Search

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. [ABSTRACT FROM AUTHOR]

Neural activity cannot be directly observed using fMRI; rather it must be inferred from the hemodynamic responses that neural activity causes. Solving this inverse problem is made possible through the use of forward models, which generate predicted hemodynamic responses given hypothesised underlying neural activity. Commonly‐used hemodynamic models were developed to explain data from healthy young participants; however, studies of ageing and dementia are increasingly shifting the focus toward elderly populations. We evaluated the validity of a range of hemodynamic models across the healthy adult lifespan: from basis sets for the linear convolution models commonly used to analyse fMRI studies, to more advanced models including nonlinear fitting of a parameterised hemodynamic response function (HRF) and nonlinear fitting of a biophysical generative model (hemodynamic modelling, HDM). Using an exceptionally large sample of participants, and a sensorimotor task optimized for detecting the shape of the BOLD response to brief stimulation, we first characterised the effects of age on descriptive features of the response (e.g., peak amplitude and latency). We then compared these to features from more complex nonlinear models, fit to four regions of interest engaged by the task, namely left auditory cortex, bilateral visual cortex, left (contralateral) motor cortex and right (ipsilateral) motor cortex. Finally, we validated the extent to which parameter estimates from these models have predictive validity, in terms of how well they predict age in cross‐validated multiple regression. We conclude that age‐related differences in the BOLD response can be captured effectively by models with three free parameters. Furthermore, we show that biophysical models like the HDM have predictive validity comparable to more common models, while additionally providing insights into underlying mechanisms, which go beyond descriptive features like peak amplitude or latency, and include estimation of nonlinear effects. Here, the HDM revealed that most of the effects of age on the BOLD response could be explained by an increased rate of vasoactive signal decay and decreased transit rate of blood, rather than changes in neural activity per se. However, in the absence of other types of neural/hemodynamic data, unique interpretation of HDM parameters is difficult from fMRI data alone, and some brain regions in some tasks (e.g., ipsilateral motor cortex) can show responses that are more difficult to capture using current models. [ABSTRACT FROM AUTHOR]

A straightforward nebulized spray system is designed to explore the hydrogenation of carbon dioxide (CO2) within water microdroplets surrounded by different gases such as carbon dioxide, nitrogen, oxygen, and compressed air. The collected droplets are analyzed using water‐suppressed nuclear magnetic resonance (NMR). Formate anion (HCOO−), acetate anion (CH3COO−), ethylene glycol (HOCH2CH2OH), and methane (CH4) are detected when water is nebulized. This pattern persisted when the water is saturated with CO2, indicating that CO2 in the nebulizing gas triggers the formation of these small organics. In a pure CO2 atmosphere, the formate anion concentration is determined to be ≈70 µm, referenced to dimethyl sulfoxide, which has been introduced as an internal standard in the collected water droplets. This study highlights the power of water microdroplets to initiate unexpected chemistry for the transformation of CO2 to small organic compounds. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The Health and Retirement Study International Partner Surveys (HRS IPS) have rich longitudinal data, but the brevity of cognitive batteries is a limitation. METHODS: We used data from a substudy of the English Longitudinal Study of Ageing (ELSA) administering detailed cognitive assessments with the Harmonized Cognitive Assessment Protocol (ELSA‐HCAP) (N = 1273) to inform approaches for estimating cognition in ELSA (N = 11,213). We compared two novel approaches: confirmatory factor analysis (CFA)‐ and regression‐based prediction. RESULTS: Compared to estimates from the full HCAP battery, estimated cognitive functioning derived using regression models or CFA had high correlations (regression: r = 0.85 [95% confidence interval [CI]: 0.83 to 0.87]; CFA: r = 0.83 [95% CI: 0.81 to 0.85]) and reasonable mean squared error (regression: 0.25 [0.22 to 0.27]; CFA: 0.29 [0.26 to 0.32]) in held‐out data. The use of additional items from waves 7 to 9 improved performance. DISCUSSION: Both approaches are recommended for future research; the similarity in approaches may be due to the brevity of available cognitive assessments in ELSA. Highlights: Estimates of cognitive functioning informed by English Longitudinal Study of Ageing‐Harmonized Cognitive Assessment Protocol (ELSA‐HCAP) data had an adequate performance.Standard errors were smaller for associations with example risks when using measures informed by ELSA‐HCAP.Performance was better when including additional cognitive measures available in waves 7 to 9.Conceptual advantages to the confirmatory factor analysis (CFA) approach were not important in practice due to the brevity of the ELSA cognitive battery. [ABSTRACT FROM AUTHOR]

Invertebrates account for over 90% of all described species and provide crucial ecosystem services. Land clearing, including the removal of abiotic habitat features, threatens invertebrate biodiversity, making environmental restoration crucial for conservation. However, little is known about the effects of abiotic restoration compared to the restoration of biotic features. To determine if rock addition increased invertebrate biodiversity, we introduced 120 t of rocks to 10 sites across five grassland reserves in the Australian Capital Territory in a before‐after‐control‐impact design. We sampled invertebrates using pitfall traps before treatment in 2016 and after rock addition in 2019 (during record‐breaking drought). We recorded 29,164 individual invertebrates from 19 orders and undertook a functional trait‐based analysis of rock effects on the invertebrate community. No effects of rock addition were observed on the probability of occurrence, richness, diversity, community similarity, or abundance of any taxonomic or functional group. The abundance of snare‐building spiders and large ants was higher in the control plots at the end of the experiment. These abundance responses in 2019 did not differ from the control or treatment plots in 2016. Thus, some combination of drought and rock addition appears to have neutralized a positive temporal change that was evident without rocks. Despite a regionwide, replicated restoration effort and an extensive functional analysis of invertebrate communities, very little positive response to rock addition was recorded. Rock addition did not have a negative effect on grassland invertebrate biodiversity and may still be beneficial to the long‐term conservation and restoration of vertebrate and invertebrate communities. [ABSTRACT FROM AUTHOR]

