Dosing Strategies Research Articles

Potential therapeutic uses of L-citrulline beyond genetic urea cycle disorders.

L-citrulline (referred to hereafter as citrulline), a non-essential amino acid and an intermediate in the urea cycle, is widely recognized for its role in managing genetic urea cycle disorders (UCDs). Recent studies, however, suggest that citrulline's therapeutic potential extends beyond UCDs, particularly in conditions associated with nitric oxide (NO) deficiency, endothelial dysfunction, and oxidative stress. This review explores citrulline's emerging applications in sickle cell disease (SCD), post-operative pulmonary hypertension (PH), hepatic veno-occlusive disease (HVOD), and bronchopulmonary dysplasia (BPD), as well as its speculative use in asthma and acute respiratory distress syndrome (ARDS). In SCD, citrulline may restore NO bioavailability, potentially reducing the incidence and severity of vaso-occlusive crises and preventing complications like pulmonary hypertension. In the context of post-operative PH, citrulline's capacity to enhance NO production can improve pulmonary vascular resistance, decrease right ventricular strain, and reduce the need for mechanical ventilation. Citrulline's protective effects on endothelial function and its ability to mitigate oxidative stress offer promising adjunctive therapy for HVOD, particularly in patients undergoing bone marrow transplantation. In BPD, citrulline could promote alveolar development, reduce inflammation, and improve long-term respiratory outcomes. Despite these promising findings, further research is necessary to determine optimal dosing strategies and to evaluate long-term efficacy and safety. The potential role of citrulline in modulating NO production in conditions like asthma and ARDS also warrants further investigation. This review underscores the versatile therapeutic potential of citrulline and highlights the need for continued research into its applications across various conditions associated with NO deficiency and endothelial dysfunction.

Population Pharmacokinetic/Pharmacodynamic Study of Linezolid in Hospital-Acquired Pneumonia Patients with Renal Insufficiency.

The optimal treatment strategy in patients with hospital-acquired pneumonia (HAP) due to Gram-positive bacteria and renal insufficiency remains challenging. The objective of this study was to compare the outcomes of linezolid versus teicoplanin in HAP patients with renal insufficiency and to explore optimal dosage strategy for linezolid. The retrospective study enrolled adult patients treated with intravenous linezolid or teicoplanin at Suzhou Municipal Hospital between July 2018 and August 2023. For the comparative pharmacodynamic study, effectiveness, safety and target attainment of trough concentration (Cmin) for teicoplanin versus linezolid treatment in HAP patients with document Gram-positive bacteria and renal insufficiency were compared. For the population pharmacokinetics (PPK) analyses, linezolid concentrations collected exclusively from HAP patients with renal insufficiency were used and the optimal dosage strategy was investigated using Monte Carlo simulations. Linezolid-treated patients had a higher bacterial eradication rate than teicoplanin-treated patients (88.5% vs 63.4%, P < 0.001). A higher proportion of patients in the linezolid group experienced at least one adverse reaction (42.0% vs 25.0%, P = 0.025). Significantly more supratherapeutic Cmin, less therapeutic Cmin were achieved in the linezolid group (adjusted P < 0.05). A total of 207 linezolid concentrations from 166 patients with renal insufficiency were available for the PPK analysis. Age and creatinine clearance (CrCL) were identified as significant covariates that influenced clearance. Simulations show that 300 mg q12h provide the optimal exposure in patients with a CrCL of 60 or 45 mL/min, and 200 mg q12h was recommended for patients with a CrCL of 30 or 15 mL/min. Linezolid-treated patients with HAP and renal insufficiency had higher bacterial eradication rates, supratherapeutic exposure and adverse reactions than teicoplanin-treated patients. Linezolid dose reduction in patients with renal insufficiency improved the probability of achieving optimal exposure.

Progress on the Mechanisms and Neuroprotective Benefits of Dexmedetomidine in Brain Diseases.

