Search

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dr Nanthakumar is a recipient of the Mid-career Investigator Award from the Heart & Stroke Foundation of Ontario Background Recent trials in ventricular tachycardia (VT) ablation suggest that early ablation could reduce VT burden. A method to predict which patients will have substrate ablation targets based on non-invasive testing prior to the procedure does not exist and could be of value in selecting ideal patients for early VT substrate ablation. Decrement-evoked potential (DeEP) mapping is used to identify VT substrate ablation targets.1 A method for predicting which patients would have DeEP targets on a pre-ablation 12-lead ECG has not yet been developed. Objective To develop a metric to predict the presence of physiological substrate VT ablation targets from the 12-lead ECG. Method 22 electrophysiology (EP) lab VT cases that had undergone DeEP mapping were extracted from the CARTO® 3 system and were analysed retrospectively. For each case, DeEP was calculated by subtracting last component of the nearfield evoked response in the pacing train (S1) from the latest component of the nearfield evoked decremented response of the extra stimulus (S2). By inference, 12-lead ECG prediction was calculated by subtracting the width of the 12-lead surface ECG envelope of S1 from the width of the 12-lead ECG envelope of S2. Cases were divided into three categories: - Cases displaying intracardiac DeEP between 0-10ms – no ablation targets - Cases displaying intracardiac DeEP between 10-50ms – DeEP positive - Cases displaying intracardiac DeEP >50ms – prominent DeEP present Results Out of the 22 cases, 8 were characterised as no ablation targets, 12 as DeEP positive, and 2 as prominent DeEP present. The 12-lead surface ECG measurement means were 3.5±4.6ms for the no ablation target group, 23.2±9.1ms for positive DeEP group, and 80.9±8.1ms for prominent DeEP group. The surface ECG decrement was significantly different P Conclusion It may be possible to detect which patients will have substrate ablation targets based on 12-lead ECG, prior to the VT ablation procedure. Additionally, this prediction rule, based on its association with arrhythmogenic potentials, may be able to predict which ambulatory patients who have not had manifest VT, may be prone to develop VT thus help identify early VT ablation candidates. This concept should be validated in larger data sets and is ideal for training and testing using surface ECG envelopes with artificial intelligence algorithms.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Professor Nanthakumar is a recipient of the Mid-career Investigator Award from the Heart & Stroke Foundation of Ontario. Background Ablation targets in the era of early ventricular tachycardia (VT) ablation will likely be driven by substrate-based physiological target approaches rather than activation mapping. Decrement evoked potentials (DeEP) have been co-localized to the diastolic VT circuit and are used as a method to perform VT ablation when VT cannot or should not be induced.1 Traditionally these potentials are evoked by a single extrastimulus. The incremental utility of a second extrastimulus in detecting these potentials has not been evaluated. Purpose We studied the utility of the second extra stimulus (S3) in detecting substrate ablation over the first extra stimulus (S2) following a drivetrain (S1) of 8 beats at 600ms. Methods DeEP was measured as the time difference between the pacing stimulus and the nearfield local activation delay on the bipolar electrogram during the S1 drivetrain and after the S2 or S3 respectively. Decrement of ≥10ms was considered a positive DeEP site. A total of 157 sites from 6 patients with VT were analysed. The incremental value of S3-induced DeEP was compared to the S2-induced DeEP. Results The mean decrement was significantly greater on the S3 compared to the S2 (41.8±35.6ms for S3 vs 25.8±20.4ms for S2, P Conclusion When physiological substrate is present on the first extra stimulus, the second extra stimulus magnifies the identification of the target. However, we found in our study that the second extrastimulus uncovered a hidden arrhythmogenic substrate in only 3.1% additional mapped sites. Consequently, the utility of the second extrastimulus in identification of hidden substrate needs to be balanced with the risk of induction of potentially unstable rhythms.

