteria's minimal inhibitory concentration during the whole dosing interval. The demographic and clinical covariates associated with target attainment were evaluated. Results: A total of 170 patients were included (426 blood samples). The percentages of empirical ß-lactam underdosing at D1 were 66% for cefepime, 43% for cefotaxime, 47% for ceftazidime, and 14% for meropenem. Indexed creatinine clearance was independently associated with treatment underdose if increased (adjusted odds ratio per unit, 1.01; 95% CI, 1.00 to 1.01; p = 0.014) or overdose if decreased (adjusted odds ratio per unit, 0.95; 95% CI, 0.94 to 0.97; p < 0.001). Pharmacokinetic/pharmacodynamic target attainment was significantly increased after ß-lactam dosage adjustment between day 1 and day 4 vs. no adjustment (53.1% vs. 26.2%; p = 0.018). Conclusions: This study increases our knowledge on the optimization of ß-lactam therapy in ICU patients. A large inter- and intra-patient variability in plasmatic concentrations was observed, leading to inadequate exposure. A combined indexed creatinine clearance and TDM approach enables adequate dosing for better pharmacokinetic/pharmacodynamic target attainment. [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic (PBPK) models represent computational technology to characterize drug behavior within the context of detailed human physiology. Today, PBPK is routinely used in drug development and regulatory approval to support decisions on how a medicine can be used under certain clinical conditions. As such, PBPK has the potential to enhance medicine use for populations that are often under-served globally in drug development and clinical care, namely pediatric patients, pregnant and lactating women. To facilitate broader applications of PBPK for these populations, we joined force and organized five hands-on workshops primarily to non-modelers on the principles of PBPK and its potential applications in pediatric and obstetric pharmacology in 2021 and 2022. In this open letter, we report learning objectives and content of such workshops and to highlight the significant value of these educational efforts.

Background: Recent systematic reviews and meta-analyses have suggested that low-dose steroids are effective in the treatment of acute respiratory distress syndrome (ARDS). Recent guidelines recommend the use of low-dose steroids instead of high-dose steroids. These systematic reviews were conducted based on the concept that the effect of steroids is constant regardless of their type. We discuss whether the type of steroid used influences the outcomes in patients with ARDS. Main body: From a pharmacological standpoint, methylprednisolone has little activity as a mineralocorticoid and may cause pulmonary hypertension. The results of the rank probability of our previous network meta-analysis revealed that low-dose methylprednisolone might be an optimal treatment compared to using other types of steroids or no steroids in terms of ventilator-free days. Similarly, an analysis of individual data from four randomized controlled trials suggested that low-dose methylprednisolone was associated with decreased mortality in patients with ARDS. Dexamethasone has attracted the attention of clinicians as a novel adjunct therapy for ARDS. Conclusion: Recent evidence has shown that low-dose methylprednisolone may be an effective treatment option for ARDS. The timing of initiation and duration of low-dose methylprednisolone therapy should be verified in future studies. [ABSTRACT FROM AUTHOR]

Understanding the effects of dosing non-toxigenic Clostridia to cows is rare and has received little attention so far. In the present study, a total of eight lactating dairy cows were divided in two groups: control (n = 4) or Clostridia challenged (oral supplementation of five diverse strains of Paraclostridium bifermentans, n = 4). Bacterial communities were analyzed by qPCR and next-generation sequencing (NGS) in the buccal mucosa as well as digesta and mucosal samples of the gastrointestinal (GI) tract from rumen to rectum (10 compartments), as well as fecal samples. Transcriptomic analysis of barrier and immune-related gene expression was performed on rumen, jejunum, and liver samples. We observed increased microbial populations with the Clostridial challenge in the buccal tissues and the proximal GI tract (forestomach), correlating with Clostridial loads in the feed. Otherwise, there were no significant differences in microbial populations (p > 0.05) throughout the distal part of the GI tract. The NGS approach, however, revealed that the Clostridial challenge changed the relative abundance of gut and fecal microbiota. In particular, in the challenge group, no Bifidobacterium was observed in the mucosa-associated microbiota and abundance of Pseudomonadota increased in the feces. These results indicated potential adverse effects of Clostridia to cow health. In general, immune responses to the Clostridial challenge were weak. However, transcriptional analysis revealed the down-regulation of junction adhesion molecule encoding gene (-1.44 of log2 fold-change), which might impact intestinal permeability. [ABSTRACT FROM AUTHOR]

