Pharmacokinetic-pharmacodynamic modelling and simulation of methotrexate dosing in patients with rheumatoid arthritis.

AIMS: To develop a non-linear mixed-effects population pharmacokinetic and pharmacodynamic (PK-PD) model describing the change in the concentration of methotrexate polyglutamates in erythrocytes (ery-MTX-PGn with "n" number of glutamate, representing PK component) and how this relates to modified 28-joint Disease Activity Score incorporating erythrocyte sedimentation rate (DAS-28-3) for rheumatoid arthritis (RA), representing PD component. METHODS: An existing PK model was fitted to data from a study consisting of 117 RA patients. The estimation of population PK-PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2 weeks, then 20mg weekly oral methotrexate). RESULTS: Every 40 nmol/L increase in ery-MTX-PG3-5 total concentration correlated with 1-unit reduction in DAS-28-3. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS-28-3 when other variables were constant) and patient age (every 10-year increase in age correlated with 3.4% increase in DAS-28-3 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%). CONCLUSIONS: A loading dose regimen was more likely to achieve higher ery-MTX-PG concentration and better therapeutic response after 4 weeks of methotrexate treatment.

Spatial localization of hippocampal replay requires dopamine signaling.

Sequenced reactivations of hippocampal neurons called replays, concomitant with sharp-wave ripples in the local field potential, are critical for the consolidation of episodic memory, but whether replays depend on the brain's reward or novelty signals is unknown. Here we combined chemogenetic silencing of dopamine neurons in ventral tegmental area (VTA) and simultaneous electrophysiological recordings in dorsal hippocampal CA1, in freely behaving rats experiencing changes to reward magnitude and environmental novelty. Surprisingly, VTA silencing did not prevent ripple increases where reward was increased, but caused dramatic, aberrant ripple increases where reward was unchanged. These increases were associated with increased reverse-ordered replays. On familiar tracks this effect disappeared, and ripples tracked reward prediction error, indicating that non-VTA reward signals were sufficient to direct replay. Our results reveal a novel dependence of hippocampal replay on dopamine, and a role for a VTA-independent reward prediction error signal that is reliable only in familiar environments.

Where does the carbon go? Long-term effects of forest management on the carbon budget of a temperate-forest water-supply watershed.

While forest management commonly seeks to increase carbon (C) capture and sequestration, in some settings, a high density of C storage may be detrimental to other land uses and ecosystem services. We study a forested, drinking-water-supply watershed to determine the effects of forest management on C storage with the implicit understanding that greater storage of C will lead to increased quantity of carbon exported hydrologically into a source-water reservoir. Using a custom implementation of CBM-CFS3, a Canadian model to simulate C transformations and movement in forested systems, and a custom forest disturbance and management model, we simulate various management scenarios and their C outcomes. The largest forest C pool, mineral soils, is very slow to change and manipulating DOC export through this pool would likely not be feasible within human management timescales. Other pools, in which C has lower residence time and from which C is more readily mobilized, are a more promising area for future research into hydrologic DOC export under varying management regimes. Our findings indicate that management activities can serve to reduce forest C storage, but further research is required to connect these outcomes to hydrologic export.

Misidentifying illuminant changes in natural scenes due to failures in relational colour constancy.

The colours of surfaces in a scene may not appear constant with a change in the colour of the illumination. Yet even when colour constancy fails, human observers can usually discriminate changes in lighting from changes in surface reflecting properties. This operational ability has been attributed to the constancy of perceived colour relations between surfaces under illuminant changes, in turn based on approximately invariant spatial ratios of cone photoreceptor excitations. Natural deviations in these ratios may, however, lead to illuminant changes being misidentified. The aim of this work was to test whether such misidentifications occur with natural scenes and whether they are due to failures in relational colour constancy. Pairs of scene images from hyperspectral data were presented side-by-side on a computer-controlled display. On one side, the scene underwent illuminant changes and on the other side, it underwent the same changes but with images corrected for any residual deviations in spatial ratios. Observers systematically misidentified the corrected images as being due to illuminant changes. The frequency of errors increased with the size of the deviations, which were closely correlated with the estimated failures in relational colour constancy.