Nearly two decades after the Peck and Cross article '"Getting the dose right: facts, a blueprint, and encouragements" was published, a review of dose recommendations for biologics shows that the success in getting the dose right appears to have improved given the relatively low incidence of drug withdrawals and dosing/label changes. However, the clinical experience with monoclonal antibodies (MAbs) following approval has been less than perfect. In inflammatory diseases, the disease burden changes with time and high treatment failure rates have been reported. In addition, the use of concomitant steroids and immunosuppressant drugs with MAbs is common. These concomitant agents have their own safety issues and many immunosuppressant agents are not well‐tolerated although they have been shown to reduce the incidence of anti‐drug antibodies (ADA). This same complexity is seen in MAbs used in oncology as well, although with these agents the doses appear to be higher than needed, which results in high treatment costs and incidence of adverse events. Given the complexity of MAb pharmacokinetics, which makes providing a detailed description of dose options difficult, product labeling should include the options for alternative dose strategies and potentially include the use of therapeutic drug monitoring with dose individualization which have been shown to improve clinical response and reduce the incidence of ADA. So, while the recommended dosing for biologics seems improved over the issues noted 17 years ago, we still have some work to do. [ABSTRACT FROM AUTHOR]

Background: Serious games enhance learner engagement and knowledge, yet few medical education games target older adults' healthcare. Addressing this gap, we developed Geri‐POP (Geriatrics Population Health), focusing on the Age‐Friendly Health System (AFHS) framework and Geriatric 4Ms. Methods: Geri‐POP, a healthcare game is aimed at educating health profession learners about the AFHS framework. Geri‐POP employs plan–do–study–act cycles of rapid improvement to apply AFHS principles and explore evidence‐based geriatric practices within the game environment while garnering points for insight, trust and outcomes. Faculty and medical students were surveyed for feedback on an alpha version of Geri‐POP. Results: Players manage patient panels across three age groups (65–74, 75–84, and 85 years and older) while engaging in plan–do–study–act (PDSA) cycles, applying Geriatric 4Ms (What Matters, Medications, Mentation, and Mobility), and refining strategies based on resource utilization, health outcomes, and real‐time feedback. Alpha testing of the game received mixed perceptions on graphics, with faculty endorsing the game for training and integration into the curriculum, while students prioritize academic commitments. Suggestions include enhancing graphics and refining dialogue for a more professional tone. Conclusions: Geri‐POP demonstrates the potential of gamifying older adult population health and quality improvement around AFHS. Feedback on a prototype game revealed different attitudes between faculty and students, thus emphasizing the importance of game development as an iterative process that accounts for educator and learner‐centric needs. A future consideration is whether the game informs user's clinical practices and changes healthcare outcomes for older adults. [ABSTRACT FROM AUTHOR]

The article revisits the meaning of cognitive impairment in older adults using the Aging, Demographics and Memory Study (ADAMS). Topics discussed include the methods used in the study, the performance of Mini-Mental State Examination (MMSE) as a screening tool for dementia, and the clinical implications of a low MMSE score.

This study assesses the reliability of resting‐state dynamic causal modelling (DCM) of magnetoencephalography (MEG) under conductance‐based canonical microcircuit models, in terms of both posterior parameter estimates and model evidence. We use resting‐state MEG data from two sessions, acquired 2 weeks apart, from a cohort with high between‐subject variance arising from Alzheimer's disease. Our focus is not on the effect of disease, but on the reliability of the methods (as within‐subject between‐session agreement), which is crucial for future studies of disease progression and drug intervention. To assess the reliability of first‐level DCMs, we compare model evidence associated with the covariance among subject‐specific free energies (i.e., the 'quality' of the models) with versus without interclass correlations. We then used parametric empirical Bayes (PEB) to investigate the differences between the inferred DCM parameter probability distributions at the between subject level. Specifically, we examined the evidence for or against parameter differences (i) within‐subject, within‐session, and between‐epochs; (ii) within‐subject between‐session; and (iii) within‐site between‐subjects, accommodating the conditional dependency among parameter estimates. We show that for data acquired close in time, and under similar circumstances, more than 95% of inferred DCM parameters are unlikely to differ, speaking to mutual predictability over sessions. Using PEB, we show a reciprocal relationship between a conventional definition of 'reliability' and the conditional dependency among inferred model parameters. Our analyses confirm the reliability and reproducibility of the conductance‐based DCMs for resting‐state neurophysiological data. In this respect, the implicit generative modelling is suitable for interventional and longitudinal studies of neurological and psychiatric disorders. [ABSTRACT FROM AUTHOR]