• Antipsychotics differ in their propensity to cause akathisia. • The dose-response curves for akathisia in most antipsychotics are either monotonic or hyperbolic, indicating that higher doses carry a greater or equal risk compared to lower doses. • Monitoring is needed when prescribing antipsychotics that carry a high risk of akathisia at certain doses. Antipsychotic-induced akathisia is severely distressing. We aimed to investigate relationships between antipsychotic doses and akathisia risk. We searched for randomised controlled trials that investigated monotherapy of 17 antipsychotics in adults with acute schizophrenia until 06 March 2022. The primary outcome was the number of participants with akathisia, which was analysed with odds ratios (ORs). We applied one-stage random-effects dose-response meta-analyses using restricted cubic splines to model the dose-response relationships. We included 98 studies (343 dose arms, 34,225 participants), most of which were short-term and had low-to-moderate risk of bias. We obtained data on all antipsychotics except clozapine and zotepine. In patients with acute exacerbations of chronic schizophrenia, from moderate to high certainty of evidence, our analysis showed that sertindole and quetiapine carried negligible risks for akathisia across examined doses (flat curves), while most of the other antipsychotics had their risks increase initially with increasing doses and then either plateaued (hyperbolic curves) or continued to rise (monotonic curves), with maximum ORs ranging from 1.76 with 95% Confidence Intervals [1.24, 2.52] for risperidone at 5.4 mg/day to OR 11.92 [5.18, 27.43] for lurasidone at 240 mg/day. We found limited or no data on akathisia risk in patients with predominant negative symptoms, first-episode schizophrenia, or elderly patients. In conclusion, liability of akathisia varies between antipsychotics and is dose-related. The dose-response curves for akathisia in most antipsychotics are either monotonic or hyperbolic, indicating that higher doses carry a greater or equal risk compared to lower doses. [ABSTRACT FROM AUTHOR]

The article discusses the challenges and future considerations in evaluating pharmacokinetics (PK) in liver disease, particularly hepatic dysfunction (HI), and the benefit of in silico methods. It highlights the prevalence of liver disease in the United States and the exclusion of patients with underlying liver disease from clinical trials. It also mentions the potential use of physiologically based pharmacokinetic (PBPK) modeling to predict PK changes in silico.

PURPOSE: This study aimed to explore stander use in individuals with Duchenne Muscular Dystrophy (DMD). METHODS: This mixed method research study employed a survey with categorical and open-ended questions related to stander use. Categorical responses were analyzed quantitatively. Qualitative analysis of open-ended responses was linked to the International Classification of Function. Qualitative and quantitative results were merged to derive meta-inferences. RESULTS: Of 147 respondents, 28.6% (n = 42) reported stander use. Equipment used included sit-to-stand stander (n = 27), power standing feature in a wheelchair (n = 13), and unspecified equipment (n = 2). Economic services were the most common barrier to stander obtainment. Age of loss of ambulation (LOA) and age of start of stander use were positively correlated (r = 0.61, p < 0.0001, n = 36), with 59.5% initiating stander use after LOA. Twenty-nine respondents reported standing less than the recommended dose of 60–90 minutes at least five days a week, with frequency directionally less than five days per week (p = 0.06) and time significantly less than 60–90 minutes (p = 0.002). Respondents' total dose was significantly lower than the recommended 300 minutes (p = 0.02). Lack of time and presence of contractures contributed to decreased duration of use. CONCLUSION: This study provides a greater understanding of stander use among individuals with DMD and can assist with decision making about stander use prior to complications of disease progression to promote optimal health despite reported barriers. [ABSTRACT FROM AUTHOR]

Optimal dosing of opioid agonist therapy (OAT) is essential for treatment success. However, initiation and maintenance of OAT in hospital settings can be challenging given differing levels of opioid tolerance, withdrawal, and intoxication among patients. The objective of this study was to characterize the prevalence and factors associated with in-hospital patient perceived suboptimal OAT dosing among people who use illicit drugs (PWUD) in Vancouver, Canada. Data were derived from three prospective cohorts of PWUD in Vancouver, Canada. Bivariable and multivariable logistic regression models were used to examine factors associated with patient perceived suboptimal in-hospital OAT dose. 273 study participants were prescribed OAT while in hospital: 83 (30.4%) participants perceived their OAT dose to be suboptimal. In a multivariable model, factors positively associated with a perceived suboptimal OAT dose included: homelessness (adjusted odds ratio [AOR] = 2.85; 95% CI: 1.53–5.28), daily stimulant use (AOR = 2.03; 95% CI: 1.14–3.63) and illicit drug use while in hospital (AOR = 2.33; 95% CI: 1.31–4.16). Almost one third of participants perceived receiving a suboptimal OAT dose while in hospital. These observed correlations indicate that a patient's perception of suboptimal OAT dosing in hospital may be more prevalent for patients who are homeless, report polysubstance use with stimulants and opioids and who obtain illicit drugs while hospitalized. While cautious prescribing of OAT in patients experiencing hospitalization is important, these findings demonstrate a high prevalence of and apparent risk factors for perceived suboptimal OAT dosing. [ABSTRACT FROM AUTHOR]

