A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod—a Toll-like receptor 8 (TLR8) ...agonist that stimulates robust innate immune responses—combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death.
Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 versus >6–12 months) and Gynecologic Oncology Group (GOG) performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression.
The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided P=0.923, HR=1.22) or progression-free survival (PFS; log rank one-sided P=0.943, HR=1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared with those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS.
The addition of motolimod to PLD did not improve clinical outcomes compared with placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches.
Clinicaltrials.gov, NCT 01666444.
Management decisions involving groundwater supply and remediation often rely on optimization techniques to determine an effective strategy. We introduce several derivative-free sampling methods for ...solving constrained optimization problems that have not yet been considered in this field, and we include a genetic algorithm for completeness. Two well-documented community problems are used for illustration purposes: a groundwater supply problem and a hydraulic capture problem. The community problems were found to be challenging applications due to the objective functions being nonsmooth, nonlinear, and having many local minima. Because the results were found to be sensitive to initial iterates for some methods, guidance is provided in selecting initial iterates for these problems that improve the likelihood of achieving significant reductions in the objective function to be minimized. In addition, we suggest some potentially fruitful areas for future research.
Ultrasound examination is both accurate and cost-effective for the confirmation of a clinical diagnosis of carpal tunnel syndrome. Previous studies have shown electrodiagnostic testing and ultrasound ...to be similar with regard to sensitivity and specificity. The purpose of this study was to compare the sensitivity and specificity of ultrasound and electrodiagnostic testing by using a validated clinical diagnostic tool as the reference standard.
All consecutive patients referred to an upper-extremity practice for electrodiagnostic testing for any reason over a three-month period were recruited to participate in this study. All patients were evaluated with the use of the Carpal Tunnel Syndrome 6 (CTS-6) clinical diagnostic tool, and a score of ≥12 was considered positive for carpal tunnel syndrome. A positive finding on ultrasound was considered to be a cross-sectional area of the median nerve, measured just proximal to the level of the pisiform, of ≥10 mm(2). A positive finding on electrodiagnostic testing was a distal motor latency of ≥4.2 ms and/or a distal sensory latency of ≥3.2 ms. Sensitivity, specificity, and accuracy were calculated for ultrasound and electrodiagnostic testing with use of the CTS-6 as the reference standard.
With use of the CTS-6 as the reference standard, ultrasound had a sensitivity of 89% and a specificity of 90% in our series of eighty-five patients. Electrodiagnostic testing had a sensitivity of 89% and a specificity of 80%. The positive predictive value of ultrasound was 94% compared with 89% for electrodiagnostic testing. The negative predictive value of ultrasound was 82% compared with 80% for electrodiagnostic testing. Ultrasound was accurate in seventy-six (89%) of the eighty-five cases whereas electrodiagnostic testing was accurate in seventy-three (86%) of the eighty-five cases (p = 0.5).
While ultrasound will not replace electrodiagnostic testing in complicated or unclear cases, in a select group of patients with a positive CTS-6, ultrasound can be used to confirm the diagnosis of carpal tunnel syndrome with better specificity and equal sensitivity as compared with those of electrodiagnostic testing.
Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence.
Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes ...blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements.
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► Alu RNA accumulation due to DICER1 deficiency activates NLRP3 inflammasome in RPE ► Pharmacological inhibition of the inflammasome, MyD88, or IL18 prevents degeneration ► Alu RNA induced RPE degeneration via mitochondrial ROS production, IL18, and MyD88 ► RPE in human geographic atrophy eyes display evidence of NLRP3 and MyD88 activation
Age-related macular degeneration (AMD) is an untreatable form of blindness caused by cell death in the retina. In AMD, the accumulation of Alu RNAs trigger cell death by activating the NLRP3 inflammasome; blocking these pathways pharmacologically prevents degeneration.
A study has been made of the way in which the number of events available for analysis in a clinical trial was dependent on the recruitment period, the maximum follow-up time on individual patients ...and the length of time between the start of the trial and its analysis. The events considered were deaths, local recurrences and late radiation effects on normal tissue in patients treated for cancer of the laryngo-pharynx by two different fractionation regimes. The relationship is demonstrated between the number of events and the 95% confidence intervals that can be placed on differences between results in the two arms of the trial. It was found, in this particular trial, that no significant improvement in precision was gained by following up patients beyond 5 years or carrying out the analysis later than 2 years after the end of recruitment. The results are discussed in the context of the initial design of clinical trials, particularly those in which the aim is to test therapeutic equivalence.
