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JAMA Ophthalmology Feb 2023Tumor necrosis factor inhibitors (TNFis) can induce antidrug antibody (ADA) formation and loss of therapeutic response. However, the utility of ADA testing and the...
IMPORTANCE
Tumor necrosis factor inhibitors (TNFis) can induce antidrug antibody (ADA) formation and loss of therapeutic response. However, the utility of ADA testing and the association between ADAs and treatment response in patients with noninfectious uveitis (NIU) is not well understood.
OBJECTIVE
To assess the frequency of ADAs and their association with drug levels and clinical response in patients with NIU treated with adalimumab or infliximab.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cross-sectional study included patients diagnosed with NIU who received adalimumab or infliximab and underwent testing for serum drug level and ADAs at the National Eye Institute from September 2017 to July 2021.
EXPOSURES
Serum drug level testing with reflex testing for ADA levels was performed.
MAIN OUTCOMES AND MEASURES
The main outcome was the association between drug levels and ADAs, clinical response, and concurrent antimetabolite use in patients treated with TNFis for NIU.
RESULTS
Of 54 patients included in the study, 42 received adalimumab (mean [SD] age, 43.6 [19.6] years; 25 [59.5%] female) and 12 received infliximab (mean [SD] age, 42.7 [20.4] years; 7 [58.3%] male). In the adalimumab group, mean (SD) drug level was 9.72 (6.82) μg/mL, mean (SD) ADA level was 84.2 (172.9) arbitrary units/mL, and ADA frequency was 35.7% (15 of 42 patients). Mean drug level was lower in those with ADAs compared with those without ADAs (mean [SD], 2.8 [2.6] μg/mL vs 13.6 [5.2] μg/mL; difference: 10.8 μg/mL; 95% CI, 8.3-13.2 μg/mL; P < .001). There was a higher mean drug level with concurrent antimetabolite use compared with monotherapy (mean [SD], 11.0 [7.3] μg/mL vs 6.8 [4.5] μg/mL; difference: -4.2 μg/mL; 95% CI, -8.7 to 0.2 μg/mL; P = .06). Multivariable modeling showed that a 1-arbitrary unit increase in ADAs was associated with a -0.02 μg/mL (95% CI, -0.01 to -0.34 μg/mL) difference in mean drug level (P < .001). Favorable clinical response was associated with a threshold drug level above 2.7 μg/mL or an antibody level below 15.2 μg/mL. The mean (SD) drug level in the infliximab group was 27.02 (18.15) μg/mL, and no ADAs were detected.
CONCLUSIONS AND RELEVANCE
In this study, 35.7% of adalimumab-treated patients with NIU had ADAs. The presence of ADAs was associated with lower drug levels, and higher ADA levels were associated with increased risk of TNFi treatment failure. Although limited by the retrospective design, our results suggest that therapeutic drug monitoring may be considered among patients experiencing therapy failure to help exclude ADAs as a potential cause of treatment failure.
Topics: Humans; Male; Female; Adult; Infliximab; Adalimumab; Tumor Necrosis Factor-alpha; Retrospective Studies; Drug Monitoring; Cross-Sectional Studies; Antibodies; Immunologic Factors; Immunosuppressive Agents; Uveitis; Antimetabolites
PubMed: 36547953
DOI: 10.1001/jamaophthalmol.2022.5584 -
Optics Express May 2018Metasurfaces provide an alternative way to design three-dimensional arbitrary-shaped carpet cloaks with ultrathin thicknesses. Nevertheless, the previous metasurface...
Metasurfaces provide an alternative way to design three-dimensional arbitrary-shaped carpet cloaks with ultrathin thicknesses. Nevertheless, the previous metasurface carpet cloaks work only at a single frequency. To overcome this challenge, we here propose a macroscopic metasurface carpet cloak. The cloak is designed with a metasurface of a few layers that exhibit a special spatial distribution of the conductance and inductance in the unit cell; therefore, it can fully control the reflection phases at several independent frequencies simultaneously. Because of this, the present metasurface cloak can work at dual frequencies based on multi-resonance principle. The proposed design methodology will be very useful in future broadband macroscopic cloaks design with low profiles, light weights, and easy access.
