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symptoms, which could have important implications for decreasing unnecessary activation of pre-hospital services.LC/MS quantification of leukotoxin (LTX) and leukotoxin diol (LTXdiol) in plasma has been previously reported, however large sample volumes are required for achieving stated assay Lower Limit of Quantification (LLOQ). Reported here is a fit-for-purpose LC/MS method that reduces plasma volume from 700 to 25 µL and omits pre-concentration steps. These improvements make for a method with increased utility in mouse studies offering limited sample volumes. Additionally, omitting pre-concentration steps streamlines sample processing, which can now be completed in under 10 min. This method can be used to quickly answer if the ratio of LTX to LTXdiol changes with the dose of the therapeutic drug so this could be used as a potential biomarker for correlating PK/PD effects. No extensive assay characterization was performed before application to an exploratory in-life study. Basal levels of LTX and LTXdiol in plasma were quantified by LC-MRM across 10 individual mice, and the average signal-to-noise was 36 for LTX and 3039 for LTXdiol, with CVs of 29.4% and 15.2%, respectively. Addition of LTX and LTXdiol reference standard at 5, 25, and 75 ng/mL into pooled mouse plasma was quantifiable within 30% relative error using a surrogate matrix calibration curve ranging from 0.8 to 200 ng/mL. The average ratio of LTX to LTXdiol across the 10 mice was 0.32, consistent with previous reports. Finally, the method was applied to a mouse PK/PD study to monitor LTX/LTXdiol kinetics after a single oral dose of a soluble epoxide hydrolase inhibitor. The mean plasma ratio of LTX to LTXdiol increased up to 10-fold by 3 h post-dose followed by a decrease to near pre-dose levels by 24 h, consistent with transient inhibition of sEH-mediated conversion of LTX to LTXdiol. The method improvements described here will make subsequent quantification of LTX and LTXdiol in mouse studies significantly easier.
There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker.
CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m
every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used tone NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.We must be aware that new respiratory virus pandemic can happen frequently. Standard lung function tests should keep their crucial role to assist the clinicians in the decision-making process, but they are at risk for the spread of infection because of the generated droplets. We used opto-electronic plethysmography to investigate the post-COVID-19 syndrome on 12 patients after ICU. We found normal ventilatory pattern at rest, a restrictive pattern located in the ribcage during vital capacity and surgical mask to significantly increase minute ventilation. The attention on unconventional respiratory function tests should be sponsored for the important information they can provide.The power of biological systems can be harnessed with higher efficiency when biosynthetic reactions are decoupled from cellular physiology. This can be achieved by cell-free synthesis, which relies on the in vitro use of cellular machinery under optimized reaction conditions. As exemplified by the recent development of mRNA vaccines and therapeutics, the cell-free synthesis of biomolecules is fast, efficient and flexible. Cell-free synthesis of industrial chemicals and biofuels is drawing considerable attention as a promising alternative to microbial fermentation processes, which currently show low conversion yields and toxicity to host cells. Here, we provide a brief overview of the history of cell-free synthesis systems and the state-of-the-art cell-free technologies used to produce diverse chemicals and biofuels. We also discuss the future directions of cell-free synthesis that can fully harness the synthetic power of biological systems.
Long-acting injectable depot buprenorphine is an important new treatment option for the management of opioid dependence, delivering therapeutic doses in weekly or monthly formulations. Depot buprenorphine aims to overcome challenges associated with traditional opioid agonist therapy (OAT), including poor patient adherence; inconvenience of regular attendance for dosing; and, risk of non-medical use of takeaway doses. However, little is known about patients' experiences of depot buprenorphine. This qualitative study aimed to explore patients' experiences of the practical and social affordances of depot buprenorphine.
Participants were recruited from sites in Sydney, regional New South Wales, and Melbourne, Victoria, Australia. Thirty participants (16 men, 14 women; mean age 47.3 years) participated in semi-structured interviews. Participants had histories of both heroin and prescription opioid use, and previous OAT including daily dosing of buprenorphine and methadone.
Depot buprenorphine afforded positing depot buprenorphine to reduce the risk of unintended consequences including disruption to clinical supports.
In DSM-5, definitions of substance use disorders (SUD) were changed considerably from DSM-IV, yet little is known about how well DSM-IV and DSM-5 SUD diagnoses agree among substance users. Because data from many studies are based on DSM-IV diagnostic criteria, understanding the agreement between DSM-5 and DSM-IV SUD diagnoses and reasons for discordance between these diagnoses is crucial for comparing results across studies.
