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Background Context: With improvements in neurological imaging, there are increasing reports of symptomatic spinal synovial cysts. Surgical excision has been recognized as the definitive treatment for symptomatic juxtafacet cysts. However, the role for concomitant fusion and the incidence of recurrent back pain and recurrent cyst formation after surgery remain unclear.Purpose: To determine the cumulative incidence of postoperative symptomatic relief, recurrent back and leg pain after cyst resection and decompression, and synovial cyst recurrence.Study Design: Systematic review of the literature.Patient Sample: All published studies to date reporting outcomes of synovial cyst excision with and without spinal fusion.Outcome Measures: Cyst recurrence and Kawabata, Macnab, Prolo, or Stauffer pain scales.Methods: We performed a systematic literature review of all articles published between 1970 and 2009 reporting outcomes after surgical management of spinal synovial cysts.Results: Eighty-two published studies encompassing 966 patients were identified and reviewed. Six hundred seventy-two (69.6%) patients presented with radicular pain and 467 (48.3%) with back pain. The most commonly involved spinal level was L4-L5 (75.4%), with only 25 (2.6%) and 12 (1.2%) reported synovial cysts in the cervical or thoracic area, respectively. Eight hundred eleven (84.0%) patients were treated with decompressive surgical excision alone, whereas 155 (16.0%) received additional concomitant spinal fusion. Six hundred fifty-four (92.5%) and 880 (91.1%) patients experienced complete resolution of their back or leg pain after surgery, respectively. By a mean follow-up of 25.4 months, back and leg pain recurred in 155 (21.9%) and 123 (12.7%) patients, respectively. Sixty (6.2%) patients required reoperation, of which the majority (n=47) required fusion for correction of spinal instability and mechanical back pain. Same-level synovial cyst recurrence occurred in 17 (1.8%) patients after decompression alone but has been reported in no (0%) patients after decompression and fusion.Conclusions: Surgical decompression results in symptomatic resolution in the vast majority of patients; however, recurrent back pain occurs in a significant number of patients. Cyst recurrence occurs in less than 2% of patients but has never been reported after cyst excision with concomitant fusion. The lack of cyst recurrence after concomitant fusion supports the need to investigate the value of fusion of the involved motion segment in the treatment of symptomatic synovial cysts of the spine. [ABSTRACT FROM AUTHOR]

Objectives: To describe the population pharmacokinetics of cefazolin in infected hospitalized patients requiring intermittent haemodialysis (IHD)., Methods: This prospective population pharmacokinetic study was conducted in IHD patients prescribed cefazolin 2 g three times weekly. Plasma samples were collected at prespecified timepoints and assayed for total and unbound concentrations using validated LC. Pharmacokinetic modelling and dosing simulations were performed using Pmetrics®. PTA in plasma suitable for MSSA (unbound trough concentrations of ≥2 mg/L for the final 24 h of a 72 h interval) were simulated for different dosing regimens. A PTA of ≥95% was deemed acceptable., Results: A total of 260 cefazolin concentrations (130 total, 130 unbound) were collected from 16 patients (14 female) with a median age of 51 years. The median (IQR) pre-dialysis unbound cefazolin concentration for a 3 day dose interval trough was 17.7 (13.5-31.4) mg/L. The median (IQR) unbound fraction was 0.38 (0.32-0.46). The lowest pre-dialysis unbound concentration was 9.1 mg/L. A two-compartment model with a complex protein-binding component adequately described the data. The mean unbound cefazolin CL during IHD was 16.4 ± 4.26 L/h, compared with 0.40 ± 0.19 L/h when dialysis was off. Duration of time on haemodialysis (TOH) was the only covariate supported in the final model. The 2 g three-times-weekly regimen was associated with a PTA of 99.7% on dosing simulations to maintain unbound concentrations of ≥2 mg/L with TOH of 6 months. The 1 g three-times-weekly post-dialysis was associated with a PTA of 95.4%., Conclusions: A 2 g three-times-weekly post-dialysis cefazolin regimen is supported for MSSA infections., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Patients undergoing elective pelvic exenteration surgery who receive piperacillin/tazobactam as surgical prophylaxis are at risk of suboptimal intraoperative antibiotic exposure. With this work, we aimed to study the plasma pharmacokinetics of piperacillin and tazobactam in this population to provide dosing recommendations that optimize antibiotic exposure. We developed a prospective, observational, pharmacokinetic study of piperacillin/tazobactam in patients undergoing pelvic exenteration. Population pharmacokinetic analysis and Monte Carlo simulations were performed with Monolix and Simulx software. Probabilities of target attainment of different dosing regimens against the minimum inhibitory concentration (MIC) breakpoints (8 and 16 mg/L) were calculated. Twelve patients were included in the study, with a median age of 50.0 years [interquartile interval (45.3-57.5)] and a median weight of 79.0 kg (61.3-88.3). Median surgical time was 10.5 h (9.8-11.7). A two-compartment linear model best fitted piperacillin and tazobactam data (190 plasma samples). Monte Carlo simulations showed that a lower dose of 2 g/0.25 g loading dose followed by 4 g/0.5 g q8h by continuous infusion provided ≥90% probability of target attainment for MIC = 16 mg/L for most of the patients. For non-continuous infusion regimens, only the 2-hourly bolus re-dosing achieved intraoperative concentrations of piperacillin ≥16 mg/L. Patients with weights ≥ 100 kg and glomerular filtration rates ≥ 120 mL/min required 4 g/0.5 g q6h by continuous infusion after a loading dose. In conclusion, continuous infusion of lower doses of piperacillin/tazobactam is as adequate as the 2-hourly re-dosing recommended by the current guidelines for surgical prophylaxis in pelvic exenteration. Patients with higher weights and glomerular filtration rates are at greater risk of inadequate exposure.