PubMed: 29877455
DOI: 10.1364/OE.26.014123 -
Hippocampus Jul 2020The encoding of information in spike phase relative to local field potential (LFP) oscillations offers several theoretical advantages over equivalent firing rate codes....
The encoding of information in spike phase relative to local field potential (LFP) oscillations offers several theoretical advantages over equivalent firing rate codes. One notable example is provided by place and grid cells in the rodent hippocampal formation, which exhibit phase precession-firing at progressively earlier phases of the 6-12 Hz movement-related theta rhythm as their spatial firing fields are traversed. It is often assumed that such phase coding relies on a high amplitude baseline oscillation with relatively constant frequency. However, sustained oscillations with fixed frequency are generally absent in LFP and spike train recordings from the human brain. Hence, we examine phase coding relative to LFP signals with broadband low-frequency (2-20 Hz) power but without regular rhythmicity. We simulate a population of grid cells that exhibit phase precession against a baseline oscillation recorded from depth electrodes in human hippocampus. We show that this allows grid cell firing patterns to multiplex information about location, running speed and movement direction, alongside an arbitrary fourth variable encoded in LFP frequency. This is of particular importance given recent demonstrations that movement direction, which is essential for path integration, cannot be recovered from head direction cell firing rates. In addition, we investigate how firing phase might reduce errors in decoded location, including those arising from differences in firing rate across grid fields. Finally, we describe analytical methods that can identify phase coding in the absence of high amplitude LFP oscillations with approximately constant frequency, as in single unit recordings from the human brain and consistent with recent data from the flying bat. We note that these methods could also be used to detect phase coding outside of the spatial domain, and that multi-unit activity can substitute for the LFP signal. In summary, we demonstrate that the computational advantages offered by phase coding are not contingent on, and can be detected without, regular rhythmicity in neural activity.
Topics: Action Potentials; Grid Cells; Hippocampus; Humans; Periodicity
PubMed: 32065488
DOI: 10.1002/hipo.23199 -
Andrology Nov 2016The discontinuation rate with phosphodiesterase type 5 inhibitors (PDE5i) remains very high. The aim of this study was to review and meta-analyze currently available... (Meta-Analysis)
Meta-Analysis Review
The discontinuation rate with phosphodiesterase type 5 inhibitors (PDE5i) remains very high. The aim of this study was to review and meta-analyze currently available data regarding dropout of the first-generation of PDE5i including sildenafil, vardenafil, and tadalafil. An extensive Medline Embase and Cochrane search was performed including the following words: 'PDE5i', 'discontinuation'. All observational studies reporting the dropout rate of PDE5i and its specific causes without any arbitrary restrictions were included. Out of 103 retrieved articles, 22 were included in the study. Retrieved trials included a total of 162,936 patients with a mean age of 58.8 ± 7.9 years. Prevalence of reported comorbid diabetes and hypertension were 27.7% and 36.9%, respectively. PDE5i were associated with a mean discontinuation rate of 4% per month (almost 50% after one year). This rate was higher in younger subjects and in those reporting a higher prevalence of associated morbidities. Six main reasons of PDE5i dropout were identified in the evaluated trials. Partner-related problems and lack of efficacy represented the most important reasons for PDE5i discontinuation, although no significant difference among factors was detected. In conclusion, despite their high efficacy and easy administration, the discontinuation rate and dissatisfaction with PDE5i are still very high. Our data showed that no single factor plays a major role in PDE5i dropout, suggesting that the discontinuation rate is usually because of a combination of both medical problems and psychosocial and relational factors.
Topics: Erectile Dysfunction; Humans; Male; Patient Dropouts; Patient Satisfaction; Phosphodiesterase 5 Inhibitors; Treatment Failure
PubMed: 27636710
DOI: 10.1111/andr.12255 -
Critical Care (London, England) 2007Withdrawal and limitation of life support in the intensive care unit is common, although how this decision is reached can be varied and arbitrary. Inevitably, the... (Review)
Review
Withdrawal and limitation of life support in the intensive care unit is common, although how this decision is reached can be varied and arbitrary. Inevitably, the patient is unable to participate in this discussion because their capacity is limited by the nature of the illness and the effects of its treatment. Physicians often discuss these decisions with relatives in an attempt to respect the patient's wishes despite evidence suggesting that the relatives may not correctly reflect the patient's desires. Advance decisions, commonly known as 'living wills', have been proposed as a way of facilitating the maintenance of an individual's autonomy when they become incapacitated. Others have argued that legalising advance decisions is euthanasia by the back door. In October 2007 in England and Wales, advance decisions will become legally binding as part of the 2005 Mental Capacity Act. This has been the case in the USA for many years. The purpose of the present review is to examine the published literature regarding the effect of advance decisions in relation to the provision of adult critical care.