Dexmedetomidine, a highly specific α2 agonist, has been extensively utilized in clinical sedation and surgical anesthesia since its introduction in 2000 due to its excellent sympatholytic, sedative, and analgesic effects. This review aimed to identify new approaches for the treatment of patients with brain disorders by thoroughly describing the mechanism of action of dexmedetomidine and examining its neuroprotective effects from the standpoints of basic and clinical research. The PubMed and Web of Science databases were searched using the keywords dexmedetomidine and related brain diseases, although relevant articles from the last decade were included for detailed summarization and analysis. Dexmedetomidine has shown strong neuroprotective effects, such as protection of the blood-brain barrier, decreased neuronal death, maintained hemodynamic stability, and reduced postoperative agitation and cognitive dysfunction. Furthermore, dexmedetomidine has been shown to exert various neuroprotective effects, including anti-inflammatory and antioxidative stress effects, modulation of autophagy, and reduction of apoptosis in cerebral diseases. Dexmedetomidine acts as a neuroprotective agent against brain diseases during all phases of treatment. However, clinical trials with larger sample sizes are required to optimize dosage and dosing strategies.

What to do when traditional rescue therapies fail in acute severe ulcerative colitis.

Acute severe ulcerative colitis (ASUC) is a medical emergency that affects approximately 25% of patients with ulcerative colitis at some point in time in their lives. Outcomes of ASUC are highly variable. Approximately 30% of patients do not respond to corticosteroids and up to 50% of patients do not respond to rescue therapy (infliximab or cyclosporin) and require emergency colectomy. Data are emerging on infliximab dosing strategies, use of cyclosporin as a bridge to slower acting biologic agents and Janus kinase inhibition as primary and sequential therapy. In this review, we outline contemporary approaches to clinical management of ASUC in the setting of failure to respond to traditional rescue therapies.

Phase I/II Investigator-Initiated Study of Olaparib and Temozolomide in SCLC: Final Analysis and CNS Outcomes.

Temozolomide plus PARP inhibition has shown promise in small cell lung cancer (SCLC). We previously reported outcomes from the first 50 patients (cohort 1) of a phase I/II trial of olaparib/temozolomide in recurrent SCLC. Here, we report a final analysis of this trial, including a second cohort with an alternate dosing strategy and an exploratory analysis of CNS-specific outcomes. This was an open-label phase I/II trial testing the combination of olaparib and temozolomide in relapsed SCLC. The primary endpoint was ORR. Secondary endpoints were safety, PFS, and OS. We tested escalating doses of olaparib/temozolomide across two cohorts, both of which had temozolomide dosed on D1-7 of each 21-days cycle. In previously published cohort 1, olaparib was dosed on D1-7; in cohort 2 olaparib was dosed continuously. Sixty-six patients were enrolled across the two cohorts, 50 in cohort 1 and 16 in cohort 2. The confirmed ORR of cohort 1 was 41.7% (20/48 evaluable), and the confirmed ORR of cohort 2 was 7% (1/14 evaluable; closed after dose escalation to enrollment for lack of observed efficacy). Among 15/66 patients (22.7%) with untreated brain metastases at enrollment, best overall intracranial response was CR in 6/15 patients, PR in 4/15 patients, and SD in 3/15 patients for a CNS disease control rate of 87% (95% CI: 59.5-98.3%). Olaparib/temozolomide may be effective in relapsed SCLC, especially for patients with CNS disease. Ongoing analyses regarding optimal dosing schedule will inform potential for future use of this combination in SCLC.

Anti-inflammatory effect of semaglutide: updated systematic review and meta-analysis