Fosfomycin has been used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections. However, there is insufficient information on dosage adjustment among critically ill patients with renal impairment. This study aims to evaluate the attainment of PK/PD targets for different dosage regimens of CRAB treatment in critically ill patients based on their renal function. Monte Carlo simulations were conducted to assess the probability of achieving time above the minimum inhibitory concentration (T > MIC) of 80% and 100% and to determine the cumulative fraction response (CFR) against institutional MICs. Our results demonstrated that administering fosfomycin 20-24 g/day to individuals with normal renal function (CrCl ≥60 mL/min) achieved the target at a MIC of ≤64 and ≤32 μg/mL during the first 24 h of treatment and at steady state, respectively. Notably, those with renal impairment achieved higher MIC values at a steady state despite dosage reduction. None of the regimens reached the target CFR. Our study suggested that administering fosfomycin at least 20 g/day to those with normal renal function provides sufficient exposure throughout the treatment course when the MIC value is ≤32 μg/mL. Less aggressive dosing regimens are advisable for patients with renal impairment. Additional clinical studies are necessary to verify our suggestions., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: Infections represent a major risk for critically ill neonatal and paediatric patients requiring extracorporeal life-saving support such as extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapies (CRRT). Patient outcomes rely on achieving target antimicrobial concentrations. In critically ill adults on extracorporeal support, suboptimal antimicrobial concentrations have been shown to be common. Our objective was to systematically review antimicrobial pharmacokinetic studies in critically ill term neonatal and paediatric patients receiving ECMO and/or CRRT and compare them to similar cohorts of patients not receiving ECMO or CRRT., Methods: Studies published between 1990 and 2022 were identified through systematic searches in PUBMED, Embase, Web of Science, Medline, Google Scholar and CINAHL. Studies were included which provided antimicrobial pharmacokinetic parameters (volume of distribution and clearance) in the neonatal and paediatric patients receiving ECMO and/or CRRT. Studies were excluded if no antimicrobial pharmacokinetic parameters were described or could be calculated., Results: Forty-four pharmacokinetic studies were identified describing 737 patients, with neonatal patients recruited in 70% of the ECMO studies and <1% of the CRRT studies. Of all the studies, 50% were case reports or case series. The pharmacokinetics were altered for gentamicin, daptomycin, ceftolozane, micafungin, voriconazole, cefepime, fluconazole, piperacillin, and vancomycin, although considerable patient variability was described., Conclusion: Significant gaps remain in our understanding of the pharmacokinetic alterations in neonatal and paediatric patients receiving ECMO and CRRT support., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Biomass is an abundantly available, underutilized feedstock for the production of bulk and fine chemicals, polymers, and sustainable and biodegradable plastics that are traditionally sourced from petrochemicals. Among potential feedstocks, 2,5-furan dicarboxylic acid (FDCA) stands out for its potential to be converted to higher-value polymeric materials such as polyethylene furandicarboxylate (PEF), a bio-based plastic alternative. In this study, the sustainable, electrocatalytic oxidation of stable furan molecule 2,5-bis(hydroxymethyl)furan (BHMF) to FDCA is investigated using a variety of TEMPO derivative electrocatalysts in a mediated electrosynthetic reaction. Three TEMPO catalysts (acetamido-TEMPO, methoxy-TEMPO, and TEMPO) facilitate full conversion to FDCA in basic conditions with >90% yield and >100% Faradaic efficiency. The remaining three TEMPO catalysts (hydroxy-TEMPO, oxo-TEMPO, and amino-TEMPO) all perform intermediate oxidation of BHMF in basic conditions but do not facilitate full conversion to FDCA. On the basis of pH studies completed on all TEMPO derivatives to assess their electrochemical reversibility and response to substrate, pH and reversibility play significant roles in the catalytic ability of each catalyst, which directly influences catalyst turnover and product formation. More broadly, this study also highlights the importance of an effective and rapid electroanalytical workflow in mediated electrosynthetic reactions, demonstrating how voltammetric catalyst screening can serve as a useful tool for predicting the reactivity and efficacy of a catalyst-substrate electrochemical system., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Co-published by Zhejiang University and American Chemical Society.)

