Factors Influencing Integration and Usability of Model-Informed Precision Dosing Software in the Intensive Care Unit.

BACKGROUND: Antimicrobial dosing in critically ill patients is challenging and model-informed precision dosing (MIPD) software may be used to optimize dosing in these patients. However, few intensive care units (ICU) currently adopt MIPD software use. OBJECTIVES: To determine the usability of MIPD software perceived by ICU clinicians and identify implementation barriers and enablers of software in the ICU. METHODS: Clinicians (pharmacists and medical staff) who participated in a wider multicenter study using MIPD software were invited to participate in this mixed-method study. Participants scored the industry validated Post-study System Usability Questionnaire (PSSUQ, assessing software usability) and Technology Acceptance Model 2 (TAM2, assessing factors impacting software acceptance) survey. Semistructured interviews were used to explore survey responses. The framework approach was used to identify factors influencing software usability and integration into the ICU from the survey and interview data. RESULTS: Seven of the eight eligible clinicians agreed to participate in the study. The PSSUQ usability scores ranked poorer than the reference norms (2.95 vs. 2.62). The TAM2 survey favorably ranked acceptance in all domains, except image. Qualitatively, key enablers to workflow integration included clear and accessible data entry, visual representation of recommendations, involvement of specialist clinicians, and local governance of software use. Barriers included rigid data entry systems and nonconformity of recommendations to local practices. CONCLUSION: Participants scored the MIPD software below the threshold that implies good usability. Factors such as availability of software support by specialist clinicians was important to participants while rigid data entry was found to be a deterrent.

Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis.

PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes.

Efficiency of dosing software using Bayesian forecasting in achieving target antibiotic exposures in critically ill patients, a prospective cohort study.

INTRODUCTION: Broad-spectrum antibiotics such as beta-lactams and vancomycin are frequently used to treat critically ill patients, however, a significant number do not achieve target exposures. Therapeutic drug monitoring (TDM) combined with Bayesian forecasting dosing software may improve target attainment in these patients. This study aims to describe the efficiency of dosing software for achieving target exposures of selected beta-lactam antibiotics and vancomycin in critically ill patients. METHODS: A prospective cohort study was undertaken in an adult intensive care unit (ICU). Patients prescribed vancomycin, piperacillin-tazobactam and meropenem were included if they exhibited a subtherapeutic or supratherapeutic exposure informed by TDM. The dosing software, ID-ODS™, was used to generate dosing recommendations which could be either accepted or rejected by the treating team. Repeat antibiotic TDM were requested to determine if target exposures were achieved. RESULTS: Between March 2020 and December 2021, 70 were included in the analysis. Software recommendations were accepted for 56 patients (80%) with 50 having repeated antibiotic measurements. Forty-three of the 50 patients (86%) achieved target exposures after one software recommendation, with 3 of the remaining 7 patients achieving target exposures after 2. Forty-seven patients out of the 50 patients (94%) achieved the secondary outcome of clinical cure. There were no antibiotic exposure-related adverse events reported. CONCLUSION: The use of TDM combined with Bayesian forecasting dosing software increases the efficiency for achieving target antibiotic exposures in the ICU. Clinical trials comparing this approach with other dosing strategies are required to further validate these findings.

Beta-Lactam Dose Optimisation in the Intensive Care Unit: Targets, Therapeutic Drug Monitoring and Toxicity.

Beta-lactams are an important family of antibiotics used to treat infections and are commonly used in critically ill patients. Optimal use of these drugs in the intensive care unit (ICU) is important because of the serious complications from sepsis. Target beta-lactam antibiotic exposures may be chosen using fundamental principles of beta-lactam activity derived from pre-clinical and clinical studies, although the debate regarding optimal beta-lactam exposure targets is ongoing. Attainment of target exposures in the ICU requires overcoming significant pharmacokinetic (PK) and pharmacodynamic (PD) challenges. For beta-lactam drugs, the use of therapeutic drug monitoring (TDM) to confirm if the desired exposure targets are achieved has shown promise, but further data are required to determine if improvement in infection-related outcomes can be achieved. Additionally, beta-lactam TDM may be useful where a relationship exists between supratherapeutic antibiotic exposure and drug adverse effects. An ideal beta-lactam TDM service should endeavor to efficiently sample and report results in identified at-risk patients in a timely manner. Consensus beta-lactam PK/PD targets associated with optimal patient outcomes are lacking and should be a focus for future research.