Various erythropoietic abnormalities are highly prevalent among patients with pulmonary arterial hypertension (PAH) and associated with worse disease severity. Given the poorly understood yet important roles of dysregulated erythropoiesis and iron metabolism in PAH, we sought to further characterize the hematologic and iron profiles in PAH and their relationship to PAH severity. We recruited 67 patients with PAH and 13 healthy controls. Hemodynamics attained within 1 year of blood sample collection were available for 36 patients. Multiple hematologic, iron, and inflammatory parameters were evaluated for their association with hemodynamics. The subset with hemodynamic data consisted of 29 females (81%). The most common etiologies were idiopathic PAH (47%) and connective tissue disease‐related PAH (33%). 19 (53%) had functional class 3 or 4 symptomatology, and 12 (33%) were on triple pulmonary vasodilator therapy. Immature reticulocyte fraction (IRF) had significant positive correlations with mean pulmonary artery (PA) pressure (mPAP) (0.59, p < 0.001), pulmonary vascular resistance (0.52, p = 0.001), and right atrial pressure (0.46, p = 0.005), and significant negative correlations with cardiac index (−0.43, p = 0.009), PA compliance (PAC) (−0.60, p < 0.001), stroke volume index (SVI) (−0.57, p < 0.001), and mixed venous oxygen saturation (−0.51, p = 0.003). IRF correlated with markers of iron deficiency (ID) and erythropoiesis. On multivariable linear regression, IRF was associated with elevated mPAP and reduced SVI and PAC independent of EPO levels, transferrin saturation, and soluble transferrin receptor levels. We identified IRF as a novel and potent biomarker of PAH hemodynamic severity, possibly related to its associations with erythropoiesis, ID, and tissue hypoxia. [ABSTRACT FROM AUTHOR]

Background: Obesity is a known risk factor for the development of osteoarthritis and the subsequent need for joint replacement. Weight loss has been shown to reduce pain, disability, and the need for joint replacement, particularly in patients with knee osteoarthritis. The aim of this study was to investigate pre‐operative weight change in patients with hip, knee, and shoulder osteoarthritis at a regional, public hospital in Australia, to identify opportunities for pre‐operative weight‐loss intervention. Methods: A retrospective review of patients who underwent elective primary total hip (THR), knee (TKR), and shoulder (TSR) replacement for osteoarthritis was conducted between December 2019 and December 2022. BMI data were collected at three time points: (1) general practitioner (GP) referral; (2) orthopaedic clinic review; and (3) pre‐admission clinic (PAC) assessment. Results: A total of 496 patients were included in the study, of which 205 underwent THR, 251 underwent TKR, and 40 underwent TSR. The mean patient age was 67 years, and 46.4% were female. At the time of GP referral, the mean body mass index (BMI) was 31.4 kg/m2. Across the study period, only 2% of patients experienced clinically significant weight loss pre‐operatively (≥5% of total body weight). Conclusion: This study has demonstrated that very few patients lose weight prior to undergoing joint replacement in the public sector in Australia. This highlights the need for targeted non‐surgical weight loss interventions for patients currently awaiting joint replacement. [ABSTRACT FROM AUTHOR]

Introduction: Medication safety incidents have been identified as an important target to improve patient safety in mental healthcare. Despite this, the causes of preventable medication safety incidents affecting patients with mental illness have historically been poorly understood, with research now addressing this knowledge gap through a healthcare professional lens. However, patients and carers can also provide complimentary insight into safety issues, and as key stakeholders in healthcare, it is vital to consider their needs when designing effective interventions. Methods: A two‐stage approach was adopted by (i) conducting three focus groups (FG) comprising 13 patients with mental illness and their carers to develop a holistic picture of medication safety in primary care with extraction of themes guided by the P‐MEDS framework; (ii) conducting two separate nominal group consensus workshops with seven patients with mental illness/carers and seven healthcare professionals to identify priority areas for targeted interventions. Results: Seven themes were identified in the FGs: communication; trust, involvement and respect; continuity and support; access; the healthcare professional; the patient and carer; and the organisation. Priority areas identified for intervention by key stakeholders included improving communication within and between clinical services, enhancing patient support with holistic continuity of care, maximising shared decision‐making and empowerment, ensuring timely access to medicines and services, strengthening healthcare professional knowledge regarding mental illnesses and associated medications, and increasing patient dignity and respect. Conclusion: This study has developed a holistic picture of contributors to medication safety incidents affecting patients with mental illness in primary care. This theory was then used by key stakeholders to inform and generate priority recommendations for targeted interventions. These findings can be used to inform future intervention research, as they consider the needs of those who access or work within primary care services. Patient or Public Contribution: An advisory group consisting of three expert patients with lived experience of mental illness was consulted on the design of both stages of this study. Patients with mental illness and/or their carers were recruited and participated in both stages of this study. Patients/carers aided with data analysis and interpretation during the patient/carer nominal group consensus workshop. [ABSTRACT FROM AUTHOR]