Background: This study describes the population pharmacokinetics of cefoxitin in obese patients undergoing elective bariatric surgery and evaluates different dosing regimens for achievement of pre-defined target exposures., Methods: Serial blood samples were collected during surgery with relevant clinical data. Total serum cefoxitin concentrations were measured by chromatographic assay and analysed using a population PK approach with Pmetrics®. The cefoxitin unbound fraction (fu) was estimated. Dosing simulations were performed to ascertain the probability of target attainment (PTA) to achieve cefoxitin fu above minimum inhibitory concentrations (MIC) from surgical incision to wound closure. Fractional target attainment (FTA) was calculated against MIC distributions of common pathogens., Results: A total of 123 obese patients (median BMI 44.3 kg/m 2 ) were included with 381 cefoxitin concentration values. Cefoxitin was best described by a one-compartment model, with a mean clearance and volume of distribution of 10.9 ± 6.1 L/h and 23.4 ± 10.5 L, respectively. In surgery <2 h, a 2 and a 4 g doses were sufficient for an MIC up to 4 and 8 mg/L (fu 50%), respectively. In prolonged surgery (2-4 h), only continuous infusion enabled optimal PTA for an MIC up to 16 mg/L. Optimal FTAs were obtained against Staphylococcus aureus and Escherichia Coli only when simulating with 50% cefoxitin protein binding (intermittent regimen) and regardless of the protein binding for the continuous infusion., Conclusion: Intermittent dosing regimens resulted in optimal FTAs against susceptible MIC distributions of S. aureus and E. coli when simulating with 50% cefoxitin protein binding. Continuous infusion of cefoxitin may improve FTA regardless of protein binding., Study Registration: Registration on ClinicalTrials.gov, NCT03306290., (Copyright © 2024 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Importance: Federally qualified health centers (FQHCs) deliver health care to nearly 30 million underserved persons across the US, yet nationwide and state-level breast, cervical, and colorectal cancer screening use in FQHCs is not described. Furthermore, it is unknown how the underscreened FQHC population contributes to the total underscreened population at national and state levels., Objective: To describe national- and state-level breast, cervical, and colorectal cancer screening use among individuals served by FQHCs in the US and to estimate the percentage of underscreened individuals in the general population served by FQHCs., Design, Setting, and Participants: This cross-sectional analysis of cancer screening used data from January 1 through December 31, 2020, from the FQHC Uniform Data System, reported by 1364 FQHCs across the US, and self-reported estimates from the Behavioral Risk Factor Surveillance System. Participants were 16 696 692 US adults served by FQHCs who were eligible for breast (age, 50-74 years), cervical (age, 21-64 years), and colorectal (age, 50-75 years) cancer screening. Analyses were conducted between January 1 and June 30, 2023., Exposures: Breast, cervical, and colorectal cancer screening., Main Outcomes and Measures: Percentages of breast, cervical, and colorectal cancer screening-eligible individuals up to date on screening., Results: A total of 3 162 882 breast, 7 444 465 cervical, and 6 089 345 colorectal screening-eligible individuals were served by FQHCs in 2020. Nationally, screening use in FQHCs was 45.4% (95% CI, 45.4%-45.5%) for breast cancer, 51.0% (95% CI, 51.0%-51.1%) for cervical cancer, and 40.2% (95% CI, 40.1%-40.2%) for colorectal cancer. Screening use among the US general population was 78.2% (95% CI, 77.6%-78.9%) for breast cancer, 82.9% (95% CI, 82.3%-83.4%) for cervical cancer, and 72.3% (95% CI, 71.7%-72.8%) for colorectal cancer. The contribution of the underscreened population served by FQHCs to the national underscreened general population was 16.9% (95% uncertainty interval [UI], 16.4%-17.4%) for breast cancer, 29.7% (95% UI, 28.8%-30.7%) for cervical cancer, and 14.7% (95% UI, 14.4%-15.0%) for colorectal cancer., Conclusions and Relevance: Findings from this national cross-sectional study indicated major gaps in cancer screening use in FQHCs in the US. Improved prevention is urgently needed to address screening disparities.