Extracorporeal membrane oxygenation (ECMO) is a life-saving cardiopulmonary bypass device used on critically ill patients with refractory heart and lung failure. Patients supported with ECMO receive numerous drugs to treat critical illnesses and the underlying diseases. Unfortunately, most drugs prescribed to patients on ECMO lack accurate dosing information. Dosing can be variable in this patient population because the ECMO circuit components can adsorb drugs and affect drug exposure substantially. Propofol is a widely used anesthetic in ECMO patients and is known to have high adsorption rates in ECMO circuits due to its high hydrophobicity. In an attempt to reduce adsorption, we encapsulated propofol with Poloxamer 407 (Polyethylene-Polypropylene Glycol). Size and polydispersity index (PDI) were characterized using dynamic light scattering. Encapsulation efficiency was analyzed using High performance liquid chromatography. Cytocompatibility of micelles was analyzed against human macrophages and the formulation was finally injected in an ex-vivo ECMO circuit to determine the adsorption of propofol. Size and PDI of micellar propofol were 25.5 ± 0.8 nm and 0.08 ± 0.01, respectively. Encapsulation efficiency of the drug was 96.1 ± 1.3%. Micellar propofol demonstrated colloidal stability at physiological temperature for a period of 7 days, and was cytocompatible with human macrophages. Micellar propofol demonstrated a significant reduction in adsorption of propofol in the ECMO circuit at earlier time points compared to free propofol (Diprivan®). We observed 97 ± 2% recovery of the propofol from the micellar formulation after an infusion. These results demonstrate the potential of micellar propofol to reduce drug adsorption to ECMO circuit. [ABSTRACT FROM AUTHOR]

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Background: Intravenous immunoglobulin (IVIg) is efficient and one of very few treatment options for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, finding the optimal dose of IVIg for individual CIDP patients remains challenging. The dose of IVIg needs to be adjusted individually. Considering the high healthcare costs of IVIg therapy, the overtreatment of some patients seen in placebo studies and the shortage of IVIg we recently experienced, as well as identifying factors associated with the required dose of IVIg in maintenance treatment, is extremely important. Thus, in this retrospective study, we analyze characteristics of patients with stable CIDP, which are associated with the required drug dose. Methods: 32 patients with stable CIDP treated with IVIg between July 2021 and July 2022 were identified from our database and included in this retrospective study. Patients’ characteristics were registered, and parameters were identified that were associated with the IVIg dose. Results: Age, cerebrospinal fluid protein elevation, disease duration, delay between symptom onset/diagnosis, Inflammatory Neuropathy Cause and Treatment (INCAT) score, and Medical Research Council Sum Score (MRC SS) were significantly associated with the required drug dose. In addition, an association of age, sex, elevated CSF protein, time interval between symptom onset and diagnosis, and the MRC SS with the required IVIg dose could be demonstrated in the multivariable regression analysis. Conclusions: Our model, which is based on routine parameters that are simple to address in the clinical practice, can be useful in adjusting the IVIg dose in patients with stable CIDP.

Abstract Using the Canadian Myeloma Research Group Database, a retrospective study of 167 newly diagnosed, transplant‐ineligible patients with multiple myeloma (MM) that received lenalidomide‐dexamethasone as front‐line treatment was conducted to understand the impact of lenalidomide dosing. Starting dose modifications were common, 42% of patients started on lenalidomide

Abstract Vancomycin (VCM) is an antimicrobial that is recommended for therapeutic drug monitoring (TDM) for maintaining the efficacy and safety of treatment. The trough monitoring has been used to guide VCM dosing regimens. However, newer guidelines recommend the use of area under the curve/minimum inhibitory concentration (AUC/MIC)-guided vancomycin dosing, and there is a need for easier and more frequent measurements of VCM concentrations. Therefore, in this study, we developed a simple and rapid analytical method for measuring urinary VCM by combining solid-phase extraction and fluorescence analysis. Urine samples are easier and less invasive than blood samples. In addition to the therapeutic range of blood VCM, this method was also able to measure 0.01–1 mg/mL, which is the concentration range of urinary VCM. The accuracy of 10, 20, and 30 μg/mL VCM solutions were between 93.18 and 109.76%. The relative standard deviation (RSD) of intra-day and inter-day analysis were less than 6.25% and 6.28%, respectively. Since this method does not use large equipment, it is expected to be better suited for clinical use.