Rhizobia diversity in the rhizosphere is one of the key promoters of biological nitrogen fixation between host legumes and microsymbionts, although related complex interaction may depend on various factors. This research was intended to assess the abundance of indigenous rhizobia isolates under various soil conditions, as well as their effectiveness to nodulate legumes such as soybeans. Factors such as soil properties and legume species influence the volume and symbiotic effectiveness of native rhizobia to nodulate crop legumes. To investigate the abundance of rhizobia isolates, legume crops were uprooted to obtain nodules for most probable number (MPN) determination of rhizobia isolates, and soybean (Glycine max.) was used to verify the presence of suitable and efficient rhizobia strains for nitrogen fixation. Soil samples were obtained from the holes out of which nodules were collected, and the laboratory analysis included pH, Mg, K, available P, organic C, Ca, and N to establish the correlation between the soil status and number of rhizobia isolates' cells. Significant variations (p‐value <.05) were observed in the cell counts of Rhizobia isolates from Glycine max, Phaseolus vulgaris, Pisum sativum, and Vigna unguiculata, particularly when compared to Arachis hypogaea isolates under acidic conditions. Notably, Pisum sativum and Vigna unguiculata showed consistent performance across all pH conditions. The number of rhizobia isolates was found to be significantly linked to total N and P deficiencies (p <.05). It was also established that total N was dependent on the number of rhizobia cells and that there is a strong correlation between organic carbon and N content. This study highlights the crucial role of understanding and optimizing conditions for rhizobia nodulation in diverse soil environments, emphasizing its potential impact on enhancing biological nitrogen fixation in legumes. [ABSTRACT FROM AUTHOR]

Precision‐dosing models forecast infliximab doses to achieve targeted trough concentrations in patients with inflammatory bowel disease (IBD). These models have shown to reduce nonresponse and improve patient outcomes. We compared infliximab doses determined by iDOSE precision dosing with standard dosing, and the associated drug costs, in patients with IBD. In this retrospective study, patients with IBD treated with infliximab every 8 weeks at 5 mg/kg were included. An infliximab dose was named dose X if 3 previous infliximab doses, laboratory values including trough infliximab concentrations, and the patient's weight were recorded. The actual dose X was compared to an iDOSE‐predicted dose X. Net drug use and costs were evaluated. A total of 174 patients—56% men; median age, 36 (interquartile range, 29‐47) years; 135 with Crohn disease; and 31 with ulcerative colitis—were included, with 417 dose X recordings. Median prior infliximab therapy was 2 (0‐4) years. Comparing actual dose X with predicted dose X, 52% and 32% of doses were subtherapeutic when aiming for trough concentrations of 5‐10 and 3‐7 μg/mL, respectively. Treatment costs increased by 102% and 29% for the 2 trough ranges, respectively. On multivariate regression analysis, subtherapeutic infliximab concentrations were associated with ulcerative colitis compared with Crohn disease (odds ratio, 9.81; 95% confidence interval, 1.28‐75.40; P =.028) and predose X infliximab trough concentration [odds ratio, 0.07; 95% confidence interval, 0.03‐0.15; P <.001]. Over half of maintenance infliximab drug doses were too low to achieve infliximab blood concentrations of 5 μg/mL or greater. While applying precision dosing may improve patient outcomes, drug costs could be considerably greater. [ABSTRACT FROM AUTHOR]

The Harmonized Cognitive Assessment Protocol (HCAP) is a major innovation that provides, for the first time, harmonized data for cross‐national comparisons of later‐life cognitive functions that are sensitive to linguistic, cultural, and educational differences across countries. However, cognitive function does not lend itself to direct comparison across diverse populations without careful consideration of the best practices for such comparisons. This perspective discusses theoretical and methodological considerations and offers a set of recommended best practices for conducting cross‐national comparisons of risk factor associations using HCAP data. Because existing and planned HCAP studies provide cognition data representing an estimated 75% of the global population ≥65 years of age, these recommended best practices will support high‐quality comparative analyses of cognitive aging around the world. The principles described in this perspective are applicable to any researcher aiming to integrate or compare harmonized data on cognitive outcomes and their risk and protective factors across diverse populations. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We conducted a cross‐national comparison of the association between main lifetime occupational skills and later‐life cognitive function across four economically and socially distinct countries. METHODS: Data were from population‐based studies of aging and their Harmonized Cognitive Assessment Protocols (HCAPs) in the US, South Africa, India, and Mexico (N = 10,037; Age range: 50 to 105 years; 2016 to 2020). Main lifetime occupational skill was classified according to the International Standard Classification of Occupations. Weighted, adjusted regression models estimated pooled and country‐specific associations between main lifetime occupational skill and later‐life general cognitive function in men and women. RESULTS: We observed positive gradients between occupational skill and later‐life cognitive function for men and women in the US and Mexico, a positive gradient for women but not men in India, and no association for men or women in South Africa. DISCUSSION: Main lifetime occupations may be a source of later‐life cognitive reserve, with cross‐national heterogeneity in this association. Highlights: No studies have examined cross‐national differences in the association of occupational skill with cognition.We used data from Harmonized Cognitive Assessment Protocols in the US, Mexico, India, and South Africa.The association of occupational skill with cognitive function varies by country and gender. [ABSTRACT FROM AUTHOR]

Antibody‐mediated rejection (AMR) is a common cause of graft failure after pig‐to‐nonhuman primate organ transplantation, even when the graft is from a pig with multiple genetic modifications. The specific factors that initiate AMR are often uncertain. We report two cases of pig kidney transplantation into immunosuppressed baboons in which we identify novel factors associated with the initiation of AMR. In the first, membranous nephropathy was the initiating factor that was then associated with the apparent loss of the therapeutic anti‐CD154 monoclonal antibody in the urine when severe proteinuria was present. This observation suggests that proteinuria may be associated with the loss of any therapeutic monoclonal antibody, for example, anti‐CD154 or eculizumab, in the urine, resulting in xenograft rejection. In the second case, the sequence of events and histopathology tentatively suggested that pyelonephritis may have initiated acute‐onset AMR. The association of a urinary infection with graft rejection has been well‐documented in ABO‐incompatible kidney allotransplantation based on the expression of an antigen on the invading microorganism shared with the kidney graft, generating an immune response to the graft. To our knowledge, these potential initiating factors of AMR in pig xenografts have not been highlighted previously. [ABSTRACT FROM AUTHOR]