Introduction: Self-sampling for human papillomavirus testing is increasingly recognized as a strategy to expand cervical cancer screening access and utilization. Acceptability is a key determinant of uptake. This study assesses the acceptability of and experiences with mailed self-sampling kits for human papillomavirus testing among underscreened patients in a safety net health system., Methods: A nested telephone survey was administered between 2021 and 2023 to a sample (n=272) of the 2,268 participants enrolled in the Prospective Evaluation of Self-Testing to Increase Screening trial. Trial participants include patients of a safety net health system aged 30-65 years who were not up to date on screening. Participants were asked about barriers to provider-performed screening. Kit users and nonusers were asked about their experiences., Results: Prevalent barriers to provider-performed screening included perceived discomfort of pelvic examination (69.4%), being uncomfortable with male providers (65.4%), and embarrassment (57.0%). Among participants who reported using the mailed kit (n=164), most reported good experiences (84.8%). Most reported self-sampling as more/equally convenient (89.0%), less/equally embarrassing (99.4%), and less/equally stressful (95.7%) than provider-performed screening. Among kit nonusers (n=43), reasons for not using the kit included forgetting about it (76.7%), preferring provider-performed screening (76.7%), and fearing cancer (67.4%)., Conclusions: Prospective Evaluation of Self-Testing to Increase Screening trial participants generally had a positive experience with self-sampling for human papillomavirus testing. Increased comfort and reduced embarrassment/anxiety with self-sampling are relevant attributes because these were the most prevalent reported barriers to provider-performed screening. High acceptability suggests potentially high uptake when self-sampling for human papillomavirus testing receives regulatory approval and is available in safety net health systems., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cerebral ventriculitis might be caused by Gram-negative bacteria, including ESBL producers. Temocillin may be a useful treatment option in this scenario; however, no consistent data are available regarding its penetration into the CSF., Objectives: To describe the population pharmacokinetics of temocillin in plasma and CSF and to determine the probability for different simulated dosing regimens to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets in the CSF., Methods: Ten post-neurosurgical critically ill adult patients requiring continuous drainage of CSF were included in this monocentric, prospective, open-label, non-randomized study. They received 2 g loading dose temocillin over 30 min IV infusion, followed by a 6 g continuous infusion over 24 h. Total and unbound concentrations were measured in plasma (n = 88 and 86) and CSF (n = 88 and 88) samples and used to build a population PK model. Monte Carlo simulations were performed to estimate the PTA at 100% Css>MIC (steady state concentration above the MIC) in CSF., Results: All patients were infected with Enterobacterales with temocillin MICs ≤8 mg/L. The median (min-max) temocillin penetration in CSF was 12.1% (4.3-25.5) at steady state. Temocillin unbound plasma pharmacokinetics were best described by a one-compartment model. PTA for the applied dosing regimen was >90% for bacteria with MIC ≤ 4 mg/L., Conclusions: The currently approved dose of 6 g by continuous infusion may be adequate for the treatment of ventriculitis by Enterobacterales with MIC ≤ 4 mg/L if considering 100% Css>MIC as the PK/PD target to reach. Higher maintenance doses could help covering higher MICs, but their safety would need to be assessed., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Pharmacokinetic studies in children are limited, in part due to challenges in blood sampling. We compare the use of capillary microsampling and conventional sampling techniques in pediatric patients to show results that can be used in the pharmacokinetic analysis of Cefazolin. Patients & Methods: Paired blood samples (n = 48) were collected from 12 patients (median age/weight 49 months/18 kg). Results: The United States Federal Drug Administration incurred sample reanalysis acceptance criteria was used and identified 79% of paired samples achieved a difference of less than 20% in magnitude with a capillary microsampling bias of -10% (SD 20%). With exclusion of PK outliers, this rose to 88%. Conclusion: Capillary microsampling is reliable, meets acceptance criteria and can be used in pharmacokinetic studies. ACTRN: 12618001469202.

Background: The current fungal meningitis outbreak caused by contaminated epidural anesthesia with Fusarium solani among patients who underwent surgical procedures in Matamoros, Mexico remains a cause of concern. Its association with an increased susceptibility for cerebrovascular complications (CVC) has not been reported. This single-center study describes 3 patients with a unique pattern of CVC attributed to fungal meningitis., Methods: A retrospective case series of patients diagnosed with fungal meningitis following surgical procedures under contaminated epidural anesthesia who developed a unique pattern of CVC during their hospitalization., Results: Three female patients (mean age, 35 years) with CVC due to iatrogenic fungal meningitis were included. Positive Fungitell β-D-glucan assay in cerebrospinal fluid was documented in all cases, and F . solani was confirmed by polymerase chain reaction in case 3. All cases were complicated by severe vertebrobasilar circulation vasculopathy and arterial dissections with resultant subarachnoid hemorrhage and intraventricular hemorrhage, ultimately leading to patients' death., Conclusions: The death toll from the ongoing fungal meningitis outbreak keeps rising, underscoring the need for early recognition and aggressive treatment. We highlight the risk for vertebrobasilar circulation CVC among these patients. The angioinvasive nature of F . solani is yet to be clarified; however, a clear pattern has been observed. Public health awareness should be raised and a strong response should be pursued., Competing Interests: Disclosures Dr Choi reports stock options in ACASTI Pharm. Dr P.R. Chen reports grants from Stryker. The other authors report no conflicts.