Background and Aims: Recommendations on paediatric single-injection local anaesthetic (LA) dosing for peripheral nerve blocks (PNBs) are based on the children's weight and limited by weight-based toxicity concerns. In this study, we assessed the extent of circumferential spread and block characteristics following the injection of an age-based volume (age in years = LA volume) of 0.25% bupivacaine following popliteal sciatic nerve block (PSNB). Methods: Thirty children aged between 2 and 12 years with the American Society of Anesthesiologists (ASA) physical status I and II and undergoing foot and ankle surgical procedures were given single-injection ultrasound-guided subparaneural PSNB using 0.25% bupivacaine at age-based LA volume after the administration of anaesthesia. The circumferential pattern of LA spread (primary objective) was assessed along the nerve (both cephalad and caudal) using ultrasound from the point of administration and the block characteristics in terms of duration of sensory block. Results: The mean [standard deviation (SD)] cephalic circumferential LA spread distance was 2.52 (0.68) [95% confidence interval (CI): 2.27–2.76] cm. The mean (SD) caudal circumferential LA spread distance was 2.27 (0.48) [95% CI: 2.09–2.44] cm. The mean (SD) duration of the sensory block was 9.03 (0.97) [95% CI: 8.67–9.38] h. Conclusion: The age-based LA volume of bupivacaine for ultrasound-guided PSNB resulted in a longitudinal circumferential spread of around 4.7 cm (adding both cephalic and caudal spread) and provided adequate analgesia for nine postoperative hours.

PurposePortal vein embolization (PVE) is an established neoadjuvant method to induce future liver remnant hypertrophy prior to surgical resection of hepatic tumors. The purpose of our study was to examine the feasibility of PVE with glass 90Y microspheres (Y90 PVE) in Sprague-Dawley rats. We tested the hypothesis that increased doses of Y90 PVE would increase target lobe fibrosis and atrophy.MethodsTwenty-two rats were assigned to four groups for Y90 PVE to the right median lobe: very high- (273.8 MBq; n = 2), high- (99.9 MBq; n = 10), medium- (48.1 MBq; n = 5), and low-dose (14.8 MBq; n = 5). An untreated control group included seven rats. 90Y PET/CT of 90Y distributions confirmed lobar targeting. MRI volumes were measured at baseline, 2-, 4-, 8- and 12-weeks. Explanted hepatic lobes were weighed, sectioned, and stained for H&E and immunohistochemistry. Digitized slides allowed quantitative measurements of fibrosis (20 foci/slide).ResultsEx vivo measurements confirmed 91-97% activity was localized to the target lobe (n = 4). The percent growth of the target lobe relative to baseline was - 5.0% (95% CI - 17.0-6.9%) for high-, medium dose rats compared to + 18.6% (95% CI + 7.6-29.7%) in the low-dose group at 12-weeks (p = 0.0043). Radiation fibrosis increased in a dose-dependent fashion. Fibrotic area/microsphere was 22,893.5, 14,946.2 ± 2253.3, 15,304.5 ± 4716.6, and 5268.8 ± 2297.2 μm2 for very high- (n = 1), high- (n = 4), medium- (n = 3), and low-dose groups (n = 5), respectively.ConclusionY90 PVE was feasible in the rat model, resulted in target lobe atrophy, and dose-dependent increases in hepatic fibrosis at 12 weeks. The onset of imaging-based volumetric changes was 8-12 weeks.