The article discusses the concept of the "gratitude paradox" in healthcare, using examples from the field of transplantation and other contexts. The authors argue that there is an expectation for disadvantaged and vulnerable populations to be grateful for minimal improvements in their lives, and that expressing a desire for more and better care options is often met with backlash. They call on healthcare professionals to validate the conflicting emotions that patients experience and strive to offer improved treatment options. The authors also emphasize the need for empathy, collaboration, and resistance against societal forces that hinder progress in healthcare. [Extracted from the article]

We report examples of C(sp2)−N, C(sp2)−S, and C(sp2)−P bond‐forming transformations in water microdroplets at room temperature and atmospheric pressure using N2 as a nebulizing gas. When an aqueous solution of vinylic acid and amine is electrosprayed (+3 kV), the corresponding C(sp2)−N product is formed in a single step, which was characterized using mass spectrometry (MS) and tandem mass spectrometry (MS2). The scope of this reaction was extended to other amines and other unsaturated acids, including acrylic (CH2=CHCOOH) and crotonic (CH3CH=CHCOOH) acids. We also found that thiols and phosphines are viable nucleophiles, and the corresponding C(sp2)−S and C(sp2)−P products are observed in positive ion mode using MS and MS2. [ABSTRACT FROM AUTHOR]

Monitoring is critical for detecting population trends, determining efficacy of management intervention, assessing species or community responses to ecological threats and informing conservation policies. While the intention of threatened species monitoring programmes is generally in the best interest of the target species, the sampling techniques used can often have negative impacts on individuals, populations, species or even the ecosystem. The Pink‐tailed Worm‐lizard Aprasia parapulchella, a threatened species, is a small fossorial, legless lizard found along the western slopes of the Great Dividing Range in south‐eastern Australia. The most commonly used survey method for the species is searching beneath shallowly embedded rocks. Like other active hand search methods, rock‐turning can have a detrimental effect on the target species and microhabitat. The aim of this study was to develop a low‐impact monitoring method for A. parapulchella, using artificial shelters (bricks), that would reduce monitoring impacts and allow monitoring to be undertaken more frequently. We found that annual artificial shelter surveys for A. parapulchella achieved similar detection rates to rock‐turning surveys. We also found that artificial shelters provided similar habitat attributes as natural habitat rocks and importantly, we showed that artificial shelter surveys did not negatively affect either A. parapulchella or habitat condition. The novel, low‐impact monitoring method allows monitoring for the species to be undertaken more frequently and thereby allows land managers and conservation practitioners an opportunity to respond faster to population change. [ABSTRACT FROM AUTHOR]

Background: Examining the associations of social determinants of health (SDOH) with postoperative delirium in older adults will broaden our understanding of this potentially devastating condition. We explored the association between SDOH factors and incident postoperative delirium. Methods: A retrospective study of a prospective cohort of patients enrolled from June 18, 2010, to August 8, 2013, across two academic medical centers in Boston, Massachusetts. Overall, 560 older adults age ≥70 years undergoing major elective non‐cardiac surgery were included in this analysis. Exposure variables included income, lack of private insurance, and neighborhood disadvantage. Our main outcome was incident postoperative delirium, measured using the Confusion Assessment Method long form. Results: Older age (odds ratio, OR: 1.01, 95% confidence interval, CI: 1.00, 1.02), income <20,000 a year (OR: 1.12, 95% CI: 1.00, 1.26), lack of private insurance (OR: 1.19, 95% CI: 1.04, 1.38), higher depressive symptomatology (OR: 1.02, 95% CI: 1.01, 1.04), and the Area Deprivation Index (OR: 1.02, 95% CI: 1.01, 1.04) were significantly associated with increased risk of postoperative delirium in bivariable analyses. In a multivariable model, explaining 27% of the variance in postoperative delirium, significant independent variables were older age (OR 1.01, 95% CI 1.00, 1.02), lack of private insurance (OR 1.18, 95% CI 1.02, 1.36), and depressive symptoms (OR 1.02, 95% CI 1.00, 1.03). Household income was no longer a significant independent predictor of delirium in the multivariable model (OR:1.02, 95% CI: 0.90, 1.15). The type of medical insurance significantly mediated the association between household income and incident delirium. Conclusions: Lack of private insurance, a social determinant of health reflecting socioeconomic status, emerged as a novel and important independent risk factor for delirium. Future efforts should consider targeting SDOH factors to prevent postoperative delirium in older adults. [ABSTRACT FROM AUTHOR]

Transposable elements have created the majority of the sequence in many genomes. In mammals, LINE-1 retrotransposons have been expanding for more than 100 million years as distinct, consecutive lineages; however, the drivers of this recurrent lineage emergence and disappearance are unknown. Most human genome assemblies provide a record of this ancient evolution, but fail to resolve ongoing LINE-1 retrotranspositions. Utilizing the human CHM1 long-read-based haploid assembly, we identified and cloned all full-length, intact LINE-1s, and found 29 LINE-1s with measurable in vitro retrotransposition activity. Among individuals, these LINE- 1s varied in their presence, their allelic sequences, and their activity. We found that recently retrotransposed LINE-1s tend to be active in vitro and polymorphic in the population relative to more ancient LINE-1s. However, some rare allelic forms of old LINE-1s retain activity, suggesting older lineages can persist longer than expected. Finally, in LINE-1s with in vitro activity and in vivo fitness, we identified mutations that may have increased replication in ancient genomes and may prove promising candidates for mechanistic investigations of the drivers of LINE-1 evolution and which LINE-1 sequences contribute to human disease. [ABSTRACT FROM AUTHOR]