Plumbagin, a bioactive naphthoquinone, has demonstrated potent antitumor potential. However, plumbagin is a sparingly water-soluble compound; therefore, clinical translation requires and will be facilitated by the development of a new pharmaceutical formulation. We have generated an oil-in-water nanoemulsion formulation of plumbagin using a low-energy spontaneous emulsification process with propylene glycol caprylate (Capryol 90) as an oil phase and Labrasol/Kolliphor RH40 as surfactant and cosurfactant excipients. Formulation studies using Capryol 90/Labrasol/Kolliphor RH40 components, based on pseudoternary diagram and analysis of particle size distribution and polydispersity determined by dynamic light scattering (DLS), identified an optimized composition of excipients for nanoparticle formulation. The nanoemulsion loaded with plumbagin as an active pharmaceutical ingredient had an average hydrodynamic diameter of 30.9 nm with narrow polydispersity. The nanoemulsion exhibited long-term stability, as well as good retention of particle size in simulated physiological environments. Furthermore, plumbagin-loaded nanoemulsion showed an augmented cytotoxicity against prostate cancer cells PTEN-P2 in comparison to free drug. In conclusion, we generated a formulation of plumbagin with high loading drug capacity, robust stability, and scalable production. Novel Capryol 90-based nanoemulsion formulation of plumbagin demonstrated antiproliferative activity against prostate cancer cells, warranting thus further pharmaceutical development.

Background Left ventricular function parameters, such as ejection fraction and global longitudinal strain are widely accepted prognostic parameters after myocardial infarction. Left atrial strain has been suggested as a novel risk parameter in this population. Objective To investigate whether left atrial (LA) deformation parameters (LA reservoir strain, LARS) can improve prognostic value of traditional echo parameters in prediction of heart failure and dead in patients after myocardial infarction. Moreover, to study relationship between LARS and established LV function parameters, and test its reproducibility between the readers. Method A total of 380 patients with myocardial infarction, hospitalized at our university hospital between 2008–2014, underwent echocardiography during hospital stay. The collected images was reanalyzed with respect to left atrial strain. Patients were followed up within the Swedish myocardial infarction registry (SWEDEHEART). Results To the final analysis a total of 253 patients (64 years of age, 81% men) were included, and followed up over median of 4.9 years. Among the parameters tested in the univariate analysis, LARS was able to predict long-term risk of heart failure admissions and death in patients with myocardial infarction (HR 0.95, 95% CI 0.91–0.99 for combined end-point). LARS below 27.2% identifies patients with higher risk of combined endpoint with AUC 0.68 (p=0.001). After adjustment for background characteristics and established LV function measures, LARS has lost significance, meaning that it provides no additional information in this population. LARS correlates moderately with LV GLS (r=−0.52, p Conclusions LARS is a good prognosticator of death and heart failure hospitalizations after myocardial infarction, but not independent of the established LV function parameters. We showed a good correlation between LARS and LV strain parameters and its near perfect inter-reader reproducibility. Funding Acknowledgement Type of funding sources: None.

Background Global longitudinal strain (GLS) by 2D speckle tracking echocardiography has emerged as a new method for assessing left ventricular (LV) function, however its added value in long-term risk prediction after Acute Coronary Syndrome (ACS) has not been clearly established. This study aimed to investigate GLS as a predictor of death and heart failure re-hospitalization after ACS in relation to more established echocardiographic measures. Method 1385 consecutive patients with acute coronary syndrome (47% STEMI, 45% NSTEMI, unstable angina 3.6% and unspecified ACS 4.5%), admitted between 2008 and 2014 to the three participating Swedish university hospitals were reported to the SWEDEHEART registry and underwent routine echocardiography during their hospital stay. The echo data was retrospectively collected from each study site and reviewed at a Core Lab. The prognostic value of systolic left ventricular function parameters (LVEF and GLS) regarding all-cause mortality and heart failure (HF) hospitalizations (median follow-up 6.8 years) was studied using the Cox proportional Hazards model. A nested model comparison was performed with C-statistics. Results In the 942 patients remaining after exclusion (median age 65 years, 77% men) median LVEF was 55% (inter quartile range (IQR) 47–60) and median GLS −14.8% (IQR −17.8–11.8). The combined endpoint of HF hospitalization and all-cause death was reached in 17.7% of the patients, 12.1% of the patients died and 8.7% were re-admitted due to HF. After adjustment for baseline characteristics, both LVEF and GLS were individual independent predictors of the combined endpoint, HR 0.964 (95% CI 0.949–0.980, p Conclusion In a large cohort of patients with ACS and normal or near-normal ejection fraction, GLS emerged as an independent long-term risk predictor of all-cause mortality and heart failure hospitalizations. The incremental predictive value of GLS on top of clinical background and LVEF was statistically significant, but of limited clinical significance. Funding Acknowledgement Type of funding sources: None.