Abstract Background Glucagon-like peptide-1 (GLP-1RA) receptor agonists possess multiple favourable metabolic, anti-inflammatory effects and their use is associated with marked body weight reduction. More importantly, this drug class has been shown to reduce cardiovascular events in patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk or with established cardiovascular disease. Accordingly, current guidelines recommend the use of GLP-1RA sas first-line antidiabetic therapies in patients at high cardiovascular risk. Semaglutide is a potent GLP-1RA used in the treatment of T2DM with proven cardiovascular benefits. It is currently available in formulations for oral and subcutaneous administration. The anti-inflammatory effect could be one of the mechanisms by which semaglutide reduces cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) and/or obesity. Determining the anti-inflammatory effect of semaglutide was the objective of this systematic review and meta-analysis. Methods This meta-analysis was performed according to the PRISMA guidelines. A literature search was performed to detect randomised clinical trials that have quantified the effect of semaglutide on C-reactive protein (CRP) levels compared to placebo or a control group (other glucose-lowering drugs). The primary outcome was CRP index (final CRP/basal CRP). A random-effects model was used. Results Overall, this meta-analysis shows that semaglutide therapy was associated with lower CRP index values compared to placebo (SMD -0.56; 95% CI -0.69 to -0.43, I2 92%) or when comparing semaglutide treatment versus a control group consisting of patients medicated with other glucose-lowering drugs (SMD -0.45; 95% CI -0.68 to -0.23, I 3 82%). The stratified analysis was performed by analysing only the trials that used a placebo group as comparator, When the trials were analysed according to the different dosing schemes (subcutaneous vs. oral), the results were not statistically significantly different (oral semaglutide group: SMD -0.33; 95% CI -0.75 to 0.08, I2 95%); semaglutide subcutaneous dose group: SMD -0.69; 95% CI -0.78 to -0.60, I2 74%); interaction p = 0.098. Furthermore, when the trials were analysed according to the included populations (patients with or without T2DM), the results were similar (patients with T2DM: SMD -0.32; 95% CI -0.51 to -0.14, I2 86%); patients without T2DM: SMD -0.82; 95% CI -0.90 to -0.74, I2 58%); interaction p = &amp;lt; 0.0001. Conclusion The present meta-analysis demonstrated that the use of semaglutide was associated with a reduction in inflammation irrespective of the population evaluated or the treatment regimen used. These findings would explain one of the mechanisms by which semaglutide reduces cardiovascular events.

Systematic review of thyroid function in NKX2-1-related disorders: Treatment and follow-up.

NKX2-1, a crucial transcription factor in thyroid, lung, and brain development, is associated with rare disorders featuring thyroid dysfunction, neurological abnormalities, and respiratory symptoms. The primary challenge in managing NKX2-1-related disorders (NKX2-1-RD) is early diagnosis of the genetic defect and treating specific endocrine disorders. Levothyroxine (LT4) serves as the standard hypothyroidism treatment, with required dosages influenced by the severity of the individual's disorder, which varies widely among affected individuals. This systematic review aims to assess the effectiveness of LT4 treatment in NKX2-1-RD and explore optimal dosing strategies. The primary focus is on the challenges associated with the prompt diagnosis of genetic defects, rather than the established treatment protocols for individual endocrine failures. Adhering to PRISMA guidelines, the review includes 42 studies involving 110 genetically confirmed NKX2-1-RD patients with hypothyroidism. The study investigates congenital hypothyroidism as the most prevalent endocrine alteration, along with gestational and overt hypothyroidism. The administration of LT4 treatment, dosages, and patient responses are analyzed. Among the findings, congenital hypothyroidism emerges as the predominant endocrine alteration in 41% of patients. Notably, LT4 treatment is administered in only 10% of cases, with a mean dose of 52 μg/day. The variability in initiation and dosage is likely influenced by the age at diagnosis. Positive responses, characterized by TSH adjustments within normal ranges, are observed in 11 monitored patients. Early detection of congenital hypothyroidism is emphasized for timely LT4 initiation. Challenges in standardization are highlighted due to the variability in clinical manifestations and diagnostic procedures across NKX2-1-RD cases. While this review provides valuable insights into thyroid and pituitary disease treatment, limited details on LT4 treatment represent a significant study limitation. Key reporting points for future case studies are proposed to enhance the understanding and management of NKX2-1-RD hypothyroidism.

Population Pharmacokinetic Modelling of Norepinephrine in Healthy Volunteers Prior to and During General Anesthesia.