Topics: Advance Directives; Aged; Critical Care; Health Care Costs; Humans; Intensive Care Units; Quality of Life; Suicide, Assisted; Terminal Care; United States
PubMed: 17634087
DOI: 10.1186/cc5945 -
Biology of Sport Jul 2023The aims of this scoping review were (i) to characterize the main methodological approaches to assessing individualized running speed thresholds in team sports players;... (Review)
Review
The aims of this scoping review were (i) to characterize the main methodological approaches to assessing individualized running speed thresholds in team sports players; (ii) to assess the use of traditional arbitrary (absolute) thresholds compared to individualized running speed thresholds in team sports players; (iii) to provide an evidence gap map (EGM) about the approaches and study designs employed in investigations in team sports and (iv) to provide directions for future research and practical applications for the strength and conditioning field. Methods studies were searched for in the following databases: (i) PubMed; (ii) Scopus; (iii) SPORTDiscus and (iv) Web of Science. The search was conducted on 15/07/2022. Risk of bias was assessed using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). From 3,195 potentially relevant articles, 36 were eligible for inclusion in this review. Of the 36 included articles, 27 (75%) focused on the use of arbitrary and individualized running speed thresholds to describe the locomotor demands (e.g., high intensity running) of players. Thirty-four articles used individualized speed running thresholds based on physical fitness assessments (e.g., 40-m linear sprint) or physical performance (e.g., maximal acceleration). This scoping review supported the need for a greater focus to be placed on improving the methodological aspects of using individualized speed running thresholds in team sports. More than just creating alternatives to arbitrary thresholds, it is essential to increase the replicability of methodological conditions whilst ensuring that research comparing the most adequate measures and approaches to individualization takes into consideration the population and context of each study.
PubMed: 37398971
DOI: 10.5114/biolsport.2023.122480 -
Trends in Hearing Feb 2016The speech-to-noise ratio (SNR) in an environment plays a vital role in speech communication for both normal-hearing (NH) and hearing-impaired (HI) listeners. While...
The speech-to-noise ratio (SNR) in an environment plays a vital role in speech communication for both normal-hearing (NH) and hearing-impaired (HI) listeners. While hearing-assistance devices attempt to deliver as favorable an SNR as possible, there may be discrepancies between noticeable and meaningful improvements in SNR. Furthermore, it is not clear how much of an SNR improvement is necessary to induce intervention-seeking behavior. Here, we report on a series of experiments examining the just-meaningful difference (JMD) in SNR. All experiments used sentences in same-spectrum noise, with two intervals on each trial mimicking examples of pre- and post-benefit situations. Different groups of NH and HI adults were asked (a) to rate how much better or worse the change in SNR was in a number of paired examples, (b) if they would swap the worse for the better SNR (e.g., their current device for another), or (c) if they would be willing to go to the clinic for the given increase in SNR. The mean SNR JMD based on better or worse ratings (one arbitrary unit) was similar to the just-noticeable difference, approximately 3 dB. However, the mean SNR JMD for the more clinically relevant tasks-willingness (at least 50% of the time) to swap devices or attend the clinic for a change in SNR--was 6 to 8 dB regardless of hearing ability. This SNR JMD of the order of 6 dB provides a new benchmark, indicating the SNR improvement necessary to immediately motivate participants to seek intervention.