Little information loss with red-green color deficient vision in natural environments.

Inherited color vision deficiency affects red-green discrimination in about one in twelve men from European populations. Its effects have been studied mainly in primitive foraging but also in detecting blushing and breaking camouflage. Yet there is no obvious relationship between these specific tasks and vision in the real world. The aim here was to quantify the impact of color vision deficiency by estimating computationally the information available to observers about colored surfaces in natural scenes. With representative independent sets of 50 and 100 hyperspectral images, estimated information was found to be only a little less in red-green color vision deficiency than in normal trichromacy. Colorimetric analyses revealed the importance of large lightness variations within scenes, small redness-greenness variations, and uneven frequencies of different colored surfaces. While red-green color vision deficiency poses challenges in some tasks, it has much less effect on gaining information from natural environments.

Evaluation of Three Methods of Sensory Function Testing for the Assessment of Successful Maxillary Nerve Blockade in Horses.

Maxillary nerve blocks (MNBs) commonly facilitate dental surgeries in standing horses. The goal of this prospective, blinded, cross-over design trial including 15 client-owned horses was to evaluate 3 methods of sensory function testing for confirming a successful MNB. Testing was performed bilaterally before sedation, 5 min after sedation, and 15 and 30 min after MNB with 0.5% bupivacaine and involved a needle prick dorsal to each naris, hemostat clamping of each nostril, and gingival algometry (measuring sensitivity to pain). Responses to stimulation were numerically scored and scores were summed up to a total score. Total score increases on the blocked side by ≥ 2 between baseline and 30 min Post MNB recordings signified a successful MNB. Sedation in the preceding 6 h, presence of sino-nasal disease, side of dental pathology, age, butorphanol administration, and detomidine dosing (µg/kg/min) throughout the tooth extraction procedure were recorded. In 73% of horses, MNB was successful. Sedation in the preceding 6 h (P = .732), age (P = .936), side of pathology (P = .516), and sino-nasal disease (P = .769) were not associated with total scores. Detomidine dosage and butorphanol use did not differ between horses in which the MNB was considered successful and for those in which it was not (P = .967 and P = .538, respectively). Scores obtained with gingival algometry were less closely associated with total scores (rho = .649) than those obtained with needle prick and nostril clamping (rho = .819 and .892, respectively). Therefore, needle prick and nostril clamping are considered the more reliable methods for use in clinical practice to determine the success of an MNB.

Regulation of mTOR by phosphatidic acid.

mTORC1, the mammalian target of rapamycin complex 1, is a key regulator of cellular physiology. The lipid metabolite phosphatidic acid (PA) binds to and activates mTORC1 in response to nutrients and growth factors. We review structural findings and propose a model for PA activation of mTORC1. PA binds to a highly conserved sequence in the α4 helix of the FK506 binding protein 12 (FKBP12)/rapamycin-binding (FRB) domain of mTOR. It is proposed that PA binding to two adjacent positively charged amino acids breaks and shortens the C-terminal region of helix α4. This has profound consequences for both substrate binding and the catalytic activity of mTORC1.

Efficient quantization of painting images by relevant colors.

Realistic images often contain complex variations in color, which can make economical descriptions difficult. Yet human observers can readily reduce the number of colors in paintings to a small proportion they judge as relevant. These relevant colors provide a way to simplify images by effectively quantizing them. The aim here was to estimate the information captured by this process and to compare it with algorithmic estimates of the maximum information possible by colorimetric and general optimization methods. The images tested were of 20 conventionally representational paintings. Information was quantified by Shannon's mutual information. It was found that the estimated mutual information in observers' choices reached about 90% of the algorithmic maxima. For comparison, JPEG compression delivered somewhat less. Observers seem to be efficient at effectively quantizing colored images, an ability that may have applications in the real world.

Core outcome domains for lichen sclerosus: a CORALS initiative consensus statement.

BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory condition mainly affecting genital skin. It causes distressing symptoms that impact daily quality of life (QoL). It causes progressive anatomical changes and a potential risk of cancer. Published randomized controlled trials are of varying methodological quality and difficult to combine in meta-analyses. This is partly due to lack of agreed outcome measures to assess treatment response. Identification of core outcome sets (COSs), which standardize key outcomes to be measured in all future trials, is a solution to this problem. OBJECTIVES: To obtain international agreement on which outcome domains should be measured in interventional trials of genital LS. METHODS: Recommended best practice for COS domain development was followed: (i) identification of potential outcome domains: a long list was generated through an up-to-date LS literature search, including information collected during the LS priority-setting partnership; (ii) provisional agreement of outcome domains: a three-stage multi-stakeholder international electronic-Delphi (e-Delphi) consensus study; (iii) final agreement of outcome domains: online consensus meeting with international stakeholders including anonymized voting. RESULTS: In total, 123 participants (77 patients, 44 health professionals, 2 researchers) from 20 countries completed three rounds of the e-Delphi study. Eleven outcome domains were rated as 'critical' and were discussed at the online consensus meetings. The first set of consensus meetings involved 42 participants from 12 countries. Consensus was met for 'symptoms' (100% agreed) and 'QoL - LS-specific' (92% agreed). After the second set of meetings, involving 29 participants from 12 countries, 'clinical (visible) signs' also met consensus (97% agreed). CONCLUSIONS: The international community has agreed on three key outcome domains to measure in all future LS clinical trials. We recommend that trialists and systematic reviewers incorporate these domains into study protocols with immediate effect. CORALS will now work with stakeholders to select an outcome measurement instrument per prioritized core domain.

Women's Experience of Living with Vulvodynia Pain: Why They Participated in a Randomized Controlled Trial of Acupuncture.

Introduction: Vulvodynia is vulvar pain lasting at least 3-months without clear identifiable cause that may have other associated factors. The aim, to explore motivations of women participating in a double-blind randomized controlled trial of acupuncture for vulvodynia. Methods: Responses to the question: "Tell me about why you decided to participate in this study" were analyzed using conceptual content analysis to identify patterns in motivation for study participation. Results: Four patterns emerged: 1) desire to address uncontrolled pain, 2) desire for understanding, 3) wish to contribute to knowledge generation, and 4) need to remove cost barriers. Conclusion: Motivations indicate vulvodynia-specific aspects of acceptability of acupuncture. Clinical Trial Registration: NCT03364127.

A Health System's Approach to Using CBPR Principles with Multi-sector Collaboration to Design and Implement a COVID-19 Vaccine Outreach Program.

The COVID-19 pandemic required collaboration to address vaccine hesitancy in populations of color. A large not-for-profit health system collaborated with a philanthropic organization and a technology company, using principles of community-based participatory research, to develop an outreach program aimed at increasing access to COVID-19 vaccines in two geographically distinct locations.

Protocol for double-blind RCT of acupuncture for vulvodynia.

Background: Vulvodynia, vulvar pain of unknown origin lasting at least 3 months, affects 7% of American women. Dyspareunia, its frequent companion, renders sexual intercourse virtually impossible. Although few therapies are efficacious and rapid pain relief is rarely possible, there have been no sham/placebo-controlled studies of acupuncture for vulvodynia. Aims are to: 1) determine efficacy of acupuncture for vulvodynia, 2) explore duration of the acupuncture effect. Methods: In a pretest/posttest randomized controlled, double-blind (practitioner-patient) efficacy trial of a standardized acupuncture protocol, we will randomize 80 participants 1:1 to either penetrating needle or skin-touch placebo needle groups. Both types of needles are designed to blind both the acupuncturist and participant. Participants with vulvodynia will insert and remove a tampon as a standardized stimulus and complete primary measures of vulvar pain (pain intensity) and secondary measures of dyspareunia (Female Sexual Function Index, FSFI dyspareunia subscale score) and sexual function (FSFI total score) pretreatment, after the 10th acupuncture session, and pain measures weekly until return to pretest levels. Upon study completion control group participants will be offered 10 free real acupuncture sessions. Discussion: This is the first multi-needle multi-session RCT using double-blind acupuncture needles as a reliable sham. We hypothesize that controlling for baseline, at posttest there will be statistically significant less vulvar pain and dyspareunia and more sexual function over five weeks in the penetrating needle group compared to the skin touch placebo group. Conclusion: This study is responsive to the need for efficacious pain management for women with vulvodynia.ClinicalTrials.gov Identifier: NCT03364127.

Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.

Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid-a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt-a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase-indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas.

Information gains from commercial spectral filters in anomalous trichromacy.

Red-green color discrimination is compromised in anomalous trichromacy, the most common inherited color vision deficiency. This computational analysis tested whether three commercial optical filters with medium-to-long-wavelength stop bands increased information about colored surfaces. The surfaces were sampled from 50 hyperspectral images of outdoor scenes. At best, potential gains in the effective number of surfaces discriminable solely by color reached 9% in protanomaly and 15% in deuteranomaly, much less than with normal trichromacy. Gains were still less with lower scene illumination and more severe color vision deficiency. Stop-band filters may offer little improvement in objective real-world color discrimination.

A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations.

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.

Development and validation of a measure to assess patients' perceptions of their safety in an acute hospital setting.

BACKGROUND: Safety measurement tools have traditionally examined safety climate and culture from the perspective of healthcare professionals. A small number of studies have used tools to measure patients' perceptions of safety. AIM: To develop and check the validity of a questionnaire, the King's Patient Safety Measure (KPSM), that assesses how patients perceive their safety when receiving acute care. DISCUSSION: A cross-sectional survey of 158 patients was undertaken that was constructed to establish the validity and reliability of a 13-item questionnaire. A general linear model statistically tested how patients perceived the safety of their care and whether those views were associated with covariates that included characteristics such as age, gender, ethnic identity, socio-economic factors, how long they stayed in hospital and the way they were admitted to hospital. CONCLUSION: The KPSM is a validated tool consisting of a single factor that is internally consistent. IMPLICATIONS FOR PRACTICE: The KPSM is appropriate for and potentially applicable to a diverse range of patients and could act as an early warning tool.

Your best day: An interactive app to translate how time reallocations within a 24-hour day are associated with health measures.

Reallocations of time between daily activities such as sleep, sedentary behavior and physical activity are differentially associated with markers of physical, mental and social health. An individual's most desirable allocation of time may differ depending on which outcomes they value most, with these outcomes potentially competing with each other for reallocations. We aimed to develop an interactive app that translates how self-selected time reallocations are associated with multiple health measures. We used data from the Australian Child Health CheckPoint study (n = 1685, 48% female, 11-12 y), with time spent in daily activities derived from a validated 24-h recall instrument, %body fat from bioelectric impedance, psychosocial health from the Pediatric Quality of Life Inventory and academic performance (writing) from national standardized tests. We created a user-interface to the compositional isotemporal substitution model with interactive sliders that can be manipulated to self-select time reallocations between activities. The time-use composition was significantly associated with body fat percentage (F = 2.66, P < .001), psychosocial health (F = 4.02, P < .001), and academic performance (F = 2.76, P < .001). Dragging the sliders on the app shows how self-selected time reallocations are associated with the health measures. For example, reallocating 60 minutes from screen time to physical activity was associated with -0.8 [95% CI -1.0 to -0.5] %body fat, +1.9 [1.4 to 2.5] psychosocial score and +4.5 [1.8 to 7.2] academic performance. Our app allows the health associations of time reallocations to be compared against each other. Interactive interfaces provide flexibility in selecting which time reallocations to investigate, and may transform how research findings are disseminated.

The association of depression and anxiety with treatment outcomes in patients with rheumatoid arthritis - a pooled analysis of five randomised controlled trials.