The oil-and-gas industry is known to be part of the most safety-critical domains. Safety culture has prompted such companies to implement new systems to support decision-making. In this paper, we explore the use of digital twins to support situation awareness as a crucial part of real-time decisionmaking processes. Therefore, this paper presents requirements for the development of an eight components digital twin. Human-centered approach contributes to add useful information based on user needs and user experience to the usual theoretical process. This user-centered information helped shape both digital twin components and the situation awareness model.

Hand and wrist volar wounds are a common cause of emergency room (ER) visits. These wounds are explored surgically in the operating room at most hospitals. The main objective of our study was to prospectively assess the correlation between clinical examination in the ER performed by a surgical resident and the tendon, vascular and/or nerve damage found during surgery in hand and wrist volar wounds. The second objective was to describe the lesions based on their mechanism, as well as their topography. Eighty patients from two hand surgery referral centers were included. Patients' past medical history was obtained, as well as records of their physical examination in the ER and description of lesions found during surgery. In 28% of wounds with a normal clinical examination, tendon, vascular or nerve damage was found on surgical exploration. Out of the cases that tested negative for tendon injury in the ER, 16% had partial tendon injury or digital tunnel wound discovered during surgery. Nerve damage was found during surgery in 12% of cases that had not been detected clinically preoperatively. Based on our findings, we recommend performing surgical exploration for all volar hand and wrist wounds in the operating room, as physical examination does not detect all tendons, vascular or nerve injuries.

Resume La remediation cognitive (RC) est une approche breve et focalisee favorisant un meilleur fonctionnement neuropsychologique et une meilleure qualite de vie. Les processus neuropsychologiques cibles concernent les fonctions executives ; l’attention et la cognition sociale. En intervention precoce la RC vise a eviter un surhandicap chez les enfants et les adolescents presentant un trouble du neurodeveloppement en prevenant aussi des complications emotionnelles et/ou comportementales associees. Elle complete les prises en charge habituelles ou les optimise. Concernant la cognition sociale, elle favorise le developpement de la theorie de l’esprit et protege d’une faiblesse de l’inhibition comportementale. Facteur de rehabilitation chez les adultes, la RC est facteur d’inclusion chez les plus jeunes et favorise le maintien dans leur environnement ecologique. Nous proposons le programme de remediation cognitive NEAR (Neuropsychological Educational Approach to Remediation), developpe depuis 2002 par Alice Medalia, a des collegiens avec trouble du spectre de l’autisme (TSA) ou Trouble deficit de l’attention avec ou sans hyperactivite (TDA/H). Outil therapeutique attractif pour les plus jeunes il a fait preuve de son interet chez les adultes ; integre la metacognition et optimise la generalisation dans la vie quotidienne. La realisation d’un bilan medical et neuropsychologique au C3RP-Enfants/Adolescents (Centre referent en remediation cognitive et rehabilitation psycho-sociale) est un prerequis et les benefices sont evalues au terme du programme. Dans une etude de faisabilite, les jeunes ont temoigne se sentir plus motives, confiants et competents. La RC semble representer une nouvelle ressource therapeutique pour les plus jeunes dont l’efficience reste a evaluer scientifiquement.