During veno-venous extracorporeal membrane oxygenation (vv ECMO) therapy, antimicrobial drugs are frequently used, and appropriate dosing is challenging due to there being limited data to support the dosage. Linezolid is effective against multidrug-resistant Gram-positive pathogens frequently isolated in ECMO patients. In total, 53 steady-state linezolid levels were obtained following 600 mg intravenous (IV) injections every 8 h, and these were used to develop a population pharmacokinetic (PopPK) model in patients with COVID-19-associated acute respiratory distress syndrome (CARDS) on vv ECMO. The data were analyzed using a nonlinear mixed-effects modelling approach. Monte Carlo simulation generated 5000 patients’ individual PK parameters and corresponding concentration–time profiles using the PopPK model, following the administration of 600 mg/8 h (a higher-than-standard dosing) and 600 mg/12 h (standard). The probabilities of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) and the cumulative fraction of responses (CFR) for three pathogens were calculated and compared between the two dosing scenarios. Linezolid 600 mg/8 h was predicted to achieve greater than or equal to 85%Tf>MIC in at least 90% of the patients with CARDS on vv ECMO compared to only approximately two thirds of the patients after dosing every 12 h at a minimal inhibitory concentration (MIC) of 2 mg/L. In addition, for the same MIC, fAUC24/MIC ≥ 80 was achieved in almost three times the number of patients following an 8-h versus a 12-h interval. PopPK simulation predicted that a significantly higher proportion of the patients with CARDS on vv ECMO would achieve the PK/PD targets following the 8-h dosing interval compared to standard linezolid dosing. Nevertheless, the safety concern, in particular, for thrombocytopenia, with higher-than-standard linezolid dosage is reasonable, and consequently, monitoring is essential.

This article discusses the need for a standardized diagnostic response test in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Currently, there is no established definition of therapeutic response or a response test for intravenous immunoglobulin (IVIg) therapy in CIDP. The authors propose a practical clinical approach supported by current literature, suggesting a standardized IVIg response test that could help avoid prolonged therapy without benefit for the patient and ensure timely treatment adjustments. The article also highlights the efficacy and safety of IVIg based on a recent study, which supports its use for diagnostic response testing in CIDP patients. [Extracted from the article]

Drinking–water Treatment Plants (DWTP) dosing coagulant chemicals determines the success of water quality. The addition of these compounds is usually a manual procedure performed by trained people. This task is quite difficult because it requires a lot of experience for a correct dosage. To solve this problem, this study is based on the analysis of data collected from a raw water source located in Ecuador. Then, using the information on the physical-chemical parameters of the raw water, the definition of the doses of Polyaluminum Chloride (PAC), and the input and output variables of the dosage process are identified. Consequently, the implementation of an intelligent control system based on Artificial Neural Networks (ANN) is proposed. These experiments start with data collection and analysis in order to establish the variables involved in the process. The proposed neural model has three hidden layers, and it uses adaptive gradient algorithms. An analysis of the results was performed using Mean Absolute Percentage Error (MAPE) and Root Mean Square Error (RMSE). The PAC predictive model in the training phase gives a MAPE value of 0.0425 for the not adjusted values and 0.0262 for the adjusted numerical values. However, in the test phase the neural model achieves a MAPE of 0.057 for the not adjusted PAC values and 0.041 for the adjusted values. It can be concluded that this alternative provides an efficient solution when solving dosing problems in DWTPs, having reliable results from the RMSE and MAPE metrics.

Most of the interventions performed by obstetric providers involve the administration of drugs. Pregnant patients are pharmacologically and physiologically different from nonpregnant young adults. Therefore, dosages that are effective and safe for the general public may be inadequate or unsafe for the pregnant patient and her fetus. Establishing dosing regimens appropriate for pregnancy requires evidence generated from pharmacokinetic studies performed in pregnant people. However, performing these studies during pregnancy often requires special design considerations, evaluations of both maternal and fetal exposures, and recognition that pregnancy is a dynamic process that changes as gestational age advances. In this article, we address design challenges unique to pregnancy and discuss options for investigators, including timing of drug sampling during pregnancy, appropriate selection of control groups, pros and cons of dedicated and nested pharmacokinetic studies, single‐dose and multiple‐dose analyses, dose selection strategies, and the importance of integrating pharmacodynamic changes into these protocols. Examples of completed pharmacokinetic studies in pregnancy are provided for illustration. [ABSTRACT FROM AUTHOR]

Pexidartinib, an oral small molecule inhibitor of the colony‐stimulating factor 1 receptor, is approved for treatment of adults with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. The original dosing regimen is 400 mg of pexidartinib (2 × 200‐mg capsules) twice daily, administered on an empty stomach at least 1 hour before or 2 hours after a meal or snack. Because pexidartinib is likely to be taken over an extended period of time, the ability to take pexidartinib with a meal would simplify timing of administration and potentially improve compliance. Since administering 400 mg of pexidartinib with a low‐fat meal increases exposure by ≈60% relative to the fasted state, administering 250 mg of pexidartinib with a low‐fat meal (low‐fat meal dosing regimen) was predicted to achieve an exposure similar to 400 mg administered during a fasted state (original dosing regimen). Based on clinical trial simulations with two one‐sided t‐tests and bootstrapping (ie, resampling) analyses, a bioequivalence study (n = 24) would have >90% power to conclude that the original dosing regimen (400 mg fasted twice daily) and the low‐fat meal dosing regimen (250 mg with a low‐fat meal twice daily) are bioequivalent. This report provides the outcome of the implementation of the model‐informed drug development strategy to recommend and justify a low‐fat meal dosing regimen for pexidartinib that has the potential to improve patient compliance while maintaining drug exposure. [ABSTRACT FROM AUTHOR]