Background: The Successful Aging after Elective Surgery (SAGES) II Study was designed to examine the relationship between delirium and Alzheimer's disease and related dementias (AD/ADRD), by capturing novel fluid biomarkers, neuroimaging markers, and neurophysiological measurements. The goal of this paper is to provide the first complete description of the enrolled cohort, which details the baseline characteristics and data completion. We also describe the study modifications necessitated by the COVID‐19 pandemic, and lay the foundation for future work using this cohort. Methods: SAGES II is a prospective observational cohort study of community‐dwelling adults age 65 and older undergoing major non‐cardiac surgery. Participants were assessed preoperatively, throughout hospitalization, and at 1, 2, 6, 12, and 18 months following discharge to assess cognitive and physical functioning. Since participants were enrolled throughout the COVID‐19 pandemic, procedural modifications were designed to reduce missing data and allow for high data quality. Results: About 420 participants were enrolled with a mean (standard deviation) age of 73.4 (5.6) years, including 14% minority participants. Eighty‐eight percent of participants had either total knee or hip replacements; the most common surgery was total knee replacement with 210 participants (50%). Despite the challenges posed by the COVID‐19 pandemic, which required the use of novel procedures such as video assessments, there were minimal missing interviews during hospitalization and up to 1‐month follow‐up; nearly 90% of enrolled participants completed interviews through 6‐month follow‐up. Conclusion: While there are many longitudinal studies of older adults, this study is unique in measuring health outcomes following surgery, along with risk factors for delirium through the application of novel biomarkers—including fluid (plasma and cerebrospinal fluid), imaging, and electrophysiological markers. This paper is the first to describe the characteristics of this unique cohort and the data collected, enabling future work using this novel and important resource. [ABSTRACT FROM AUTHOR]

Objectives: Determine if biomarkers of Alzheimer's disease and neural injury may play a role in the prediction of delirium risk. Methods: In a cohort of older adults who underwent elective surgery, delirium case‐no delirium control pairs (N = 70, or 35 matched pairs) were matched by age, sex and vascular comorbidities. Biomarkers from CSF and plasma samples collected prior to surgery, including amyloid beta (Aβ)42, Aβ40, total (t)‐Tau, phosphorylated (p)‐Tau181, neurofilament‐light (NfL), and glial fibrillary acid protein (GFAP) were measured in cerebrospinal fluid (CSF) and plasma using sandwich enzyme‐linked immunosorbent assays (ELISAs) or ultrasensitive single molecule array (Simoa) immunoassays. Results: Plasma GFAP correlated significantly with CSF GFAP and both plasma and CSF GFAP values were nearly two‐fold higher in delirium cases. The median paired difference between delirium case and control without delirium for plasma GFAP was not significant (p = 0.074) but higher levels were associated with a greater risk for delirium (odds ratio 1.52, 95% confidence interval 0.85, 2.72 per standard deviation increase in plasma GFAP concentration) in this small study. No matched pair differences or associations with delirium were observed for NfL, p‐Tau 181, Aβ40 and Aβ42. Conclusions: These preliminary findings suggest that plasma GFAP, a marker of astroglial activation, may be worth further investigation as a predictive risk marker for delirium. Key points: Delirium is a common complication of hospitalization associated with poor outcomes, but the underlying pathophsysiology of this condition is poorly understoodThere is a close interrelationship between delirium and dementia, therefore CSF and blood biomarkers for Alzheimer's Disease and neural injury might be associated with deliriumWe found that plasma and CSF glial fibrillary acid protein (GFAP), a marker of reactive gliosis known to be elevated in neurodegeneration, appears to be related to delirium risk, with a nearly two‐fold greater odds of deliriumFurther larger studies are needed to understand the potential role of GFAP as a predictive risk marker for delirium [ABSTRACT FROM AUTHOR]

Background: Assessment of self‐perceived cognitive decline (SCD) is relevant in the context of Alzheimer's disease and related disorders, but heterogeneity in measurement limits its interpretability and usability. Selection of optimal content for a questionnaire measuring SCD requires statistical information and expert opinion to ensure reliability as well as acceptability and feasibility. This study aims to survey experts about their perspectives on essential features of SCD measurement. Method: The survey was distributed through the ISTAART Subjective Cognitive Decline PIA, International Neuropsychological Society's Dementia Special Interest Group, and authors' professional networks. Targeted experts included professionals working with older adults with SCD through research and/or clinical practice. Main topics were item content, item format, and questionnaire features. Topics were evaluated with multiple choice questions and open‐ended questions. Furthermore, experts were shown items from existing SCD questionnaires with relatively high information value as identified in a previous statistical harmonization effort using Item Response Theory analyses (see Rabin et al., 2021), and asked to select items they viewed as most relevant. Frequency analyses were performed. Result: Ninety‐one experts (66% female) across four continents completed the questionnaire (Table 1). Thirty‐nine experts (43%) indicated routinely using an instrument to assess SCD (17 different instruments were mentioned). Seventy‐nine experts (87%) perceived a need for a harmonized SCD instrument. Whereas most experts (72%) responded that a questionnaire should measure both current ability and change in ability, views on the most relevant timeframe varied substantially (top choices: past year (33%) and past six months (25%)). Figure 1a and 1b show that items with the highest statistical information value were not necessarily selected as most relevant by experts. Preferred practical features of a questionnaire were availability of an informant version and coverage of multiple cognitive domains (chosen by 13% and 14% respectively). Preferred validation approaches were distinguishing psychiatric illness from neurodegenerative disorders and the correlation with neuropsychological test performance (both chosen by 20%). Conclusion: Despite agreeing on the need for a harmonized SCD instrument, experts express varying views on optimal content, format, and validation approaches. The complementary information derived from statistical results and expert opinion can facilitate more comprehensive measurement of SCD. [ABSTRACT FROM AUTHOR]