Intraoperation hypotension (IOH) is commonly observed in patients undergoing surgery under general anesthesia, and even a brief episode of IOH can lead to unfavorable outcomes. To reduce the risk, blood pressure is closely measured during general anesthesia, and norepinephrine (NE) is frequently administered if hypotension is detected. Despite its routine application, information on the dose-exposure-response relationship of NE remains limited. Additionally, quantification of the influence of general anesthesia on the pharmacokinetics (PK) of NE is lacking. In this study, we aimed to describe NE PK in healthy volunteers and the influence of general anesthesia on its PK. A single-center, cross-over study was conducted in healthy volunteers. The volunteers received a step-up NE dosing scheme (0.04, 0.08, 0.12, 0.16 and 0.20 mcg-1/kg-1/min-1) first in the awake state and then under general anesthesia. General anesthesia was administered using a propofol/remifentanil Eleveld target-controlled infusion. During general anesthesia, a 30-second electrical stimulus was given as surrogate for surgical incision to the volunteers at each dosage step. Blood samples were drawn before the initial dosing and after each dosing step, and plasma NE, propofol and remifentanil concentrations were subsequently determined. A population PK model was developed using non-linear mixed effects modelling. Simulations were conducted to predict the plasma NE concentration in patients at different measured propofol concentrations. A total of 1219 samples were analyzed from 36 volunteers. A two-compartment model with a first-order elimination best described the data. Weight, age, and session effect (awake vs general anesthesia) were identified as relevant covariates on the clearance (CL) of NE. A 10% decrease in NE CL was observed after general anesthesia induction. This difference between sessions is better explained by the measured concentration of propofol, rather than the anticipated impact of cardiac output. The estimated post-stimulation NE concentration is 0.66 nmol/L-1 (95% CI 0.06-1.20 nmol/L-1) lower than the pre-stimulation NE concentration. Model simulation indicates that patients at a higher measured propofol concentration (e.g., 6 mcg/mL-1) exhibited higher NE concentrations (95% PI 18.10-43.89 nmol/L-1) than patients at a lower measured propofol concentration (e.g., 3 mcg/mL-1) (95% PI 16.81-38.91 nmol L-1). The NE PK is well described with a two-compartment model with a first-order elimination. NE CL exhibiting a 10% decrease under general anesthesia, with this difference being attributed to the measured concentration of propofol. The impact of stimulation on NE PK under general anesthesia is very limited. NL9312.

Recovery of ammonia assimilating microbiome after Cr (VI) shock by bio-accelerators

The pretreatment process is often unable to completely intercept heavy metals in wastewater, facing a huge risk of leakage, increasing the difficulty of treating pollutants in the subsequent biochemical process or even leading to the collapse of the system, and facing the difficulty of inoperability and rehabilitation. Heterotrophic ammonia assimilation has the potential to maintain some stability after heavy metal shock, thanks to its rapid microbial proliferation, robust resistance to high loads, remarkable environmental adaptability, and inherent stability. Bio-accelerators dosing strategies could strengthen the performance recovery ability of traditional bio-system after heavy metal impact. However, no recovery strategies for inhibiting HAA have been reported. Herein, three bio-accelerants, specifically, vitamin A, 6-benzylaminopurine, and α-ketoglutaric acid, were investigated for their potential to restore the HAA system impacted by 20 mg/L Cr (VI). The three bio-accelerants effectively mitigated the toxicity of the HAA system, resulting in a 60.4% increase in NH4+-N removal efficiency within just 6 days with cytokinin. During toxicity remediation, three bio-accelerants facilitated the production of extracellular protein components in soluble microbial products and stimulated the secretion of extracellular polymeric substances. The three bio-accelerants enhanced competition among genera and influenced community assembly processes to regulate community structure and enhance functional gene expression. This study offers a practical approach to enhancing the HAA process and remediating microbial toxicity.

Evaluation of Effective Half-Life and Its Impact on Time to Steady State for Oral MeltDose Tacrolimus (LCPT) in De Novo Kidney Transplant Recipients.

For extended-release drug formulations, effective half-life (t1/2eff) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t1/2eff and terminal half-life (t1/2z) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T1/2eff was estimated using within-participant accumulation ratios. T1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile. The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t1/2eff and t1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively. Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation.

Safety of the reduced fixed dose of mycophenolate mofetil confirmed via therapeutic drug monitoring in de novo kidney transplant recipients.