Objective: Reimbursement trends for common procedures have persistently declined over the past 2 decades. Spinal instrumentational and fusion procedures are increasingly utilized and have increased in clinical complexity, yet longitudinal inflation-adjusted data for Medicare reimbursements of these procedures have not been evaluated., Methods: The Centers for Medicare and Medicaid Services (CMS) Physician Fee Schedule Look-Up Tool was used to extract Medicare reimbursements for the 5 most common spinal procedures and associated instrumentations from 2000-2020. Current Procedural Terminology (CPT) codes include 22551, 22600, 22633, 63030, and 63047 as well as instrumentation CPT codes 22840 and 22842-6. The nominal values were adjusted for inflation according to the latest consumer price index (U.S. Bureau of Labor Statistics; reported as 2020 USD) and used to calculate average annual percent changes and compound annual growth rates (CAGRs) in reimbursements., Results: After inflation adjustment, the physician fee reimbursement decreased by 11.05% ± 8.46% (mean ± s.d., from $2,009.89 in 2011 to $1,787.85 in 2020) for anterior cervical discectomy and fusion (ACDF), 28.38% ± 8.42% (from $1,889.38 in 2000 to $1,353.14 in 2020) for posterior cervical fusion, 7.85% ± 8.20% (from $2,111.20 in 2012 to $1,945.49 in 2020) for transforaminal lumbar interbody fusion (TLIF), 28.17% ± 13.88% (from $1,421.78 in 2000 to $1,021.22 in 2020) for lower back disc surgery, and 31.88% ± 8.22% (from $1,700.38 in 2000 to $1,158.25 in 2020) for lumbar laminectomy. Instrumentation reimbursements showed an average decrease of 33.43% ± 8.4% over this period. Average CAGR was -1.7% ± .41% for procedures and -2.02% ± .14% for instrumentation., Conclusion: Our analysis reveals a persistent decline in reimbursement rates of the most common spine procedures and instrumentation since the year 2000. If unaddressed, this trend can serve as a substantial disincentive for physicians to perform these procedures and can significantly limit access to spinal care at the population level., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To describe the total and unbound population pharmacokinetics of a 2 g three-times-weekly post-dialysis ceftriaxone regimen in Indigenous Australian patients requiring hemodialysis., Methods: A pharmacokinetic study was carried out in the dialysis unit of a remote Australian hospital. Adult Indigenous patients on intermittent hemodialysis (using a high-flux dialyzer) and treated with a 2 g three-times-weekly ceftriaxone regimen were recruited. Plasma samples were serially collected over two dosing intervals and assayed using validated methodology. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics in R. The probability of pharmacokinetic/pharmacodynamic target attainment (unbound trough concentrations ≥1 mg/L) and toxicity [trough concentrations (total)  ≥100 mg/L] were simulated for various dosing strategies., Results: Total and unbound concentrations were measured in 122 plasma samples collected from 16 patients (13 female) with median age 57 years. A two-compartment model including protein-binding adequately described the data, with serum bilirubin concentrations associated (inversely) with ceftriaxone clearance. The 2 g three-times-weekly regimen achieved 98% probability to maintain unbound ceftriaxone concentrations ≥1 mg/L for a serum bilirubin of 5 µmol/L. Incremental accumulation of ceftriaxone was observed in those with bilirubin concentrations >5 µmol/L. Three-times-weekly regimens were less probable to achieve toxic exposures compared with once-daily regimens. Ceftriaxone clearance was increased by >10-fold during dialysis., Conclusions: A novel 2 g three-times-weekly post-dialysis ceftriaxone regimen can be recommended for a bacterial infection with an MIC ≤1 mg/L. A 1 g three-times-weekly post-dialysis regimen is recommended for those with serum bilirubin ≥10 µmol/L. Administration of ceftriaxone during dialysis is not recommended., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: The Hispanic population is heterogeneous with differences in health behaviors across subgroups by nativity and preferred language. We evaluated cervical cancer screening adherence among English- and Spanish-speaking Hispanic patients receiving care at a safety net health system., Methods: Electronic health records were used to identify 46,094 women aged 30-65. Up to date (UTD) screening was defined based on date of last Pap test, human papillomavirus (HPV) test, or Pap/HPV co-test., Results: Overall, 81.5% of 31,297 Hispanic women were UTD. English-speaking Hispanic women had a lower prevalence of being UTD when compared to Spanish-speaking Hispanic women (aPR: 0.94, 95% CI: 0.93 - 0.96). Further, those with indigent healthcare plans had a higher prevalence of being UTD when compared to those with private insurance (aPR: 1.10, 95% CI: 1.09 - 1.12), while all other health insurance plans were associated with lower UTD screening when compared to private insurance., Conclusions: These findings suggest screening differences within the Hispanic population, highlighting the need for disaggregated research assessing heterogeneity within racial/ethnic groups, specifically among Hispanic populations., (© 2023. The Author(s).)

Background: Patients with tuberculosis (TB) may develop multi-organ failure and require admission to intensive care. In these cases, the mortality rates are as high as 78% and may be caused by suboptimal serum concentrations of first-line TB drugs. This study aims to compare the pharmacokinetics of oral rifampin, isoniazid, pyrazinamide and ethambutol patients in intensive care units (ICU) to outpatients and to evaluate drug serum concentrations as a potential cause of mortality., Methods: A prospective pharmacokinetic (PK) study was performed in Amazonas State, Brazil. The primary PK parameters of outpatients who achieved clinical and microbiological cure were used as a comparative target in a non-compartmental analysis., Results: Thirteen ICU and twenty outpatients were recruited. The clearance and volume of distribution were lower for rifampin, isoniazid, pyrazinamide and ethambutol. ICU thirty-day mortality was 77% versus a cure rate of 89% in outpatients., Conclusions: ICU patients had a lower clearance and volume of distribution for rifampin, isoniazid, pyrazinamide and ethambutol compared to the outpatient group. These may reflect changes to organ function, impeded absorption and distribution to the site of infection in ICU patients and have the potential to impact clinical outcomes.

Aim: To describe the stability of nafamostat in infusion solutions, during blood sample collection and in extracted plasma samples in the autosampler. Methods: Nafamostat infusion solutions were stored at room temperature in the light for 24 h. For sample collection stability, fresh blood spiked with nafamostat was subjected to combinations of anticoagulants, added esterase inhibitor and temperature. Nafamostat was monitored in the extracted plasma samples in the autosampler. Results: Nafamostat was stable in infusion solutions. Nafamostat in whole blood was stable for 3 h before centrifugation when collected in sodium fluoride/potassium oxalate tubes (4°C). Nafamostat in extracted plasma samples degraded at 4.7 ± 0.7% per h. Conclusion: Viable samples can be obtained using blood collection tubes with sodium fluoride, chilling and processing promptly.