We compare modern machine learning (MML) techniques to ordinary least squares (OLS) regression on out‐of‐sample (OOS) operational validity, adverse impact, and dropped predictor counts within a common selection scenario: the prediction of job performance from a battery of diverse psychometrically‐validated tests. In total, scores from 1.2 billion validation study participants were simulated to describe outcomes across 31,752 combinations selection system design and scoring decisions. The most consistently valuable improvement from adopting MML over traditional regression was from dropping predictors rather than by improving prediction. On average, MML improved prediction of performance from psychometric scale composites only when the ratio of sample size to scale count was less than approximately 3, although algorithm choice, predictor count, and selection ratio affected outcomes as well. We also simulated the effects of design choices when combining item scores, which showed consistent, superior predictive accuracy for several MML algorithms, especially elastic net and random forest, over traditional regression. Given these results, we suggest the potential of machine learning for employee selection is unlikely to be realized in selection systems focusing on the combination of scale composites from previously validated psychometric tests. Instead, it will be realized in unconventional design scenarios, such as the use of individual items to make multiple trait inferences, or with novel data formats like text, image, audio, video, and behavioral traces. We therefore recommend researchers focus on the potential value of MML in future selection contexts rather than continuing to focus on the current value of MML in current selection contexts. [ABSTRACT FROM AUTHOR]

The article provides information on the Network for Investigation of Delirium: Unifying Scientists (NIDUS) which aims to develop the collaborative network and infrastructure to advance scientific research and train on the causes, mechanisms, outcomes, diagnosis, prevention, and treatment of delirium in older adults. Topics include the renewal of NIDUS as NIDUS II in 2020, structure of NIDUS, and summary of NIDUS-I and NIDUS-II accomplishments.

Thrombomodulin is important for the production of activated protein C (APC), a molecule with significant regulatory roles in coagulation and inflammation. To address known molecular incompatibilities between pig thrombomodulin and human thrombin that affect the conversion of protein C into APC, GalTKO.hCD46 pigs have been genetically modified to express human thrombomodulin (hTBM). The aim of this study was to evaluate the impact of transgenic hTBM expression on the coagulation dysregulation that is observed in association with lung xenograft injury in an established lung perfusion model, with and without additional blockade of nonphysiologic interactions between pig vWF and human GPIb axis. Expression of hTBM was variable between pigs at the transcriptional and protein level. hTBM increased the activation of human protein C and inhibited thrombosis in an in vitro flow perfusion assay, confirming that the expressed protein was functional. Decreased platelet activation was observed during ex vivo perfusion of GalTKO.hCD46 lungs expressing hTBM and, in conjunction with transgenic hTBM, blockade of the platelet GPIb receptor further inhibited platelets and increased survival time. Altogether, our data indicate that expression of transgenic hTBM partially addresses coagulation pathway dysregulation associated with pig lung xenograft injury and, in combination with vWF‐GP1b‐directed strategies, is a promising approach to improve the outcomes of lung xenotransplantation. [ABSTRACT FROM AUTHOR]

Introduction: Carers of people with mental illness may face distinct challenges, including navigating fragmented health and social services during discharge from mental health hospitals. Currently, limited examples of interventions that support carers of people with mental illness in improving patient safety during transitions of care exist. We aimed to identify problems and solutions to inform future carer‐led discharge interventions, which is imperative for ensuring patient safety and the well‐being of carers. Methods: The nominal group technique was used which combines both qualitative and quantitative data collection methods in four distinct phases: (1) problem identification, (2) solution generation, (3) decision making and (4) prioritisation. The aim was to combine expertise from different stakeholder groups (patients, carers and academics with expertise in primary/secondary care, social care or public health) to identify problems and generate solutions. Results: Twenty‐eight participants generated potential solutions that were grouped into four themes. The most acceptable solution for each was as follows: (1) 'Carer Involvement and Improving Carer Experience' a dedicated family liaison worker, (2) 'Patient Wellness and Education' adapting and implementing existing approaches to help implement the patient care plan, (3) 'Carer Wellness and Education' peer/social support interventions for carers and (4) 'Policy and System Improvements' understanding the co‐ordination of care. Conclusion: The stakeholder group concurred that the transition from mental health hospitals to the community is a distressing period, where patients and carers are particularly vulnerable to safety and well‐being risks. We identified numerous feasible/acceptable solutions to enable carers to improve patient safety and maintain their own mental wellbeing. Patient and Public Contribution: Patient and public contributors were represented in the workshop and the focus of the workshop was to identify the problems they faced and co‐design potential solutions. Patient and public contributors were involved in the funding application and study design. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We evaluated the accuracy of remote and in‐person digital tests to distinguish between older adults with and without AD pathological change and used the Montreal Cognitive Assessment (MoCA) as a comparison test. METHODS: Participants were 69 cognitively normal older adults with known beta‐amyloid (Aβ) PET status. Participants completed smartphone‐based assessments 3×/day for 8 days, followed by TabCAT tasks, DCTclock™, and MoCA at an in‐person study visit. We calculated the area under the curve (AUC) to compare task accuracies to distinguish Aβ status. RESULTS: Average performance on the episodic memory (Prices) smartphone task showed the highest accuracy (AUC = 0.77) to distinguish Aβ status. On in‐person measures, accuracy to distinguish Aβ status was greatest for the TabCAT Favorites task (AUC = 0.76), relative to the DCTclockTM (AUC = 0.73) and MoCA (AUC = 0.74). DISCUSSION: Although further validation is needed, our results suggest that several digital assessments may be suitable for more widespread cognitive screening application. [ABSTRACT FROM AUTHOR]