Poly(ADP-ribose) polymerase (PARP) inhibitors are currently used in the clinic for the treatment of tumors with a defective DNA damage response (DDR). When PARP1 or PARP2 binds damaged DNA, it adds poly(ADP-ribose) chains to its own backbone and to other DDR proteins, which recruits and activates them. PARylated PARP1/2 next detaches from the DNA so that the other PARylated proteins can initiate the repair process. It has been observed that some PARP inhibitors prevent PARP1/2 from dissociating the DNA. The continuous presence of PARP at the site of damage prevents repair and blocks replication, leading to cell death. Therefore, drugs that trap PARP1/2 to the DNA tend to be significantly more cytotoxic than other PARP inhibitors, which is highly desirable. This study describes the design and optimization of novel PARPtrap assays to specifically assess the ability of a drug to trap PARP onto DNA. The assay is based on principles of fluorescence polarization and uses fluorescently labeled DNA probes that are excited by polarized light and emit light with a degree of polarization that is proportional to the rate of molecular rotation. The free DNA probes that rotate fast have low fluorescence polarization (FP), but high FP when are bound to PARP1 or PARP2. When NAD+ is added, the PARylated enzymes detach from the probe, reducing FP levels. If a PARP inhibitor is added, the inhibitor’s trapping ability increases FP in a dose-dependent manner. Proof-of-principle titration of known PARP-trapping inhibitors (Talazoparib, AZD305, Olaparib and Veliparib) was performed to validate the assay. We observed that: i)The known relative trapping efficacies of Talazoparib, Olaparib and Veliparib were similar to known relative efficacies. ii)Talazoparib, Olaparib and Veliparib had similar trapping efficacy against PARP1 and PARP2, as measured by their EC50, whereas AZD305 was 1,000 times more efficient at trapping PARP1 than it was PARP2, demonstrating selectivity between PARP1 and PARP2. iii)AZD305 displayed as efficient DNA trapping activity toward PARP1 as best-in-class Talazoparib. In summary, we have designed an innovative PARPtrap assay designed for the high throughput screening of small molecule libraries to specifically identify or compare inhibitors that are capable of trapping PARP1 and/or PARP2 onto DNA. Citation Format: Kasia Zientara-Rytter, Veronique T. Baron, Junguk Park, Pavel Shashkin, Henry Zhu. Design of a small molecule screening assay to detect DNA trapping of PARP1/2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6111.

IntroductionThe Dextroamphetamine Transdermal System (d-ATS) was developed as an alternative to oral amphetamine (AMP) formulations for ADHD. In a pivotal study, d-ATS met primary and secondary efficacy endpoints for ADHD in children and adolescents. Study subjects wore d-ATS for 9 hours, and an improvement in Swanson, Kotkin, Agler, M-Flynn, and Pelham scale (SKAMP) total score was observed from 2 through 12 hours after application. Patients with ADHD may need varying durations of treatment for symptoms from day to day. This analysis describes the exposure-response (E-R) relationship for d-ATS and explores possible outcomes for wear times ≤9 hours under varying assumptions.MethodsA population pharmacokinetic (PK) model was developed to describe AMP disposition following d-ATS administration. This model was used to construct a population pharmacokinetic/pharmacodynamic (PK/PD) model from SKAMP total score data from two pediatric clinical studies to characterize onset and duration of effect after d-ATS administration. The integrated PK/PD model was used to describe the d-ATS E-R relationship and simulate the potential onset and duration of effect of d-ATS in response to various removal times (when ResultsData from 81 children and 41 adolescents, 6–17 years old, were included. The model provided a reasonable description of the SKAMP score over time, showing an initial decline ~2 hours after patch application. In approximately 50% of children and adolescents, the maximum decline in SKAMP scores was observed within the first 4 hours after patch application. Earlier simulated d-ATS removal times were associated with reduced systemic exposure and earlier return to near-baseline scores across the range of assumptions tested.Under different assumptions, the graphs changed modestly but not dramatically. For example, with moderate/conservative assumptions, following a 9-hour wear time, SKAMP scores returned to within 90% of baseline value in ~49% of subjects by 12 hours and ~80% of subjects by 16 hours. Following a 4-hour wear time, percentages were ~74% by 12 hours and ~95% by 16 hours.ConclusionsSimulation results suggest that the duration of d-ATS efficacy may be related to wear time, which can be adjusted according to treatment needs, consistent with published observations for another transdermal stimulant. The d-ATS patch provides the ability to control medication exposure by shortening wear time, allowing treatment duration to be individualized and optimized in ADHD patients who have varying schedules and needs.FundingNoven Pharmaceuticals, Inc.

Received 12th May 2021. Accepted 17th May 2021. Published online 28th May 2021. Issue published 1st August 2021.

Summary Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. Interpretation Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. Funding The National Institute of Allergy and Infectious Diseases (USA).