Topics: Acoustic Stimulation; Acoustics; Adult; Audiometry, Pure-Tone; Audiometry, Speech; Auditory Threshold; Case-Control Studies; Comprehension; Female; Hearing Aids; Hearing Disorders; Humans; Judgment; Male; Middle Aged; Noise; Patient Acceptance of Health Care; Perceptual Masking; Persons With Hearing Impairments; Signal Detection, Psychological; Signal Processing, Computer-Assisted; Signal-To-Noise Ratio; Speech Intelligibility; Speech Perception; Young Adult
PubMed: 26834121
DOI: 10.1177/2331216515626570 -
Minerva Anestesiologica Feb 2020This review aimed at summarizing the available evidence on liver transplantation from uncontrolled donation after circulatory death (uDCD) on differences in protocols,... (Review)
Review
This review aimed at summarizing the available evidence on liver transplantation from uncontrolled donation after circulatory death (uDCD) on differences in protocols, donor management, in and ex vivo perfusion techniques from center to center. Uncontrolled DCDs represent a unique, complex model of ischemia-reperfusion injury, so far not completely understood. Nevertheless, results on liver transplantation from uDCDs are promising in terms of long-term graft survival. True difficulties still remain since common/shared protocols are not achievable due to legal differences between countries (i.e. no touch period duration). To date, there is no reliable metrics to determine whether a liver is safe to be ex situ perfused or to be transplanted since existing criteria, as stated by investigators themselves, are so far arbitrary. Values and kinetics of transaminanes during normothermic regional perfusion (nRP) should not considered absolute contraindication at least for ex vivo perfusion. Intraoperative evaluation at organ recovery remains pivotal since macroscopic alterations (i.e. hepatic rupture, an abnormal appearance of gall bladder and choledocus) still represent contraindications for organ retrieval. Concerning ex vivo perfusion, the debate is still open, since the choice of type of machine perfusion (mainly hypothermic vs. normothermic) varies from center to center, mainly relying to the single center experience (especially in controlled DCD), surgeons' believes and/or criteria translated from animal models.
Topics: Death; Graft Survival; Humans; Ischemia; Liver Circulation; Liver Transplantation; Organ Preservation; Shock; Tissue Donors
PubMed: 31334618
DOI: 10.23736/S0375-9393.19.13746-7 -
Advances in Neural Information... Nov 2022Training with backpropagation (BP) in standard deep learning consists of two main steps: a forward pass that maps a data point to its prediction, and a backward pass...
Training with backpropagation (BP) in standard deep learning consists of two main steps: a forward pass that maps a data point to its prediction, and a backward pass that propagates the error of this prediction back through the network. This process is highly effective when the goal is to minimize a specific objective function. However, it does not allow training on networks with cyclic or backward connections. This is an obstacle to reaching brain-like capabilities, as the highly complex heterarchical structure of the neural connections in the neocortex are potentially fundamental for its effectiveness. In this paper, we show how predictive coding (PC), a theory of information processing in the cortex, can be used to perform inference and learning on arbitrary graph topologies. We experimentally show how this formulation, called , can be used to flexibly perform different tasks with the same network by simply stimulating specific neurons. This enables the model to be queried on stimuli with different structures, such as partial images, images with labels, or images without labels. We conclude by investigating how the topology of the graph influences the final performance, and comparing against simple baselines trained with BP.
PubMed: 37090087
DOI: No ID Found -
Journal of the American Statistical... Jun 2019Panel data, also known as longitudinal data, consist of a collection of time series. Each time series, which could itself be multivariate, comprises a sequence of...
Panel data, also known as longitudinal data, consist of a collection of time series. Each time series, which could itself be multivariate, comprises a sequence of measurements taken on a distinct unit. Mechanistic modeling involves writing down scientifically motivated equations describing the collection of dynamic systems giving rise to the observations on each unit. A defining characteristic of panel systems is that the dynamic interaction between units should be negligible. Panel models therefore consist of a collection of independent stochastic processes, generally linked through shared parameters while also having unit-specific parameters. To give the scientist flexibility in model specification, we are motivated to develop a framework for inference on panel data permitting the consideration of arbitrary nonlinear, partially observed panel models. We build on iterated filtering techniques that provide likelihood-based inference on nonlinear partially observed Markov process models for time series data. Our methodology depends on the latent Markov process only through simulation; this plug-and-play property ensures applicability to a large class of models. We demonstrate our methodology on a toy example and two epidemiological case studies. We address inferential and computational issues arising due to the combination of model complexity and dataset size. Supplementary materials for this article are available online.
PubMed: 32905476
DOI: 10.1080/01621459.2019.1604367