Few studies have examined the time-dependent effects of stress on fear learning. Previously, we found that stress immediately before fear conditioning enhanced fear learning. Here, we aimed to extend these findings by assessing the effects of stress 30 min prior to fear conditioning on fear learning and fear generalization. Two hundred and twenty-one healthy adults underwent stress (socially evaluated cold pressor test) or a control manipulation 30 min before completing differential fear conditioning in a fear-potentiated startle paradigm. One visual stimulus (CS+), but not another (CS-), was associated with an aversive airblast to the throat (US) during acquisition. The next day, participants were tested for their fear responses to the CS+, CS-, and several generalization stimuli. Stress impaired the acquisition of fear on Day 1 but had no significant impact on fear generalization. The stress-induced impairment of fear learning was particularly evident in participants who exhibited a robust cortisol response to the stressor. These findings are consistent with the notion that stress administered 30 min before learning impairs memory formation via corticosteroid-related mechanisms and may help us understand how fear memories are altered in stress-related psychological disorders.

Transferring biomolecules from solution to vacuum facilitates a detailed analysis of molecular structure and dynamics by isolating molecules of interest from a complex environment. However, inherent in the ion desolvation process is the loss of solvent hydrogen bonding partners, which are critical for the stability of a condensed-phase structure. Thus, transfer of ions to vacuum can favor structural rearrangement, especially near solvent-accessible charge sites, which tend to adopt intramolecular hydrogen bonding motifs in the absence of solvent. Complexation of monoalkylammonium moieties (e.g., lysine side chains) with crown ethers such as 18-crown-6 can disfavor structural rearrangement of protonated sites, but no equivalent ligand has been investigated for deprotonated groups. Herein we describe diserinol isophthalamide (DIP), a novel reagent for the gas-phase complexation of anionic moieties within biomolecules. Complexation is observed to the C-terminus or side chains of the small model peptides GD, GE, GG, DF-OMe, VYV, YGGFL, and EYMPME in electrospray ionization mass spectrometry (ESI-MS) studies. In addition, complexation is observed with the phosphate and carboxylate moieities of phosphoserine and phosphotyrosine. DIP performs favorably in comparison to an existing anion recognition reagent, 1,1'-(1,2-phenylene)bis(3-phenylurea), that exhibits moderate carboxylate binding in organic solvent. This improved performance in ESI-MS experiments is attributed to reduced steric constraints to complexation with carboxylate groups of larger molecules. Overall, diserinol isophthalamide is an effective complexation reagent that can be applied in future work to study retention of solution-phase structure, investigate intrinsic molecular properties, and examine solvation effects.

Objective: To test the feasibility of conducting a randomised controlled trial to evaluate the impact of a closed-loop blood sampling system and blood conservation bundle., Methods: Single site, parallel group, pilot randomised control trial comparing open system sampling to closed system sampling and conservation bundle aligned with national guidelines. Randomisation sequence was generated by an independent statistician and allocation concealment maintained via sealed opaque envelopes. The study setting was the general intensive care unit of a major metropolitan public hospital in Queensland, Australia. Participants were ≥ 18 years who had an arterial catheter inserted in intensive care. Main outcome measures included trial feasibility, blood sample loss, haematocrit (HCT) change, and packed red blood cell transfusion use., Results: Eighty patients were randomised (n = 39 open group, n = 41 closed group). Characteristics in each group were equal at baseline with overall median age 60 years (IQR 48.6-70.4), 58 % male, and median APACHE II score 16 (IQR 11-22). The proportion of patients eligible was 29 % and missed eligible was 65 %. Otherwise, feasibility criteria were met with proportion of eligible patients agreeing to enrolment 99 %, 100 % of patients receiving allocated treatment; only 1 % of data missing. Analysis demonstrated a significant reduction in mean daily blood sample losses (open 32.7 (SD 1.58) mL vs closed 15.5 (SD 5.79) mL, t = -8.454, df = 78, p < 0.001)., Conclusions: A large, multi-site trial is feasible with enhanced eligibility criteria, increased recruitment support. The intervention reduced daily blood sample volumes and transfusion use. Further trials are required to provide both effectiveness and implementation outcomes., Competing Interests: Declaration of Competing Interest S Keogh’s employer (QUT) has received on her behalf for education consultancy from BD Medical and ITL Biomedical unrelated to this study. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Rationale & Objective: Kidney transplant recipients require frequent venipunctures. Microsampling methods that use a finger-prick draw of capillary blood, like volumetric absorptive microsamplers (VAMS), have the potential to reduce the pain, inconvenience, and volume of blood loss associated with venipuncture. This study aimed to provide diagnostic accuracy using VAMS for measurement of tacrolimus and creatinine compared to gold standard venous blood in adult kidney transplant recipients., Study Design: Diagnostic test study. Prospective blood samples for measurement of tacrolimus and creatinine were collected using Mitra VAMS and venipuncture immediately before and 2 hours after tacrolimus dosing., Setting & Participants: A convenience sample of 40 adult kidney transplant participants in the outpatient setting., Tests Compared: Method comparison was assessed by Passing-Bablok regression and Bland-Altman analysis. The predictive performance of VAMS measurement compared to venipuncture was also assessed through estimation of the median prediction error and median absolute percentage prediction error., Results: A total of 74 tacrolimus samples and 70 creatinine samples were analyzed from 40 participants. Passing-Bablok regression showed a systematic difference between VAMS and venipuncture when measuring tacrolimus and creatinine with a slope of 1.08 (95% CI, 1.03-1.13) and a slope of 0.65 (95% CI, 0.6-0.7), respectively. These values were then corrected for the systematic difference. When used for Bland-Altman analysis, corrected values of tacrolimus and creatinine showed a bias of -0.1 μg/L and 0.04 mg/dL, respectively. Tacrolimus (corrected) and creatinine (corrected) microsampling values when compared to corresponding venipuncture values met median prediction error and median absolute percentage prediction error predefined acceptability limits of <15%., Limitations: This study was conducted in a controlled environment using a trained nurse to collect VAMS samples., Conclusions: In this study, VAMS was used to reliably measured tacrolimus and creatinine. This represents a clear opportunity for more frequent and less invasive sampling for patients., (© 2023 The Authors.)