To describe Patient-Controlled Analgesia (PCA) administration in pediatric patients admitted with sickle cell vaso-occlusive episode (VOE). This single-center retrospective study included all inpatient hematology admissions for VOE between 2014 and 2020. PCA-ratio was calculated as the ratio of bolus over continuous IV opioids dose, and time to PCA adjustment as time between first PCA order and a subsequent order that increased dosing or changed opioid medication. A total of 866 encounters (172 unique patients) with PCA for VOE were included. The mean age was 15.4 years old (SD = 5.0). On average, after admission (hospital arrival), the first opioid dose was given at 1 hour, PCA started at 3.5 hours, and mean length of stay was 4.3 days (SD = 2.5). The mean initial PCA-ratio was 1.7 (SD = 0.6). There were no significant associations between age, gender, initial pain score, or admission hemoglobin and PCA-ratio (linear regression model P = 0.443). In 24.7% of encounters, the PCA was adjusted within 6 hours. After adjusting by age and gender, lower admission pain scores (OR = 1.15, P = 0.004), lower PCA-ratio (OR = 2.1, P = 0.003), longer time to PCA start (OR = 1.2, P = 0.001), and no adjuvant ketamine (OR = 2.4, P < 0.001) were associated with PCA unadjusted within 6 hours. At our institution, patients with VOE received opioids and PCA within the first hours of admission. PCAs were started at a ratio of 1.5–1.8, considered normal continuous. While no specific PCA-ratio was clearly superior for pain control, lower ratios (high continuous infusion) were associated with not requiring PCA adjustments at 6 hours. Prospective studies are needed. [ABSTRACT FROM AUTHOR]

Purpose: Sublingual immunotherapy is currently promoted by various companies, with administration schedules variable in the different products even though almost all are standardized immunologically. So, this study was planned to examine the efficacy of simple nondaily dosing of sublingual immunotherapy instead of the widely used daily schedule. Materials and Methods: Fifty-two patients with allergic rhinitis and bronchial asthma were enrolled. Sublingual immunotherapy (manufactured at the allergen immunotherapy preparation unit at Mansoura University) was given in suitable bottles with a dropper mechanism that permits comfortable dosing under the tongue. The physician recommended that the patient put the drops under his/her tongue and leave the drops beneath the tongue for 2 minutes before swallowing. This was repeated every 3 days, with the drop number and concentration gradually rising. Results: After 2 months of follow-up, 65.8% responded partially to the symptom score and 26.3% responded completely to the medication score. There was a significant decline in the symptom and medication scores from the baseline scores (p<0.0001). After 4 months of follow-up, 95.8% responded partially to symptom scores and no one has not responded; 54.2% responded completely to medication scores; and 81% of studied patients had no side effects. However, the most frequent side effect was a sore throat. Conclusion: Our nondaily schedule of sublingual immunotherapy is tolerable, safe, and effective in patients with allergic rhinitis and bronchial asthma. [ABSTRACT FROM AUTHOR]

Background Linezolid-induced myelosuppression limits optimal therapy in cardiosurgical patients with deep-seated infections at current doses. Methods Adult patients who received a cardiac surgery intervention and linezolid for a documented or presumed serious gram-positive infection were evaluated. Therapeutic monitoring data, dosing, concomitant medications, and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic model was constructed to identify covariates and test potential drug–drug interactions that may account for interpatient variability. Simulations from the final model identified doses that achieve a target therapeutic trough concentration of 2–8 mg/L. Results This study included 150 patients (79.3% male) with sepsis and hospital-acquired pneumonia in 71.7% as the primary indication. The population had a median (minimum–maximum) age, body weight, and estimated glomerular filtration rate (eGFR) of 66 (30–85) years, 76 (45–130) kg, and 46.8 (4.9–153.7) mL/minute, respectively. The standard linezolid dosage regimen achieved the therapeutic range in only 54.7% of patients. Lower-than-standard doses were necessary in the majority of patients (77%). A 2-compartment Michaelis-Menten clearance model with weight, kidney function, and the number of interacting drugs identified as covariates that best fit the concentration-time data was used. Cyclosporine had the greatest effect on lowering the maximum elimination rate (Vmax) of linezolid. Empiric linezolid doses of 300–450 mg every 12 hours based on eGFR and the number of interacting medications are suggested by this analysis. Conclusions Lower empiric linezolid doses in cardiosurgical patients may avoid toxicities. Confirmatory studies are necessary to verify these potential drug interactions. [ABSTRACT FROM AUTHOR]