Mycophenolate mofetil (MMF) is usually prescribed with a reduced fixed dose in Asian kidney transplant recipients (KTRs). However, the clinical efficacy and safety of the fixed dose have not yet been investigated via therapeutic drug monitoring. We evaluated whether reduced fixed-dose MMF is an optimal dosing strategy to achieve the therapeutic target of mycophenolic acid (MPA) exposure in Korean KTRs. This open-label, prospective study enrolled 50 de novo KTRs prescribed with tacrolimus, corticosteroid, and fixed-dose MMF (1.0-1.5 g/day). The trough level (C0) and area under the curve (AUC0-12 hr) of MPA were measured at 1 and 24 weeks after kidney transplantation (KT). The relationship of body weight (BW)-adjusted MMF dose with MPA C0 and MPA AUC0-12 hr was assessed using linear regression analysis. The initial fixed dose of MMF of 1.44 ± 0.16 g/day was adjusted in 24 patients (48.0%) and then reduced to a mean dose of 1.19 ± 0.31 g/day at 24 weeks after KT. Most patients (≥84.0%) attained the minimum required MPA C0 of 1.0 μg/mL and MPA AUC0-12 hr of 30 μg × hr/mL at 1 and 24 weeks. The BW-adjusted MMF dose demonstrated significant positive correlations with MPA C0 and MPA AUC0-12 hr at 1 and 24 weeks after KT. Moreover, 14 patients (28.0%) reported MPA-related adverse events that were predictable based on MPA AUC0-12 hr (cutoff level, 46.4 μg × hr/mL). The current reduced fixed-dose MMF strategy can help achieve the therapeutic target of MPA exposure in tacrolimus-treated Korean KTRs during the early posttransplant period.

Population pharmacokinetics of cabotegravir following intramuscular thigh injections in adults with and without HIV.

Cabotegravir intramuscular gluteal injection is approved for HIV treatment (with rilpivirine) and prevention. Thigh muscle is a potential alternative injection site. We aim to characterize cabotegravir pharmacokinetics and its association with demographics following intramuscular thigh injection in comparison with gluteal injection using population pharmacokinetic (PPK) analysis. Fourteen HIV-negative participants received 600 mg single thigh injection in phase 1 study 208832 and 118 participants with HIV received thigh injections 400 mg monthly 4× or 600 mg once-every-2-months 2× after ≥3 years of gluteal injections in phase 3b study ATLAS-2M provided 1,249 cabotegravir concentrations from 366 thigh injections and 1,998 concentrations from 1,618 gluteal injections. The established gluteal PPK model was modified by adding thigh injection compartment and fit to pharmacokinetic data following both gluteal and thigh injections, enabling within-person comparison in ATLAS-2M. Gluteal parameters were fixed. Similar to the gluteal absorption rate constant (KAgluteal), the thigh absorption rate constant (KAthigh) was slower in females than males and in participants with higher BMI. KAthigh was strongly correlated with KAgluteal (correlation coefficient 0.766), best described by the additive linear relationship KAthigh = KAgluteal + 0.0002527 h-1. Terminal half-life of thigh injection was 26% (male) and 39% (female) shorter than gluteal injection. Relative bioavailability of thigh to gluteal was estimated to be 89.9%. The impact of covariates on cabotegravir exposure following thigh injections was ≤35%. In conclusion, cabotegravir absorption following thigh injection was correlated with, faster than, and 10% less bioavailable than gluteal injection, and correlated with sex and BMI. The cabotegravir thigh PPK model can inform dosing strategies and future study design.

Assessing the Effectiveness and Safety of Combination Diuretic Therapy in Heart Failure: A Systematic Review and Meta-Analysis.

Heart failure remains a significant clinical challenge due to the difficulty in managing refractory fluid overload. Combination diuretic strategies, involving various combinations, such as metolazone and furosemide, have been proposed to improve diuresis and patient outcomes. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of combination therapies. A comprehensive search of PubMed, Cochrane Library, Embase, and Web of Science identified 61 articles, of which seven randomised controlled trials met the inclusion criteria. Data on mortality, hospital readmission rates, symptom improvement, electrolyte imbalances, renal function, and adverse events were extracted and analysed. The risk of bias was assessed using the established guidelines. The analysis revealed that combination diuretic therapies significantly reduced body weight (P=0.001) but did not significantly impact mortality (RR: 0.99, 95% CI: 0.90-1.09) or hospital readmission rates (RR: 1.05, 95% CI: 0.98-1.12) compared to placebo. Adverse effects, particularly electrolyte imbalances, such as hypo and hypernatraemia and hypokalaemia, and renal function deterioration were noted in the combined diuretic group. In contrast, serious adverse events were observed more in the placebo group. The mean difference of the Kansas City Cardiomyopathy Questionnaire (KCCQ) score was 2.43 (95% CI: 0.95-3.92). The risk ratio for hospital readmission was 1.05 (95% CI: 0.98-1.12), which was statistically non-significant. We used fixed-effect models for most variables due to less heterogeneity between the studies, and the corresponding I2 values were <50% for most variables. Funnel plots indicated minimal publication bias, although some heterogeneity was observed. Comparisons with other studies in the literature, such as the DAPA-HF and EVEREST trials, supported these findings but also highlighted the need for individualised treatment approaches. Combination diuretic therapies effectively manage fluid overload and reduce body weight in patients with heart failure but do not significantly affect mortality or hospital readmission rates. The potential for adverse events, particularly electrolyte imbalances and renal function deterioration, underscores the need for careful monitoring and personalised treatment plans. Future research should focus on optimising diuretic combinations and dosing strategies to enhance their safety and efficacy. These findings align with the current guidelines emphasising individualised treatment in heart failure management and highlight the importance of integrating combination diuretics into a comprehensive care plan to improve patient outcomes.