Accuracy of a precision dosing software program for predicting antibiotic concentrations in critically ill patients.

BACKGROUND: Critically ill patients with sepsis are predisposed to physiological changes that can reduce the probability of achieving target antibiotic exposures. Precision dosing software programs may be used to improve probability of obtaining these target exposures. OBJECTIVE: To quantify the accuracy of a precision dosing software program for predicting antibiotic concentrations as well as to assess the impact of using software predictions on actual dosing adjustments. PATIENTS AND METHODS: The software program ID-ODS was used to predict concentrations for piperacillin, meropenem and vancomycin using patient covariate data with and without the use of therapeutic drug monitoring (TDM) data. The impact of these predictions on actual dosage adjustments was determined by using software predicted concentrations versus measured concentrations. RESULTS: Software predictions for piperacillin and meropenem exhibited large bias that improved with the addition of TDM data (bias improved from -28.8 to -2.0 mg/L for piperacillin and -3.0 to -0.1 mg/L for meropenem). Dosing changes using predicted concentrations of piperacillin and meropenem with TDM data versus measured concentrations were matched on 89.2% (107/120) and 71% (9/69) occasions, respectively. Although vancomycin predictions demonstrated good accuracy with and without TDM, these findings were limited by our small sample size. CONCLUSION: These data demonstrate that precision dosing software programs may have scope to reasonably predict antibiotic concentrations in critically ill patients with sepsis. The addition of TDM data improves the predictive performance of the software for all three antibiotics and the ability to anticipate the correct dose change required.

Precision dosing software to optimize antimicrobial dosing: a systematic search and follow-up survey of available programs.

BACKGROUND: Precision dosing programs are promising tools for optimising antimicrobial dosing. Selecting the ideal program for local application may be challenging due to the large variety of available programs with differing characteristics. OBJECTIVES: The objectives of this study were to systematically identify available precision dosing software programs to optimize antimicrobial dosing and describe the characteristics of each program. Details on the ability of programs to provide beta-lactam dosing support was also gathered. SOURCES: A systematic review search strategy was used to identify candidate software programs described in the literature in Embase and PubMed. A detailed survey was then developed to identify characteristics of programs, including details on the underlying methodology driving dosing software recommendations, interface characteristics, costs and regulatory affairs. Software developers from all identified programs were invited to participate in the survey. CONTENT: The systematic search results identified 18 programs. Fifteen developers responded to the survey (83%) and 11 programs provide dosing support for at least one beta-lactam. Fourteen programs can utilize measured drug concentrations to generate dosing recommendations, with 13 able to generate empiric dosing recommendations. Six programs integrate with local electronic health records and four are registered with at least one regulatory agency. Pharmacokinetic models in combination with Bayesian statistics is the most common methodology used to generate dosing recommendations, with 14 programs utilizing this method. IMPLICATIONS: There was significant variability in the available antimicrobial profiles and characteristics among dosing software programs. As healthcare providers will differ in their requirements within their local settings, clinicians should use these findings to identify potential candidate programs and, if feasible, trial these to ensure they meet their specific requirements.

Manganese(III) acetate-mediated synthesis of N-substituted fulleropyrrolines via the reaction of [60]fullerene with α-monosubstituted acetaldehydes and primary amines.

The simple one-step reaction of [60]fullerene with α-monosubstituted acetaldehydes and primary amines in the presence of Mn(OAc)3·2H2O under air conditions afforded a series of novel N-substituted fulleropyrrolines with trisubstituted CC bonds in moderate to good yields. The addition of Mn(OAc)3·2H2O played a crucial role in the successful synthesis of N-aryl fulleropyrrolines with trisubstituted CC bonds, which would be extremely difficult to prepare by known methods as a result of the decreased nucleophilicity of arylamines due to the p-π conjugation effect. Intriguingly, arylamines displayed abnormally higher reactivity as compared with non-arylamines in the current reaction system by the observation of obviously decreased equivalent of Mn(OAc)3·2H2O, higher product yields, and lower reaction temperature probably due to the radical reaction mechanism initiated by Mn(OAc)3·2H2O. On the basis of experimental observations, a plausible formation pathway for N-substituted fulleropyrrolines with trisubstituted CC bonds was proposed to elucidate the above-mentioned reaction process.