BACKGROUND: Daratumumab is a CD38-directed monoclonal antibody that is approved by the US Food and Drug Administration for the treatment of multiple myeloma and light-chain amyloidosis. Infusion-related reactions (IRRs) have been reported in 28% to 56% of individuals receiving the intravenous (IV) formulation of daratumumab, necessitating slow infusions and the frequent use of rescue medications. In 2020, subcutaneous (SC) daratumumab was approved for the treatment of multiple myeloma, and randomized data suggest a lower rate of IRRs compared with IV daratumumab. Guidelines regarding postinjection monitoring with SC daratumumab are not well-established. OBJECTIVES: To evaluate the safety of SC daratumumab and to suggest guidelines for monitoring patients after the administration of SC daratumumab. METHODS: This single-center, retrospective study included patients with multiple myeloma and/ or light-chain amyloidosis who were receiving SC daratumumab at Stanford Health Care between June 1, 2020, and December 31, 2020. The primary outcome of the study was the incidence of IRRs. The secondary outcomes include the timing and severity of IRRs based on the Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 82 patients received SC daratumumab during the study period. Of these patients, 49 (60%) had previously received IV daratumumab (daratumumab-exposed), and 33 (40%) had never received IV daratumumab previously (daratumumab-naïve). Of the total cohort, 8 (9.8%) had an IRR. All IRRs were grade 1 (N = 5; 63%) or grade 2 (N = 3; 38%) in severity. A total of 7 (21%) patients in the daratumumab-naïve group had an IRR, and 1 (2%) patient in the daratumumab- exposed group had IRRs with the first SC dose. Among the daratumumab-naïve patients, 6 had IRRs after receiving the first SC dose and 1 had IRRs after receiving the second SC dose. Of all the patients who had IRRs, 3 patients had immediate reactions (onset <15 minutes) and 4 patients had delayed reactions (onset >4 hours) after the SC administration of daratumumab (median, 11.9 hours; range, 5-24 hours). One patient had IRRs right before the 4-hour observation was completed. Among the patients with delayed reactions, 3 had reactions after being discharged from the treatment area, but their symptoms resolved without any intervention. CONCLUSIONS: In this single-center study of patients who were receiving SC daratumumab, IRRs occurred in approximately 10% of patients and were more likely after a patient received the first dose of SC daratumumab than with subsequent doses. All reactions were mild to moderate in severity and could be managed in the outpatient setting. We suggest that patients who are receiving their first dose of SC daratumumab be monitored for 1 hour after administration. Monitoring is not necessary for patients who are transitioning from IV to SC daratumumab or in patients who are receiving subsequent doses of SC daratumumab. [ABSTRACT FROM AUTHOR]

Examine: (1) whether variability in dry needling (DN) dosage affects pain outcomes, (2) if effect sizes are clinically important, and (3) how adverse events (AE) were documented and whether DN safety was determined. Nine databases were searched for randomized controlled trials (RCTs) investigating DN in symptomatic musculoskeletal disorders. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) scale. Included RCTs met PEDro criteria #1 and scored > 7/10. Data extraction included DN dosage, pain outcome measures, dichotomous AE reporting (yes/no), and AE categorization. Clinically meaningful differences were determined using the minimum clinically important difference (MCID) for pain outcomes. Out of 22 identified RCTs, 11 demonstrated significant between-group differences exceeding the MCID, suggesting a clinically meaningful change in pain outcomes. Nine documented whether AE occurred. Only five provided AEs details and four cited a standard means to report AE. There was inconsistency in reporting DN dosing parameters and AE. We could not determine if DN dosing affects outcomes, whether DN consistently produces clinically meaningful changes, or establish optimal dosage. Without more detailed reporting, replication of methods in future investigations is severely limited. A standardized method is lacking to report, classify, and provide context to AE from DN. Without more detailed AE reporting in clinical trials investigating DN efficacy, a more thorough appraisal of relative risk, severity, and frequency was not possible. Based on these inconsistencies, adopting a standardized checklist for reporting DN dosage and AE may improve internal and external validity and the generalizability of results. [ABSTRACT FROM AUTHOR]