Prevalences and chance-corrected agreement of DSM-5 SUD and DSM-IV substance dependence were evaluated in 588 substance users in a suburban inpatient addiction program and an urban medical center, using a semi-structured interview (PRISM-5). Alcohol, tobacco, cannabis, cocaine, heroin, opioid, sedative, and stimulant use disorders were examined. Cohen's kappa was used to assess agreement between DSM-5 and DSM-IV SUD (abuse or dependence), DSM-5 SUD and DSM-IV dependence, and DSM-5 moderate/severe SUD and DSM-IV dependence.
Agreement between DSM-5 and DSM-IV SUD was excellent for all substances (κ = 0.84-0.99), except for cannabis and tobacco (κ = 0.75; 0.80, respectively). The most common reason for diagnostic discrepancies was a positive DSM-5 SUD diagnosis but no DSM-IV diagnosis, due to the lowered DSM-5 SUD threshold. Agreement between DSM-5 SUD and DSM-IV dependence was excellent for all substances (κ = 0.88-0.94), except for alcohol, tobacco, and cannabis (κ = 0.63-0.75). Agreement between moderate/severe DSM-5 SUD and DSM-IV dependence was excellent across all substances.
While care should be used in interpreting results of studies using different methods, studies relying on DSM-IV or DSM-5 SUD diagnostic criteria offer similar information and thus can be compared when accumulating a body of evidence.
While care should be used in interpreting results of studies using different methods, studies relying on DSM-IV or DSM-5 SUD diagnostic criteria offer similar information and thus can be compared when accumulating a body of evidence.
Emergency care planning is an important component of healthcare transition, particularly for patients with medical complexity. Duchenne muscular dystrophy (DMD) is a complex, progressive pediatric-onset disease affecting multiple organ systems including impairment of cardiac and pulmonary function, high risk for fractures, fat embolism, adrenal crisis and malignant hyperthermia. Appropriate interdisciplinary emergency management is critical for survival for these patients. The purpose of this quality improvement project was to develop a process to reliably share an individualized emergency care plan (ECP) with patients and their families as part of a larger plan to develop an integrated transition program.
An interdisciplinary team of nurses and clinicians used the principles of quality improvement to develop a reliable process to assure patients with DMD received an individualized, multidisciplinary ECP at routine interdisciplinary clinic visits. Additionally, the project used surveys to assess patient and family satisfaction with the letter and whether it improved their knowledge of emergency care.
Sixty-two patients were seen during the study timeframe. All received an ECP. Sixty-two surveys were sent and twenty-three surveys were returned. Of those that responded, the majority stated the ECP increased their knowledge of emergency care.
ECPs can be developed and disseminated to patients with DMD and their caregivers. Epacadostat This tool can potentially promote timely and appropriate emergency care for these patients with unique and complex medical needs.
ECPs can be developed and disseminated to patients with DMD and their caregivers. This tool can potentially promote timely and appropriate emergency care for these patients with unique and complex medical needs.
Despite American Academy of Pediatrics recommendations that adolescents receive healthcare transition (HCT) services starting at age 12, few do. Electronic health record-based clinical decision support (CDS) tools are effective at promoting healthcare provider adherence to clinical guidelines. This study's purpose was to increase provider HCT services engagement through implementation of a transition-specific CDS and participation in a transition-focused Learning Collaborative (LC).
Three pediatric primary care sites of an urban, academic medical center implemented a transition CDS tool for ≥14-year-olds. Previously, one site had a version for ≥16-year-olds. Two sites participated in a LC with Plan-Do-Study-Act cycles targeting HCT services engagement, measured by CDS use and practice-level guideline implementation.
From July 2018 through June 2019, providers at LC-participating sites engaged in HCT services at 8.0% (n=480) and 5.3% (n=145) of eligible patient visits compared to the control's 3.1% (n=69). Engagement was highest for ≥18-year-olds at the LC-participating sites, 26.0% (n=263) and 12.0% (n=80), compared to the control's 7.2% (n=31). After expanding from ≥16 to ≥14-year-olds, engagement decreased by 9.5% at ≥16-year-old visits. LC-participating sites reported increased HCT guideline adherence.
Implementation of a transition-specific CDS with LC participation increased provider HCT services engagement and practice-level guideline implementation. Expansion to younger adolescents contributed to decreased engagement for older patients. Future research should assess opportunities to improve uptake and patient outcomes of transition CDS engagement.
Quality improvement activities and transition clinical decision supports can improve provider engagement in recommended transition services for adolescents and young adults.
Quality improvement activities and transition clinical decision supports can improve provider engagement in recommended transition services for adolescents and young adults.