Objectives To study the association of myocardial external efficiency (MEE) in mitral regurgitation (MR) towards routinely used quantitative indicators of disease severity and progression. Background Quantitative assessment of LV function and regurgitation in asymptomatic severe primary MR is crucial for management. MEE is a load-independent indicator of mechano-energetic coupling and can be measured non-invasively using 11C-acetate positron emission tomography (PET). The role of MEE in this setting has not been studied. Methods 48 asymptomatic patients with severe primary mitral regurgitation underwent PET, echo, and CMR on the same day. MEE was automatically derived from PET as the ratio of cardiac work (cardiac output * mean arterial pressure) and total left ventricular (LV) oxygen consumption (mean MVO2 * LV mass). LV function and mitral regurgitant volumes (RegVol) were measured by echo and CMR. MEE in MR was compared to healthy volunteers (n=9). MEE and parameters of regurgitation severity and of LV volumes and function were studied as predictors of outcome (valve surgery or death). Results MEE was reduced in MR (21.5±4.2%) vs healthy volunteers (32.0±5.6%, p0.05). Prediction by MEE was not affected by age, sex or BMI. When categorically divided by the median MEE was a strong predictor in Kaplan-Meier analysis (log-rank p=0.0004, figure 1) and remained independently significant, compared to all other univariate predictors in bivariate Cox models. Conclusions This study suggests an important role of energetic insufficiency in progression of asymptomatic severe primary MR. Reduced MEE was linked to outcome independently of standard functional measures of regurgitation severity or left ventricular size and function. Strategies for improvement of myocardial energetics in MR are warranted. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swedish Heart-Lung Foundation Figure 1

mrgsolve is an open‐source R package available on the Comprehensive R Archive Network. It combines R and C++ coding for simulation from hierarchical, ordinary differential equation–based models. Its efficient simulation engine and integration into a parallelizable, R‐based workflow makes mrgsolve a convenient tool both for simple and complex models and thus is ideal for physiologically‐based pharmacokinetic (PBPK) and quantitative systems pharmacology (QSP) model. This tutorial will first introduce the basics of the mrgsolve simulation workflow, including model specification, the introduction of interventions (dosing events) into the simulation, and simulated results postprocessing. An applied simulation example is then presented using a PBPK model for voriconazole, including a model validation step against adult and pediatric data sets. A final simulation example is then presented using a previously published QSP model for mitogen‐activated protein kinase signaling in colorectal cancer, illustrating population simulation of different combination therapies.

Introduction Sexual dysfunction is a common toxicity and detrimental for the quality of life of women treated with chemoradiotherapy for anal cancer. Sexual dysfunction occurs because the vagina is closely approximated to the anal canal and typically receives substantial doses of radiation. Strategies for mitigation have largely been focused on posttreatment therapy and symptom management. The use of daily vaginal dilator placement during radiotherapy to mitigate dose to the vagina has been previously explored with modest gains, while proton therapy is under active investigation for the treatment of anal cancer. Use of proton therapy for anal cancer reduces dose to some organs at risk but may inadvertently increase vaginal toxicity if the proton beam terminates in the vaginal tissue. Herein, we present the case histories of 2 women treated for squamous cell carcinoma of the anal canal with the novel combination of intensity-modulated proton therapy and daily vaginal dilator placement to maximally reduce dose to the vagina and protect it from areas of increased energy deposition at the end of the proton range.

International audience

This paper provides an overview of the criminal justice system’s folk-psychological understanding of people and behavior. The attempt of this paper is to explore some of the complex literature focu...

Purpose Bone reconstruction after malignant tumour of the lower limbs is a challenge. Our aim was to investigate the results of bone lengthening and transport using the Fitbone motorized lengthening nail. Methods Eight patients were included. Two patients had had a tumour involving soft tissue only without bone resection. In six patients, the initial bone defect was 15.5 cm (8 to 24). The first step of reconstruction had consisted of temporary fixation and a cement spacer. The second step had consisted of bone grafting in five patients. One patient was managed with bone transport. Eventually, five patients had a limb-length discrepancy (LLD) managed with bone lengthening only. Two patients had a LLD and a nonunion managed with bone transport and lengthening. Mean age at bone lengthening was 15.2 years (11 to 19). Mean follow-up was 30.5 months (10 to 48). Results In all, 11 nails were implanted in eight patients (eight femurs, three tibias). Mean length gain per procedure was 54.5 mm (30 to 80). Mean healing index was 48.4 days per cm (22.6 to 85.7). The complication rate was 18%. In two cases we observed a loose locking screw, which was revised. In all cases the lengthening involved the short bone (femur or tibia). Mean Musculoskeletal Tumor Society (MSTS) score improved from 52.7 (16.6 to 73.3) to 79.9 (63.3 to 96.6). Conclusions Bone reconstruction using a motorized intramedullary nail stands as a safe and reliable alternative after malignant tumour. It allows biological reconstruction with satisfactory clinical and radiological outcome and low complication rate. Level of evidence III