Metabolomic signature in ocular dosing: Exploring the metabolic impacts of sublethal high-dose naringenin on ARPE-19 cells

IntroductionNaringenin (NRG), a flavanone polyphenol found in citrus fruits, has been increasingly recognized for its potential therapeutic effects in ocular disorders. This study aimed to assess the impact of high-dose NRG on human retinal pigment epithelial cells (ARPE-19) cells through metabolomic analysis. MethodsCell viability was evaluated using the thiazolyl blue tetrazolium bromide (MTT) assay, demonstrating non-cytotoxicity at concentrations ranging from 3 to 100 μM within a 24-h exposure period. High-dose (100 μM) NRG was selected for further investigation based on its non-cytotoxic nature. Chromatographic analyses were performed using Liquid Chromatography Quadropole Time-of-Flight Mass Spectrometry (LC-Q-ToF-MS). ResultsMetabolomic analysis revealed subtle metabolic changes, with similar profiles between control and test groups, emphasizing the nuanced effects of NRG. Multivariate analysis, including Principal Component Analysis (PCA), illustrated distinct clustering of control and test groups, indicating consistent metabolic adjustments within each group. Despite maintaining cell viability, stress responses were identified in ARPE-19 cells, as evidenced by reduced glucose-6-phosphate levels and alterations in pyrimidine/purine pathways. This highlights the importance of exploring cellular responses using metabolomics beyond traditional viability metrics. ConclusionIn the broader context, this study contributes data on the interplay between NRG and retinal pigmented epithelial. As NRG is utilized in routine ocular applications, particularly as an eye drop, our findings suggest careful dosage selection, considering both non-irritability and subtle metabolic changes. Further research is needed to refine dosage strategies and comprehensively assess the safety profile of NRG in ocular applications.

The Role of Propofol in Alcohol Withdrawal Syndrome: A Systematic Review.

The objective of this review was to evaluate the efficacy and safety of propofol in the treatment of critically ill patients diagnosed with alcohol withdrawal syndrome (AWS). A review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria, and Embase, MEDLINE (PubMed), Cochrane CENTRAL, and Web of Science were queried for results through June 2024. Studies providing efficacy or safety data associated with propofol with a reported diagnosis of AWS in critically ill patients were included. Studies evaluating pediatric patients, those without quantitative and qualitative outcome data, and those not readily translatable to English were excluded. Five retrospective cohort analyses of 218 patients were included in this systematic review. Patients were found to have both significant and non-significant increases in time to resolution of AWS symptoms when treated with propofol versus the AWS standard of care. Adjunct treatment with propofol was generally associated with reductions in total benzodiazepine use and increases in both ICU length of stay and duration of mechanical ventilation. The results of this systematic review provide the evidence necessary to support the use of propofol as an efficacious and safe medication in the management of severe and refractory AWS. Further investigation is required to determine optimal dosing strategies and durations of therapy. The results of this systematic review demonstrate the clinical utility of propofol as part of the management strategy for severe and refractory AWS.