What Are the Current Approaches to Optimising Antimicrobial Dosing in the Intensive Care Unit?

Antimicrobial dosing in the intensive care unit (ICU) can be problematic due to various challenges including unique physiological changes observed in critically ill patients and the presence of pathogens with reduced susceptibility. These challenges result in reduced likelihood of standard antimicrobial dosing regimens achieving target exposures associated with optimal patient outcomes. Therefore, the aim of this review is to explore the various methods for optimisation of antimicrobial dosing in ICU patients. Dosing nomograms developed from pharmacokinetic/statistical models and therapeutic drug monitoring are commonly used. However, recent advances in mathematical and statistical modelling have resulted in the development of novel dosing software that utilise Bayesian forecasting and/or artificial intelligence. These programs utilise therapeutic drug monitoring results to further personalise antimicrobial therapy based on each patient's clinical characteristics. Studies quantifying the clinical and cost benefits associated with dosing software are required before widespread use as a point-of-care system can be justified.

A new bioactive coumestan from the seeds of Psoralea corylifolia.

A new coumestan named bavacoumestan D (1), together with five known compounds (2-6), was isolated from EtOAc-soluble extract of seeds of Psoralea corylifolia. Their structures were elucidated on the basis of spectroscopic and physico-chemical analyses. All compounds were evaluated for in vitro inhibitory activity against DGAT1, DGAT2 and α-glucosidase. Among them, compounds 1-2, 5-6 showed potential inhibitory activity on DGAT1 with IC50 values ranging from 52.3 ± 1.3 to 81.0 ± 1.0 µM. Compounds 1-3, 6 displayed the significant inhibitory activity on α-glucosidase with IC50 values ranging from 31.2 to 89.1 µM.[Formula: see text].

Efficacy and safety of active abdominal compression-decompression versus standard CPR for cardiac arrests: A systematic review and meta-analysis of 17 RCTs.

BACKGROUND & AIM: Active abdominal compression-decompression cardiopulmonary resuscitation (AACD-CPR), which applies to cardiac arrests with contraindication of standard chest compressions (SCC) CPR, has been utilized in cardiac arrest. However, the efficacy and safety of AACD-CPR still remained controversy. This analysis was designed to comprehensively compare AACD versus SCC-CPR in patients with cardiac arrest. METHODS: We searched the Cochrane Library, PubMed, EMBASE, Web of Science and CNKI up to April 22, 2019. Mean difference (MD) and risk ratio (RR) with its 95% confidence intervals (CIs) were estimated to compare outcomes of the groups. Our primary outcomes were restoration of spontaneous circulation (ROSC) and short-term survival. Two reviewers assessed trial quality and extracted data independently. All statistical analyses were performed using standard statistical procedures provided in Review Manager 5.2 and Stata 12.0. RESULTS: A total of seventeen studies (N = 1647 patients) were identified for the present analysis. Compared with standard CPR, AACD-CPR was superior in restoration of spontaneous circulation (ROSC) and short-term survival, with pooled RRs of 1.38 (95% CI 1.23-1.55; P < 0.00001) and RRs of 2.05 (95% CI 1.69-2.50; P < 0.00001) respectively. In addition, significant superiority of AACD-CPR was found in incidence of fracture, long-term survival, pressure of end-tidal carbon dioxide (PETCO2), coronary perfusion pressure (CPP) and adverse events. No significant difference was observed in incidence of vomiting. CONCLUSIONS: Generally, in this combined analysis we found a statistically significant improvement in survival and ROSC with the use of AACD-CPR as compared with the use of standard CPR. There was also significant improvement in incidence of fracture, long-term survival, PETCO2 and CPP with AACD-CPR in comparison with standard CPR; results were not statistically different between the groups regarding to vomiting rate and adverse events. The standardized, diversified and individualized methods of clinical operation of AACD-CPR need exploration and expectingly serve as a guideline for clinical application of AACD-CPR in the future.

Advances in pathological diagnosis of mesothelioma: what pulmonologists should know.