Traditional approaches to automatic control occupy a major role in today's industry and will probably continue to be mainstream for many years to come. Control systems using elements of modern intelligent control technologies are becoming increasingly popular in current conditions. In the field of public catering, workers will be able to perform the functions of a waiter, bartender, cashier, cleaner and others. The automation of the dosing of liquid products is relevant, in particular, ensuring the appropriate temperature regime when dosing beer at catering enterprises using elements of intelligent control technologies. In none of the research results published in the open access, the issue of ensuring accurate maintenance of the regulation temperature of beer during its dosing has not been resolved. At the Department of Automation of Technological Processes and Robotic Systems of the Odessa National University of Technology, as part of the research work of a master's student, a scientific study of the process of dispensing beer as a control object was carried out and a automatic control system (ACS) of the temperature regime during its dispensing based on elements of intelligent control systems was proposed. A comparative analysis of the functioning of the classical ACS and systems using fuzzy and neuroregulators showed the advantages of their use over the classical one for controlling objects with non-linear characteristics. For technical systems with a random nature of disturbances, their high-order dynamic model and with a nonlinear characteristic, we can talk about the problem of control under conditions of uncertainty. The use of fuzzy and neuroregulators provides roughness and stable convergence of transient processes in a system, so this approach should be considered appropriate. [ABSTRACT FROM AUTHOR]

BackgroundHigh doses of ampicillin are often used to achieve therapeutic drug concentrations in infants. A paradoxical antibiotic effect, often called the Eagle effect, occurs when increasing concentrations of antibiotic above a threshold results in decreased efficacy. It is unknown if infants treated with ampicillin are at risk for this paradoxical effect.MethodsWe identified infants MIC) and PK parameters using separate logistic regression models. Adjusted logistic regression and Poisson models were used to calculate the odds of prolonged bacteremia ≥3 days and the duration of bacteremia, respectively, for dose, T > MIC and multiple PK parameters.ResultsAmong 1272 infants meeting inclusion criteria, odds of death 7 or 30 days after the positive blood culture were not consistent with a paradoxical effect across any of the dosing regimens or PK parameters evaluated. The odds of prolonged bacteremia was lowest at the lowest dose category and the lowest daily dose category but not associated with the area-under-the-concentration time curve from 0 to 24 hours, or the maximum or minimum concentrations at steady state. T > MIC of ≥50% of the dosing interval was associated with decreased duration of bacteremia and odds of prolonged bacteremia.ConclusionsIt is unlikely that a paradoxical antibiotic effect will have a clinical correlate when ampicillin is used for neonatal bacteremia. A T > MIC ≥50% decreased both duration of bacteremia and odds of prolonged bacteremia.

Introduction: Urinary tract infections (UTI) are a common indication for antibiotic use in the emergency department (ED). With antibiotic resistance on the rise, it is essential that antibiotics be prescribed appropriately for UTIs. Our objective was to evaluate the appropriateness of antibiotic prescriptions by ED providers for uncomplicated cystitis and pyelonephritis.Methods: We conducted a retrospective study of females ages 2-50 years seen in an academic ED from January 2017 to April 2018 diagnosed with UTI. We assessed the appropriateness of discharge antibiotic prescriptions, as determined by adherence to clinical practice guidelines, best evidence for the particular indication (cystitis vs pyelonephritis for children and adults), and the local antibiogram.Results: A total of 421 patients were included in this study. Of these, 60 children and 198 adults were diagnosed with cystitis, and 47 children and 116 adults were diagnosed with pyelonephritis. Treatment in the absence of true infection was common, with culture-confirmed UTI occurring in only 17/50 (34%) of children and 60/129 (47%) of adults diagnosed with cystitis, and 23/40 (58%) of children and 58/87 (67%) of adults diagnosed with pyelonephritis, among patients who had urine cultures. The type of antibiotic prescribed was appropriate in 53/60 (88%) of children and 135/198 (68%) of adults with cystitis, and 38/47 (81%) of children and 53/116 (46%) of adults with pyelonephritis. The most common inappropriate antibiotic types were beta-lactams in adults (n = 92), nitrofurantoin for pyelonephritis (n = 16), and amoxicillin (n = 15). Dosing and duration errors were also common, occurring in 122/279 (44%) of prescriptions of an appropriate antibiotic type. The frequency of errors in the type of antibiotic prescribed was similar among provider types (attending physician, resident physician, and advanced practice clinician; p = 0.926).Conclusion: This study reveals room for improvement in antibiotic prescription practices across provider cohorts in the ED for the management of uncomplicated cystitis and pyelonephritis in females.