Background SARS-CoV-2 monoclonal antibodies (SMA) have demonstrated efficacy in treatment of early, mild to moderate COVID-19 in patients at high risk for progression to severe COVID-19. We created an SMA infusion clinic at a large, urban academic medical center using both internal and community-based referral mechanisms to promote the equitable distribution of treatment. Methods Data were analyzed from clinic referrals from December 13, 2020 through April 20, 2021. Patient demographics, census-based area deprivation index (ADI) scores (scale of 1-10, with 1 representing least socioeconomic deprivation and 10 representing most), and relevant comorbidities were collected. Outcomes included days of symptoms until referral, patient receipt of SMA therapy after referral, adverse events, and ER visits and hospitalizations within 14 days of SMA administration. Association between demographic factors and relevant outcomes were determined using chi-square or Wilcoxon rank-sum tests as appropriate. Results 47/433 (11%) referred patients were ineligible based on inclusion and exclusion criteria. Of eligible patients, 310/386 (80%) received treatment; patients who did not receive treatment either declined (93%), could not be contacted (5%), no-showed (1%), or were admitted for hypoxia (1%). Of treated patients, only 3 (1%) had adverse reactions. Within 14 days of SMA administration, 28 (9%) patients visited the ER or were admitted for COVID-19. Black patients had a longer median duration of symptoms prior to referral compared to White patients (5 vs. 3 days, p < 0.01) (Figure 1). White patients were more likely to receive SMA after referral compared to Black patients (88% vs. 64%, p < 0.01), as were patients with ADI score 1-5 compared to those with ADI score 6-10 (88% vs. 70%, p < 0.01) (Figures 2 and 3). Black patients who received SMA had a higher rate of ER visits or admissions than White patients, although the difference was not statistically significant (14% vs. 7%, p = 0.10). Figure 1. Bar graph displaying number of patients per race (White, Black, or Other) by duration of symptoms prior to referral. Figure 2. Bar graph displaying number of patients who did and did not receive SMA by race Figure 3. Bar graph displaying number of patients who did and did not receive SMA by ADI. Conclusion Rate of adverse reactions and COVID-related ER visits or admissions were low in patients who received SMA. Despite efforts to promote the equitable distribution of treatment through multiple referral mechanisms, racial and socioeconomic disparities still exist. Disclosures All Authors: No reported disclosures

In this paper, we present a new generation of substrates which address the demand for versatile intermediate-to-large-band surface acoustic wave devices and provides a unique solution for temperature-stable filter with excellent spectral qualities. The Piezoelectric-On-Insulator (POI) layer structure provides a breakthrough solution for addressing modern filter challenges on an extended range of specification. An implementation example is presented for a GPS filter at 1.575 GHz exhibiting a TCF smaller than 10 ppm.K-1

ObjectivesThe psychological impact of the COVID-19 pandemic on doctors is a significant concern. Due to the emergence of multiple pandemic waves, longitudinal data on the impact of COVID-19 are vital to ensure an adequate psychological care response. The primary aim was to assess the prevalence and degree of psychological distress and trauma in frontline doctors during the acceleration, peak and deceleration of the COVID-19 first wave. Personal and professional factors associated with psychological distress are also reported.DesignA prospective online three-part longitudinal survey.SettingAcute hospitals in the UK and Ireland.ParticipantsFrontline doctors working in emergency medicine, anaesthetics and intensive care medicine during the first wave of the COVID-19 pandemic in March 2020.Primary outcome measuresPsychological distress and trauma measured using the General Health Questionnaire-12 and the Impact of Events-Revised.ResultsThe initial acceleration survey distributed across networks generated a sample of 5440 doctors. Peak and deceleration response rates from the original sample were 71.6% (n=3896) and 56.6% (n=3079), respectively. Prevalence of psychological distress was 44.7% (n=1334) during the acceleration, 36.9% (n=1098) at peak and 31.5% (n=918) at the deceleration phase. The prevalence of trauma was 23.7% (n=647) at peak and 17.7% (n=484) at deceleration. The prevalence of probable post-traumatic stress disorder was 12.6% (n=343) at peak and 10.1% (n=276) at deceleration. Worry of family infection due to clinical work was the factor most strongly associated with both distress (R2=0.06) and trauma (R2=0.10).ConclusionFindings reflect a pattern of elevated distress at acceleration and peak, with some natural recovery. It is essential that policymakers seek to prevent future adverse effects through (a) provision of vital equipment to mitigate physical and psychological harm, (b) increased awareness and recognition of signs of psychological distress and (c) the development of clear pathways to effective psychological care.Trial registration numberISRCTN10666798.