Background: Rheumatoid arthritis (RA) is an inflammatory autoimmune condition associated with an increased risk of developing depression and anxiety. Depression and anxiety are associated with worse outcomes in RA, but the magnitude of the effect of each condition on RA outcomes is unclear. It is also unknown how pharmacological treatment of depression affects RA outcomes. Objective: The primary aim of this study was to investigate the association of comorbid depression and anxiety with remission in patients with RA. Secondary aims were to determine the association between comorbid depression and anxiety on patient-reported outcomes and the relationship between concomitant use of antidepressants and remission in patients with depression. Design: Data from patients with moderate to severe RA were pooled from five randomised controlled trials investigating tocilizumab and conventional synthetic disease-modifying agents. Methods: Remission was defined as a clinical disease activity index (CDAI) of ⩽2.8 and simple disease activity index (SDAI) of ⩽3.3. The association between the time to reach remission and depression and anxiety was analysed using Cox proportional hazard analysis. Results: Individual patient data were available from 5502 subjects, of whom 511 had depression, 236 had anxiety and 387 were using antidepressants. Depression was significantly associated with reduced remission [adjusted HR (95% CI): 0.62 (0.48-0.80), p < 0.001 and adjusted HR (95% CI): 0.59 (0.44-0.79), p < 0.001] using CDAI and SDAI, respectively. Depression was associated with a lower likelihood of achieving more subjective outcomes (⩽1 physician global assessment, ⩽1 patient global assessment) and ⩽1 28-swollen joint count, but not ⩽1 28-tender joint count or C-reactive protein measurement. Treatment with antidepressants did not improve outcomes for patients with depression. Anxiety was not significantly associated with RA remission. Conclusion: Comorbid depression, but not anxiety, was associated with less frequent remission. Concomitant antidepressant use was not associated with improvements in RA outcomes in patients with depression.

A postglacial paleoenvironmental dataset from New England.

This paleoenvironmental database features postglacial lake-sediment records from 31 study sites located across New England. The study sites span an environmental gradient from the cooler, northern and inland part of the region to the warmer, southern and coastal areas of New England. Sediment-core chronologies were determined using 14C dating, 210Pb analysis, and pollen evidence. Detailed analyses of sediment lithology, pollen, and charcoal were used to reconstruct changes in climate, vegetation, and fire at centennial temporal scales and subregional spatial scales for the last 14,000 years. Analyses of paleoenvironmental data provide insights into the rates, patterns, and drivers of ecosystem change, helping us anticipate future ecosystem dynamics and guiding present-day conservation strategies and land management.

Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout.

AIMS: To investigate and characterise the pharmacokinetics of febuxostat and the effect of the covariates of renal function and body size descriptors on the pharmacokinetics of the drug. METHODS: Blood samples (n = 239) were collected using sparse and rich sampling strategies from healthy (n = 9) and gouty (n = 29) subjects. Febuxostat plasma concentrations were measured by a validated high-performance liquid chromatography method. Population pharmacokinetic analysis was performed using NONMEM. A common variability on bioavailability (FVAR) approach was used to test the effect of fed status on absorption parameters. Covariates were modelled using a power model. RESULTS: The time course of the plasma concentrations of febuxostat is best described by a two-compartment model. In the final model, the population mean for apparent clearance (CL/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption rate constant (ka) and apparent intercompartmental clearance (Q/F) were 6.91 l h-1 , 32.8 l, 19.4 l, 3.6 h-1 and 1.25 l h-1 , respectively. The population parmater variability (coefficient of variation) for CL/F, Vc/F and Vp/F were 13.6, 22 and 19.5%, respectively. Food reduced the relative biovailability and ka by 67% and 87%, respectively. Renal function, as assessed by creatinine clearance, was a significant covariate for CL/F while body mass index was a significant covariate for Vc/F. CONCLUSIONS: Renal function and body mass index were significant covariates. Further work is warranted to investigate the clinical relevance of these results, notably as renal impairment and obesity are common occurrences in people with gout.