Background: Levetiracetam is an antiepileptic drug used to prevent or treat seizure in patients with severe traumatic brain injury. This study aimed to develop and validate methodology suitable for measuring levetiracetam concentrations in human plasma and urine. Methods: Plasma or urine (10 μl) samples were spiked with [ 2 H 6 ]-levetiracetam and processed using an acetonitrile precipitation. ESI-LC-MS/MS was employed for analyte detection. Results: The levetiracetam calibration was linear from 0.1 to 50 mg/l in a combined matrix of plasma and urine. Intra- and inter-assay imprecision and accuracy in plasma were <7.7 and 109%, and in urine were <7.9 and 108%, respectively. Conclusion: The validated method was applied to a pharmacokinetic study of levetiracetam in critically ill patients with severe traumatic brain injury.

Introduction: Neisseria gonorrhoeae infections are common and incidence increasing. Oropharyngeal infections are associated with greater treatment failure compared with other sites and drive transmission to anogenital sites through saliva. Gonococcal resistance is increasing and new treatments are scarce, therefore, clinicians must optimise currently available and emerging treatments in order to have efficacious therapeutic options. This requires pharmacokinetic data from the oral cavity/oropharynx, however, availability of such information is currently limited., Methods and Analysis: Healthy male volunteers (participants) recruited into the study will receive single doses of either ceftriaxone 1 g, cefixime 400 mg or ceftriaxone 500 mg plus 2 g azithromycin. Participants will provide samples at 6-8 time points (treatment regimen dependent) from four oral sites, two oral fluids, one anorectal swab and blood. Participants will complete online questionnaires about their medical history, sexual practices and any side effects experienced up to days 5-7. Saliva/oral mucosal pH and oral microbiome analysis will be undertaken. Bioanalysis will be conducted by liquid chromatography-mass spectrometry. Drug concentrations over time will be used to develop mathematical models for optimisation of drug dosing regimens and to estimate pharmacodynamic targets of efficacy., Ethics and Dissemination: This study was approved by Royal Melbourne Hospital Human Research Ethics Committee (60370/MH-2021). The study results will be submitted for publication in peer-reviewed journals and reported at conferences. Summary results will be sent to participants requesting them. All data relevant to the study will be included in the article or uploaded as supplementary information., Trial Registration Number: ACTRN12621000339853., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary microsampling to facilitate data-rich blood sampling., Methods: Patients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma samples collected at 0, 0.5, 2, 4 and 6 h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200 mL/min/1.73 m2) and body weights (4, 10, 15, 20 and 40 kg) to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets, including 100% ƒT>MIC with an MIC breakpoint of 1 mg/L., Results: Thirty-six patients (0.2-12 years) provided 160 conventional samples for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8 L/h and 39.4 L, respectively. The clearance for desacetylcefotaxime was 10.5 L/h. Standard dosing of 50 mg/kg q6h was only able to achieve the PK/PD target of 100% ƒT>MIC in patients >10 kg and with impaired renal function or patients of 40 kg with normal renal function., Conclusions: Dosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary microsampling demonstrated skin-prick sampling can facilitate data-rich pharmacokinetic studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Guidelines for surgical prophylactic dosing of cefazolin in bariatric surgery vary in terms of recommended dose. This study aimed to describe the plasma and interstitial fluid (ISF) cefazolin pharmacokinetics in patients undergoing bariatric surgery and to determine an optimum dosing regimen. Abdominal subcutaneous ISF concentrations (measured using microdialysis) and plasma samples were collected at regular time points after administration of cefazolin 2 g intravenously. Total and unbound cefazolin concentrations were assayed and then modeled using Pmetrics. Monte Carlo dosing simulations ( n  = 5,000) were used to define cefazolin dosing regimens able to achieve a fractional target attainment (FTA) of >95% in the ISF suitable for the MIC for Staphylococcus aureus in isolates of ≤2 mg · L -1 and for a surgical duration of 4 h. Fourteen patients were included, with a mean (standard deviation [SD]) bodyweight of 148 (35) kg and body mass index (BMI) of 48 kg · m -2 . Cefazolin protein binding ranged from 14 to 36% with variable penetration into ISF of 58% ± 56%. Cefazolin was best described as a four-compartment model including nonlinear protein binding. The mean central volume of distribution in the final model was 18.2 (SD 3.31) L, and the mean clearance was 32.4 (SD 20.2) L · h -1 . A standard 2-g dose achieved an FTA of >95% for all patients with BMIs ranging from 36 to 69 kg · m -2 . A 2-g prophylactic cefazolin dose achieves appropriate unbound plasma and ISF concentrations in obese and morbidly obese bariatric surgery patients.