The quality of an approximate solution for combinatorial optimization problems with a single objective can be evaluated relatively easily. However, this becomes more difficult when there are multiple ...objectives. One potential approach to solving multiple criteria combinatorial optimization problems when at least one of the single objective problems is NP-complete, is to use an a posteriori method that approximates the efficient frontier. A common difficulty in this type of approach, however, is evaluating the quality of approximate solutions, since sets of multiple solutions should be evaluated and compared. This necessitates the use of a comparison measure that is robust and accurate. Furthermore, a robust measure plays an important role in metaheuristic optimization for "tuning" various parameters for evolutionary algorithms, simulated annealing, etc., which are frequently employed for multiple criteria combinatorial optimization problems. In this paper, the performance of a new measure, which we call Integrated Convex Preference (ICP) is compared to that of other measures appearing in the literature through numerical experiments - specifically, we use two a posteriori solution techniques based on genetic algorithms for a bi-criteria parallel machine scheduling problem and evaluate their performance (in terms of solution quality) using different measures. Experimental results show that the ICP measure evaluates the solution quality of approximations robustly (i.e., similar to visual comparison results) while other alternative measures can misjudge the solution quality. We note that the ICP measure can be applied to other non-scheduling multiple objective combinatorial optimization problems, as well. PUBLICATION ABSTRACT
Non-linear loading of the utilities supply introduced significant electromagnetic field (EMF) interference severe enough to disrupt electrocardiograph (ECG) monitoring and recordings in the new ...Emergency Department (ED) at the Royal Melbourne Hospital (RMH). This interference was evident even though standard Mu-metal shielding had been installed over the main hospital power feed which runs underneath the department. Investigations revealed that the source of the interference was due to 3rd harmonic currents flowing in the mains cable. This interference was suppressed by introducing third harmonic current into the main power cable in anti-phase to the interfering signal.
Objective To determine whether antibiotic prophylaxis at the time of removal of a urinary catheter reduces the risk of subsequent symptomatic urinary tract infection.Design Systematic review and ...meta-analysis of studies published before November 2012 identified through PubMed, Embase, Scopus, and the Cochrane Library; conference abstracts for 2006-12 were also reviewed.Inclusion criteria Studies were included if they examined antibiotic prophylaxis administered to prevent symptomatic urinary tract infection after removal of a short term (≤14 days) urinary catheter.Results Seven controlled studies had symptomatic urinary tract infection after catheter removal as an endpoint; six were randomized controlled trials (five published; one in abstract form) and one was a non-randomized controlled intervention study. Five of these seven studies were in surgical patients. Studies were heterogeneous in the type and duration of antimicrobial prophylaxis and the period of observation. Overall, antibiotic prophylaxis was associated with benefit to the patient, with an absolute reduction in risk of urinary tract infection of 5.8% between intervention and control groups. The risk ratio was 0.45 (95% confidence interval 0.28 to 0.72). The number needed to treat to prevent one urinary tract infection was 17 (12 to 30).Conclusions Patients admitted to hospital who undergo short term urinary catheterization might benefit from antimicrobial prophylaxis when the catheter is removed as they experience fewer subsequent urinary tract infections. Potential disadvantages of more widespread antimicrobial prophylaxis (side effects and cost of antibiotics, development of antimicrobial resistance) might be mitigated by the identification of which patients are most likely to benefit from this approach.
The emergence of successive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) during 2020 to 2022, each exhibiting increased epidemic growth relative to earlier ...circulating variants, has created a need to understand the drivers of such growth. However, both pathogen biology and changing host characteristics-such as varying levels of immunity-can combine to influence replication and transmission of SARS-CoV-2 within and between hosts. Disentangling the role of variant and host in individual-level viral shedding of VOCs is essential to inform Coronavirus Disease 2019 (COVID-19) planning and response and interpret past epidemic trends. Using data from a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening, we developed a Bayesian hierarchical model to reconstruct individual-level viral kinetics and estimate how different factors shaped viral dynamics, measured by PCR cycle threshold (Ct) values over time. Jointly accounting for both interindividual variation in Ct values and complex host characteristics-such as vaccination status, exposure history, and age-we found that age and number of prior exposures had a strong influence on peak viral replication. Older individuals and those who had at least 5 prior antigen exposures to vaccination and/or infection typically had much lower levels of shedding. Moreover, we found evidence of a correlation between the speed of early shedding and duration of incubation period when comparing different VOCs and age groups. Our findings illustrate the value of linking information on participant characteristics, symptom profile and infecting variant with prospective PCR sampling, and the importance of accounting for increasingly complex population exposure landscapes when analysing the viral kinetics of VOCs. Trial Registration: The Legacy study is a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening for SARS-CoV-2 at University College London Hospitals or at the Francis Crick Institute (NCT04750356) (22,23). The Legacy study was approved by London Camden and Kings Cross Health Research Authority Research and Ethics committee (IRAS number 286469). The Legacy study was approved by London Camden and Kings Cross Health Research Authority Research and Ethics committee (IRAS number 286469) and is sponsored by University College London Hospitals. Written consent was given by all participants.
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