Prognostic evaluation using radiomics after stereotactic body radiotherapy in early-stage lung cancer

Non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths, is the most common subtype of lung cancer with an incidence of 85%. Stereotactic body radiotherapy (SBRT) is a curative treatment option for patients with early-stage NSCLC who cannot undergo surgery due to medical reasons or who refuse surgery. Radiomics non-invasively extracts advanced imaging features invisible to the human eye from medical images. Radiomics has prognostic value in predicting oncological outcomes after lung SBRT. Although studies on this subject are available in the literature, they are quite heterogeneous. There is a need for large-scale multicenter studies in which standard imaging techniques are used to obtain radiomic features, artificial intelligence-based segmentations are used to eliminate differences between contours, and SBRT dose schemes with appropriate therapeutic indexes are applied. This review aimed to interpret the existing studies and emphasize the clinical importance of radiomics, which can contribute to personalized treatment. A comprehensive literature search was conducted through the PubMed database using a wide range of keywords, which yielded 11 peer-reviewed articles published between 2017 and 2024. Seven articles evaluated computed tomography radiomics, and four evaluated fluorodeoxyglucose positron emission tomography-computed tomography radiomics. Oncological outcomes are not always identical in patients with a similar history receiving similar treatments at the same stage and age. Clinical, demographic, or treatment-related data are insufficient to predict prognosis and determine personalized treatment. Incorporating radiomics to these data can help establish models with higher accuracy and achieve personalized treatment.

Population Pharmacokinetic and Pharmacodynamic of Atorvastatin in Chinese Lung Transplant Recipients.

Atorvastatin is a widely prescribed cholesterol-lowering drug that inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase to reduce lipid levels. This study aimed to establish a population pharmacokinetic and pharmacodynamic model for atorvastatin in Chinese lung transplant recipients (LTRs), particularly those using voriconazole (VOR) and with different genotypes. It evaluated precise dosing regimens and analyzed the correlation between atorvastatin exposure and clinical outcomes. A nonlinear mixed-effects model was used for the population pharmacokinetic/pharmacodynamic (PK/PD) analysis. A one-compartment population PK model was developed, incorporating VOR, SLCO2A1 rs76906503, and SLC22A8 rs2187383 to assess apparent clearance and volume of distribution. LDL-C was modeled as a biomarker to evaluate atorvastatin efficacy. A Monte Carlo simulation was conducted to assess various dosing schemes and the effects of different covariates on achieving the target LDL concentration. The correlation between atorvastatin exposure and clinical outcomes was also evaluated. Results indicated that the average probability of target attainment for optimal dosing regimens across various covariate results exceeded 45.8%. Dosages of 10, 20, and 40 mg were deemed suitable for LTRs. A lower dose was recommended for LTRs taking VOR or with mutant-type genotypes to avoid overexposure and adverse reactions. The population PK/PD model offers valuable guidance for evaluating atorvastatin dosing regimens in clinical settings, particularly for LTRs using VOR and those with different genotypes.

Antibiotic Use in Medical-Surgical Intensive Care Units and General Wards in Latin American Hospitals.

The objective of this study was to identify antibiotic stewardship (AS) opportunities in Latin American medical-surgical intensive care units (MS-ICUs) and general wards (Gral-wards). We conducted serial cross-sectional point prevalence surveys in MS-ICUs and Gral-wards in 41 Latin American hospitals between March 2022 and February 2023. Patients >18 years of age in the units of interest were evaluated for antimicrobial use (AU) monthly (MS-ICUs) or quarterly (Gral-wards). Antimicrobial data were collected using a standardized form by the local AS teams and submitted to the coordinating team for analysis. We evaluated AU in 5780 MS-ICU and 7726 Gral-ward patients. The hospitals' median bed size (interquartile range) was 179 (125-330), and 52% were nonprofit. The aggregate AU prevalence was 53.5% in MS-ICUs and 25.5% in Gral-wards. Most (88%) antimicrobials were prescribed to treat infections, 7% for surgical prophylaxis and 5% for medical prophylaxis. Health care-associated infections led to 63% of MS-ICU and 38% of Gral-ward AU. Carbapenems, piperacillin-tazobactam, intravenous (IV) vancomycin, and ampicillin-sulbactam represented 50% of all AU to treat infections. A minority of IV vancomycin targeted therapy was associated with documented methicillin-resistant Staphylococcus aureus infection or therapeutic drug monitoring. In both units, 17% of antibiotics prescribed as targeted therapy represented de-escalation, while 24% and 15% in MS-ICUs and Gral-wards, respectively, represented an escalation of therapy. In Gral-wards, 32% of antibiotics were used without a microbiologic culture ordered. Half of surgical prophylaxis antibiotics were prescribed after the first 24 hours. Based on this cohort, areas to improve AU in Latin American hospitals include antibiotic selection, de-escalation, duration of therapy, and dosing strategies.