Introduction The aim of the analysis was to characterize the population pharmacokinetics (PKs) and exposure–response (E–R) for efficacy (fasting plasma glucose, glycated hemoglobin) and safety/tolerability [hypoglycemia, genital infections, urinary tract infection (UTI), and volume depletion] of the sodium glucose cotransporter 2 inhibitor, empagliflozin, in patients with type 2 diabetes mellitus. This study extends the findings of previous analyses which described the PK and pharmacodynamics (PD) using early clinical studies of up to 12 weeks in duration. Methods Population pharmacokinetic and E–R models were developed based on two Phase I, four Phase II, and four Phase III studies. Results Variability in empagliflozin exposure was primarily affected by estimated glomerular filtration rate (eGFR) (less than twofold increase in exposure in patients with severe renal impairment). Consistent with its mode of action, the efficacy of empagliflozin was increased with elevated baseline plasma glucose levels and attenuated with decreasing renal function, but was still maintained to nearly half the maximal effect with eGFR as low as 30 mL/min/1.73 m2. All other investigated covariates, including sex, body mass index, race, and age did not alter the PK or efficacy of empagliflozin to a clinically relevant extent. Compared with placebo, empagliflozin administration was associated with an exposure-independent increase in the incidence of genital infections and no significant change in the risk of UTI, hypoglycemia, or volume depletion. Conclusion Based on the results from the PK and E–R analysis, no dose adjustment is required for empagliflozin in the patient population for which the drug is approved. Funding Boehringer Ingelheim. Electronic supplementary material The online version of this article (doi:10.1007/s13300-016-0174-y) contains supplementary material, which is available to authorized users.

The goal of this work was to extend a mathematical, multiscale systems model of bone function, remodeling, and health in order to explore hypotheses related to therapeutic modulation of sclerostin and quantitatively describe purported osteocyte activity within bone remodeling events. A pharmacokinetic model with first-order absorption and dual elimination pathways was used to describe the kinetics of romosozumab, a monoclonal antibody (mAb) against sclerostin. To describe total circulating sclerostin, an extended indirect response model of inhibition of offset was developed. These models were subsequently linked to the systems model, with sclerostin signaling changes in resorption and formation through established osteocyte-mediated mechanisms. The model proposes relative contributions of the osteocyte to the RANKL pool, a major player in feedback signaling, and is used to explore hypotheses surrounding attenuation of anabolic activity after multiple doses of sclerostin mAbs, a phenomenon whose mechanism is poorly understood.

A novel semiparametric regression model is developed for evaluating the covariate-specific accuracy of a continuous medical test or biomarker. Ideally, studies designed to estimate or compare medical test accuracy will use a separate, flawless gold-standard procedure to determine the true disease status of sampled individuals. We treat this as a special case of the more complicated and increasingly common scenario in which disease status is unknown because a gold-standard procedure does not exist or is too costly or invasive for widespread use. To compensate for missing data on disease status, covariate information is used to discriminate between diseased and healthy units. We thus model the probability of disease as a function of 'disease covariates'. In addition, we model test/biomarker outcome data to depend on 'test covariates', which provides researchers the opportunity to quantify the impact of covariates on the accuracy of a medical test. We further model the distributions of test outcomes using flexible semiparametric classes. An important new theoretical result demonstrating model identifiability under mild conditions is presented. The modeling framework can be used to obtain inferences about covariate-specific test accuracy and the probability of disease based on subject-specific disease and test covariate information. The value of the model is illustrated using multiple simulation studies and data on the age-adjusted ability of soluble epidermal growth factor receptor - a ubiquitous serum protein - to serve as a biomarker of lung cancer in men. SAS code for fitting the model is provided. Copyright © 2015 John Wiley & Sons, Ltd.