Background: Conventional sampling for pharmacokinetic clinical studies requires removal of large blood volumes from patients. This can result in a physiological/emotional burden for children. Microsampling to support pharmacokinetic clinical studies in pediatrics may reduce this burden., Methods: Parents/guardians and bedside nurses completed a questionnaire describing their perception of the use of microsampling compared to conventional sampling to collect blood samples, based on their child's participation or their own role within a paired-sample pharmacokinetic clinical study. Responses were based on a seven-point Likert scale and were analyzed using frequency distributions., Results: Fifty-one parents/guardians and seven bedside nurses completed a questionnaire. Parents/guardians (96%) and bedside nurses (100%) indicated that microsampling was highly acceptable and recommended as a method for collecting blood samples for pediatric patients. Responding to a question about the child indicating pain during the blood sampling procedure, 61% of parent/guardians reported no pain in their children, 14% remained neutral, and 26% reported that their child indicated pain; 71% of the bedside nurses slightly agreed that the children indicated pain., Conclusions: This study strongly suggests that parents/guardians and bedside nurses prefer microsampling to conventional sampling to conduct pediatric pharmacokinetic clinical studies. Employing microsampling may support increased participation by children in these studies., Impact: Pharmacokinetic clinical studies require the withdrawal of blood samples at multiple times during a dosing interval. This can result in a physiological or emotional burden, particularly for neonates or pediatric patients. Microsampling offers an important opportunity for pharmacokinetic clinical studies in vulnerable patient populations, where smaller sample volumes can be collected. However, microsampling is not commonly used in clinical studies. Understanding the perceptions of parents/guardians and bedside nurses about microsampling may ascertain if this technique offers an improvement to conventional blood sample collection to perform pharmacokinetic clinical studies for pediatric patients., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Introduction: Surgical management of degenerative lumbar spine disorders is effective at improving patient pain, disability, and quality of life; however, obtaining a durable posterolateral fusion after decompression remains a challenge. Interbody fusion technologies are viable means of improving fusion rates in the lumbar spine, specifically various graft materials including autograft, structural allograft, titanium, and polyether ether ketone. This study assesses the effectiveness of Tritanium posterolateral cage in the treatment of degenerative disk disease., Methods: Nearest-neighbor 1:1 matched control transforaminal lumbar interbody fusion with PEEK vs. Tritanium posterior lumbar (PL) cage interbody fusion patients were identified using propensity scoring from patients that underwent elective surgery for degenerative disk diseases. Line graphs were generated to compare the trajectories of improvement in patient-reported outcomes (PROs) from baseline to 3 and 12 months postoperatively. The nominal data were compared via the χ 2 test, while the continuous data were compared via Student's t-test., Results: The two groups had no difference regarding either the 3- or 12-month Euro-Qol-5D (EQ-5D), numeric rating scale (NRS) leg pain, and NRS back pain; however, the Tritanium interbody cage group had better Oswestry Disability Index (ODI) scores compared to the control group of the PEEK interbody cage at both 3 and 12 months (p=0.013 and 0.048)., Conclusions: Our results indicate the Tritanium cage is an effective alternative to the previously used PEEK cage in terms of PROs, surgical safety, and radiological parameters of surgical success. The Tritanium cohort showed better ODI scores, higher fusion rates, lower subsidence, and lower indirect costs associated with surgical management, when compared to the propensity-matched PEEK cohort., Competing Interests: Conflicts of Interest: Financial support and industry affiliations: Dr. Devin reports a Stryker grant, Stryker consulting, Wright medical, defense expert witness, and Medtronic legal consulting outside the submitted work. The other authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. The authors have no personal or institutional financial interest in drugs, materials, or devices described in their submissions., (Copyright © 2022 The Japanese Society for Spine Surgery and Related Research.)

Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT > MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h−1 and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients.

Reducing the volume of blood sampled from neonatal or paediatric patients is important to facilitate research in a group that is under-represented in clinical studies. Not all patients have a cannula available for blood sampling, meaning there are real advantages in obtaining a blood microsample by skin prick. In this study, the results obtained from both capillary microsamples (CMS) and a microfluidic (MF)-CMS by skin prick are compared to conventional plasma sampled from an arterial catheter in a clinical bridging study. Six critically ill patients receiving meropenem were included with the incurred sample reanalysis test meeting the acceptance criteria for both CMS (n = 24 samples) and MF-CMS (n = 20 samples). Bland-Altman plots comparing MF-CMS to conventional arterial blood sampling revealed a difference of - 12.7 ± 22.1% (mean ± standard deviation (SD), and comparing CMS to conventional arterial blood sampling a difference of - 3.4 ± 17.0%. At - 12.7%, the bias between MF-CMS and conventional sampling is greater than the bias found with CMS, although within the limit of acceptability for analytical accuracy (that being ± 15%). Samples collected by skin prick and using CMS produced meropenem concentrations that were comparable to those obtained from conventional arterial catheter sampling. CMS samples were found to be stable when stored in the capillary tube for 24 h at 5 °C or for 4 h at room temperature., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)