Multicenter Analysis of Valganciclovir Prophylaxis in Pediatric Solid Organ Transplant Recipients

Abstract Background Valganciclovir (VGCV) prophylaxis against cytomegalovirus (CMV) infection and disease has provided an important advance in the management of pediatric solid organ transplantation (SOT) recipients over the past two decades. However, there remain significant questions regarding its relative safety and efficacy, optimal dosing strategies, and toxicities including neutropenia and lymphopenia. We performed a multi-center retrospective study of children post SOT who were to receive at least 3 months of valganciclovir. The primary outcomes were CMV DNAemia while receiving prophylaxis (breakthrough) and post-prophylaxis CMV DNAemia within the first year. Methods The study population included patients ≤ 20 years of age at the time of their first transplant between January 2016 and December 2019 from 8 US centers in PIDTRAN Network. Data for each patient was extracted from the electronic medical record and entered into a REDcap database hosted by St. Jude Children’s Research Hospital. Variables analyzed included demographics, donor/recipient CMV serostatus, immunosuppression, trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis use, rejection, other viral or bacterial infections and one-year survival. Statistics were performed using STATA software for univariate and multivariate models; p-value&amp;lt; 0.05 was considered statistically significant. Results 749 pediatric SOT patients were enrolled over the 3-year study period. Breakthrough DNAemia occurred in 85 (11.4%) patients and post-prophylaxis CMV DNAemia was documented in an additional 46 (6.9%) patients. CMV disease occurred in only 30 patients (4%). In univariate analysis, there were no differences in age, sex, race/ethnicity, or immunosuppression comparing those who experienced breakthrough or post-prophylaxis CMV DNAemia compared to those without CMV DNAemia, but there were differences based on transplanted organ (p&amp;lt; 0.001, liver and lung &amp;gt; heart &amp;gt; kidney) and CMV risk status (high and intermediate) (p&amp;lt;0.001). Neutropenia (p&amp;lt;0.001) and lymphopenia (p=0.003) as well as VGCV discontinuation or dose reduction for perceived toxicity (p&amp;lt;0.001) were associated with breakthrough CMV infection. Bacteremia (p=0.001), EBV viremia (p=0.02), and adenovirus viremia (p=0.002) were also documented more in those with breakthrough compared to those who never had CMV DNAemia. In an adjusted Cox regression hazard model using all significant univariate variables, transplanted organ, CMV risk status, toxicity related VGCV modification (p=0.005), and bacteremia (p=0.01) were independently associated with breakthrough CMV infection. Breakthrough CMV was also associated with rejection (p=0.01) in a separate logistic multivariable model. Both liver (p&amp;lt;0.001) and heart transplant (p&amp;lt;0.001) patients had a greater risk of rejection over the first year of transplantation, but only liver transplant patients had a greater risk of rejection with breakthrough CMV infection (p=0.004). Post prophylaxis CMV DNAemia was associated with mortality at 1 year in the univariate analysis in the full cohort (p=0.001). Conclusion Rates of CMV disease when using valganciclovir prophylaxis were low in this large, multicenter cohort of pediatric SOT recipients. However, breakthrough CMV infection continues to be a problem in intermediate- and high-risk CMV patients and is associated with significant morbidity and rejection, particularly in the liver transplant population. Alternative approaches to prevent breakthrough and post-prophylaxis CMV and with a better safety profile should be studied in pediatric SOT patients.

Outcomes from the International Society of Nephrology Hemolytic Uremic Syndromes International Forum

The haemolytic uraemic syndromes (HUS) are a heterogeneous group of conditions only some of which are mediated by complement (CaHUS). We report the outcome of the 2023 International Society of Nephrology HUS International Forum where a global panel of experts considered the current state of the art, identified areas of uncertainty, and proposed optimal solutions. Areas of uncertainty and areas for future research included: the nomenclature of HUS; novel complement testing strategies; identification of biomarkers; genetic predisposition to aHUS; optimal dosing and withdrawal strategies for C5 inhibitors; treatment of kidney transplantation recipients; disparity of access to treatment; and the next generation of complement inhibitors in CaHUS. The current rationale for optimal patient management is described.