Resume Introduction La sonde vesicale peut entrainer un syndrome d’inconfort (CRBD) dont le traitement repose sur les antimuscariniques. Le clonazepam est un myorelaxant ayant une action antimuscarinique. Le but de ce travail est de rechercher s’il existe des interventions pourvoyeuses de CRBD et d’evaluer l’efficacite du clonazepam. Methodes Cent patients operes necessitant une sonde vesicale ont ete evalues. Ont ete notes le sexe, l’âge, l’IMC, l’existence d’un diabete, l’intervention et la presence de CRBD evaluee a l’aide d’une EVA, le moment de survenue, la necessite de traiter par clonazepam et son efficacite. Une correlation entre les criteres preoperatoires, le type de chirurgie, la presence de CRBD et l’efficacite du traitement a ete recherchee. Resultats Il y avait 79 hommes et 21 femmes (âge 65,9 ans, IMC de 25,4). Douze patients etaient diabetiques. Trente-neuf interventions concernaient la prostate, 19 la vessie, 20 l’endo-urologie, 22 la chirurgie ouverte. Quarante patients ont eu un CRBD d’intensite 4,5, qui apparaissait 0,6 jours apres l’intervention. Il n’y avait aucune correlation entre la survenue de douleurs et les criteres preoperatoires, les douleurs etant favorisees par la resection de vessie et l’endo-urologie. Trente (75 %) des 40 patients ayant un CRBD ont ete traites avec succes par du clonazepam. Les resections de vessie etaient l’intervention la plus refractaire au traitement. Conclusion Les CBRD sont frequentes, surviennent precocement, particulierement en cas de resection de vessie. Le clonazepam est efficace dans 75 % des cas. La resection de vessie est l’intervention plus refractaire au traitement. Niveau de preuve 5.

Les plaies palmaires de la main et du poignet representent un motif frequent de consultation en service d’urgences. Ces plaies sont explorees au bloc operatoire dans une majorite de centres. L’objectif principal de notre etude etait d’evaluer prospectivement la correlation entre l’examen clinique aux urgences par un interne de chirurgie et les lesions tendineuses, vasculaires et nerveuses retrouvees en peroperatoire dans les plaies palmaires de la main et du poignet. Nous avons cherche egalement a decrire les lesions en fonction du mecanisme, ainsi que leur topographie. Quatre-vingt patients de deux centres referents en chirurgie de la main ont ete inclus. L’interrogatoire et l’examen physique du patient aux urgences etaient recueillis, ainsi que les lesions constatees en peroperatoire. Vingt-huit pour cent des plaies avec un examen clinique normal etaient associees a une lesion tendineuse ou vasculonerveuse. Un testing tendineux non deficitaire etait associe a une lesion partielle d’un tendon ou une ouverture du canal digital dans 16 % des cas et 12 % des lesions nerveuses n’avaient pas ete suspectees cliniquement. Nous recommandons que toute plaie palmaire de la main et du poignet soit exploree au bloc operatoire, l’examen clinique ne permettant pas d’affirmer l’absence de lesion tendineuse et vasculonerveuse.

Background Emergency Departments (EDs) are important sites for HIV testing. However, there is little guidance on how best to implement HIV testing in the ED. The purpose of this study was to evaluate HIV screening practices of high-risk individuals presenting to an ED in the absence (ED1) and in the presence (ED2) of an established HIV testing program within the same academic hospital. Methods We performed a retrospective chart review of all individuals 18 years or older presenting to either ED between January 1, 2016 and December 31, 2018. High-risk of HIV infection was determined by receipt of bacterial sexually transmitted infection (STI) testing for Neisseria gonorrhoeae or Chlamydia trachomatis. The primary outcome was receipt of any HIV test in the ED. Overall proportions of patients tested for HIV at the same time of STI testing were compared between sites by chi-square test. Predictors of HIV testing were analyzed by logistic regression. Results During the study period, 7,956 individuals received STI testing at ED1 and 10,815 received STI testing at ED2. The majority of individuals receiving STI testing at both sites were female, 81.2% at ED1 and 66.4% at ED2 (P Conclusion Overall, the presence of an HIV testing program in the ED significantly increased the probability that individuals would receive an HIV test at the time of bacterial STI testing and mitigated disparities in care. The results of this study will help guide ongoing interventions to improve HIV screening among high-risk individuals in the emergency department. Disclosures All authors: No reported disclosures.