PURPOSE OF REVIEW: Malignant pleural mesothelioma (MPM) is a universally fatal illness with a rising incidence, particularly in developing countries. The diagnosis can be challenging and require repeated investigations with implications for the patient and healthcare system. RECENT FINDINGS: Distinguishing between benign/reactive and malignant mesothelial proliferations can be challenging. Cytological diagnosis of MPM from pleural fluid is as reliable as histological analysis of tissue biopsies in epithelioid MPM - an approach endorsed by the International Academy of Cytology. Identification of BRCA1-associated protein 1 (BAP1) and cyclin-dependent kinase inhibitor 2A (CDKN2A) gene mutations in MPM have led to the development of new ancillary tests that can streamline the diagnostic pathway. The prognostic values of these molecules are being investigated. Clinicians should be aware of the recently described BAP1 tumor predisposition syndrome and offer genetic investigations in potential patients. Routine use of prophylactic radiotherapy in MPM patients after pleural interventions has been disproved in a randomized trial. SUMMARY: Diagnosis of epithelioid MPM can be established on pleural fluid analysis in most patients. The use of BAP1 immunostaining and CDKN2A/p16 fluorescence in-situ hybridization are particularly useful in distinguishing benign from malignant mesothelial proliferations. Clinicians should ensure these investigations are available in the pathological assessment of cases to minimize invasive investigations and the associated risks.

Hyperkalaemic periodic paralysis in pregnancy.

Hyperkalaemic periodic paralysis is a rare skeletal muscle disorder which is characterised by episodic muscle paralysis associated with hyperkalaemia. Although it is an autosomal-dominant disease, cases of de novo mutations have been reported. We report the case of a 30-year-old woman, gravida 5 para 3+1, who was planned for an elective repeated caesarean section at 38 weeks and 3 days of pregnancy. She developed recurrent episodes of hyperkalaemic periodic paralysis after receiving corticosteroids. Intravenous calcium gluconate was administered to normalise potassium levels (from 6.3 mmol/L to 4.1 mmol/L). Extra anaesthetic precautions were taken during the caesarean delivery. Postoperatively, she was well and discharged from the ward. She encountered similar symptoms in her third pregnancy, and there was no family history of muscle weakness which suggested a de novo mutation. Pregnancy seemed to result in vulnerability to hyperkalaemic attacks as she was never symptomatic outside pregnancy.

Synchronous oesophageal and gastric sarcomatoid carcinoma: first reported case in Australia.

A 75-year-old retired teacher presents with dysphagia and weight loss for a duration of 6 months. Her gastroscopy showed two synchronous submucosal masses. A 7 cm polypoid mass was seen at the distal oesophagus, arising from a thick stalk and a 4 cm mass seen at the cardia. The biopsies showed high-grade sarcomatoid cancer. Staging CT scan and Positron Emission Tomography scan did not show any distant metastasis except a lesion in the rectum that was subsequently found to be tubulovillous adenoma on transanal excision. The patient was managed with Ivor Lewis oesophagectomy. The biopsies of resection specimen showed spindle cell/sarcomatoid carcinoma with a component of poorly differentiated neuroendocrine carcinoma in oesophageal tumour and a small component of conventional invasive squamous cell carcinoma in tumour at cardia. The patient recovered well after surgery. Since then, she has completed adjuvant chemoradiotherapy. No recurrence has been noted in 10 months follow-up.

Postpartum thromboprophylaxis in a multireligious cohort: a retrospective review of indications and uptake.

Strategies to prevent mortality from obstetric venous thromboembolism begin with identification, risk stratification and subsequently, implementation of prophylactic measures. We sought to identify the burden of pharmacologic thromboprophylaxis in postpartum women, including the main clinical indications and its uptake in a multireligious population, with Islam as the official religion. A total of 2514 deliveries between 1st January to 31st December 2016, across three centres in Malaysia were reviewed retrospectively from hospital-based registries. 770 (30.62%) patients fulfilled the criteria for thromboprophylaxis based on the revised 2015 criteria proposed by the Royal College of Obstetricians and Gynaecologists. A combination of age, parity, BMI, caesarean section and preterm births were the main indications. One out of the five patients who delivered vaginally required thromboprophylaxis. In our setting with a sizable Muslim population, low molecular weight heparin was the thromboprophylaxis of choice in more than two-third of the patients. The information obtained from this study allows better local resource planning. Impact statement What is already known on this subject: Risk factors for venous thromboembolism in pregnancy and puerperium are largely drawn from registries due to the rarity of the index event. Up to 7% of women require antenatal thromboprophylaxis based on the criteria proposed by the Royal College of Obstetrician and Gynaecologists in 2009. What do the results of this study add: Using the RCOG guideline revised in 2015, a significant proportion of women delivering vaginally would require postnatal thromboprophylaxis based on age, parity and BMI. When either age or parity, both with relatively low odds ratio for thrombosis were omitted, a substantial proportion of women would not achieve the threshold for prophylaxis. Despite a sizable Muslim population in the country, the uptake of low molecular weight heparin was relatively high. What are the implications of these findings for clinical practice and/or future research: Cost-benefit studies should consider the adjusted odds ratio of individual indications on a VTE event. While uptake and acceptability is high, prospective studies on medication adherence is equally pertinent.

Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.

Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.

MiR-374a promotes the proliferation of osteosarcoma cell proliferation by targeting Axin2.

BACKGROUND: MicroRNA-374a (miR-374a) has been implicated in several cancers. However, its role in osteosarcoma (OS) remains unclear. Thus the aim of this study was to investigate its expression and role in progression of OS. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of miR-374a in OS cell lines and tissues. To further understand its role, we restored expression of miR-374a in MG63 cell line by transfection with miR-374a mimics or inhibitors. Effects of miR-374a on cell proliferation on targets were also determined. RESULTS: In the present study, our results showed that miR-374a was significantly up-regulated in both OS cell lines and OS tissues. Over expression of miR-374a markedly accelerated proliferation of OS cells, while its inhibition significantly suppressed cell proliferation. Moreover, Axin2 was identified to be a functional downstream target of miR-374a, and decreased expression of Axin2 could promote OS cell proliferation. CONCLUSION: Our study suggested that miR-374a functions as an oncogene in OS, and the miR-374a/Axin2 axis might represent a potential therapeutic target for OS intervention.

Percutaneous Repair Technique for Acute Achilles Tendon Rupture with Assistance of Kirschner Wire.

The aim of this study is to introduce a self-designed, minimally invasive technique for repairing an acute Achilles tendon rupture percutaneously. Comparing with the traditional open repair, the new technique provides obvious advantages of minimized operation-related lesions, fewer wound complications as well as a higher healing rate. However, a percutaneous technique without direct vision may be criticized by its insufficient anastomosis of Achilles tendon and may also lead to the lengthening of the Achilles tendon and a reduction in the strength of the gastrocnemius. To address the potential problems, we have improved our technique using a percutaneous Kirschner wire leverage process before suturing, which can effectively recover the length of the Achilles tendon and ensure the broken ends are in tight contact. With this improvement in technique, we have great confidence that it will become the treatment of choice for acute Achilles tendon ruptures.

Properties that influence the specific surface areas of carbon nanotubes and nanofibers.

Commercially available carbon nanotubes and nanofibers were analyzed to examine possible relationships between their Brunauer-Emmett-Teller specific surface areas (SSAs) and their physical and chemical properties. Properties found to influence surface area were number of walls/diameter, impurities, and surface functionalization with hydroxyl and carboxyl groups. Characterization by electron microscopy, energy-dispersive X-ray spectrometry, thermogravimetric analysis, and elemental analysis indicates that SSA can provide insight on carbon nanomaterials properties, which can differ vastly depending on synthesis parameters and post-production treatments. In this study, how different properties may influence surface area is discussed. The materials examined have a wide range of surface areas. The measured surface areas differed from product specifications, to varying degrees, and between similar products. Findings emphasize the multiple factors that influence surface area and mark its utility in carbon nanomaterial characterization, a prerequisite to understanding their potential applications and toxicities. Implications for occupational monitoring are discussed.

Bioluminescent orthotopic model of pancreatic cancer progression.

Pancreatic cancer has an extremely poor five-year survival rate of 4-6%. New therapeutic options are critically needed and depend on improved understanding of pancreatic cancer biology. To better understand the interaction of cancer cells with the pancreatic microenvironment, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression. Luciferase-tagged pancreatic cancer cells are resuspended in Matrigel and delivered into the pancreatic tail during laparotomy. Matrigel solidifies at body temperature to prevent leakage of cancer cells during injection. Primary tumor growth and metastasis to distant organs are monitored following injection of the luciferase substrate luciferin, using in vivo imaging of bioluminescence emission from the cancer cells. In vivo imaging also may be used to track primary tumor recurrence after resection. This orthotopic model is suited to both syngeneic and xenograft models and may be used in pre-clinical trials to investigate the impact of novel anti-cancer therapeutics on the growth of the primary pancreatic tumor and metastasis.