Wearing a silicone wristband exposes the internal surface of the wristband to glucose, lipids, and metabolites (metabolome) found in sweat and the external surface to occupational and environmental factors that could impact health found in the air (exposome). We use silicone wristband electrospray ionization mass spectrometry (SWESI‐MS) to monitor these species. A 20‐μL drop of a (1 : 1, v/v) water:methanol solution is sufficient to extract abundant metabolites and contacting chemicals derived from ingestion of drink, smoke, diet, drug, and air pollution exposure. A wide coverage of species is successfully detected and identified from a worn wristband including caffeine, glucose, nicotine, reserpine, lactate, phosphocreatinine, oleic acid, and urea. The signal from a triangular wristband surface triggered by applying a voltage of 5 kV to form a spray remains stable for at least 2 minutes. The response is linear from 10 pM to 100 μM. The SWESI‐MS method offers the advantages of onsite sampling, no preprocessing, simple testing, and automatic high‐dimensional data searching. It can be used for simultaneously monitoring hazardous chemical contamination and abnormal expression of sweat‐secreted metabolites that are indicative of some physiological condition. [ABSTRACT FROM AUTHOR]

Invasive plants threaten biodiversity worldwide and effective management must control the target invader while conserving biodiversity. Herbicide is often used to control invasive plants, but potential negative impacts on biodiversity have led to spot spraying being recommended over boom spraying to minimize the exposure of nontarget species to chemicals. We examined the influence of herbicide application methods on off‐target plant communities in threatened temperate grasslands of southeastern Australia, where spraying with the broadleaf herbicide fluroxypr is commonly used to control St. John's wort, Hypericum perforatum L. It is well established that fluroxypr effectively controls H. perforatum but few studies have examined its impact on native forbs. A spray drift experiment using water‐sensitive cards indicated that ground surface coverage was higher for spot spraying (91%–99%) than for boom spraying (5%–31%). We established a replicated, 3‐year, before‐after‐control‐impact experiment across 48 1‐m2 quadrats to determine how three herbicide application methods (spot spray, fine boom and coarse boom) affected nontarget native forbs, the group most likely to be affected by broadleaf herbicides. This experiment was conducted in grasslands where H. perforatum was almost absent, so responses would reflect the direct impacts of the chemical, rather than structural changes resulting from removal of the target invader. Spot spraying decreased the probability of occurrence of native leguminous forbs, while increasing the occurrence of exotic leguminous forbs and the richness of all exotic species and exotic annual forbs. Spot spraying reduced the occurrence of the native Desmodium varians and the abundance of the native Chrysocephalum apiculatum. During this 3‐year study, native species appeared to be impacted either directly by fluroxypr or indirectly by increased competition with exotic species. Where herbicide application is deemed crucial in these grasslands, we recommend boom spraying when H. perforatum density is moderate to high. Spot spraying should only be used when the density of H. perforatum is very low. Given the regional variation in H. perforatum density, the spatial scale of invasion, soil depth, and conservation values, we present a decision tree to assist managers in evaluating the costs and benefits of chemical control, indicating situations where alternative or modified methods could be used. [ABSTRACT FROM AUTHOR]

Objective: Sodium‐glucose cotransporter 2 inhibitors (SGLT2i) promote urinary glucose excretion, induce weight loss, and reduce fat accumulation. The effects of the SGLT2i dapagliflozin (DAPA) on subcutaneous (SC) and visceral (VIS) adipose tissue function remain unclear. The objective of this study is to evaluate SC and VIS adipose tissue function in an insulin‐resistant canine model. Methods: A total of 12 dogs were fed a high‐fat diet (HFD) for 6 weeks and then were given a single low dose of streptozotocin (18.5 mg/kg) to induce insulin resistance. Animals were then randomized and exposed to DAPA (n = 6, 1.25 mg/kg) or placebo (n = 6) once per day for 6 weeks while remaining on the HFD. Results: DAPA prevented further weight gain induced by the HFD and normalized fat mass. DAPA reduced fasting glucose and increased free fatty acids, adiponectin, and β‐hydroxybutyrate. DAPA reduced adipocyte diameter and cell distribution. Furthermore, DAPA increased genes associated with beiging, lipolysis, and adiponectin secretion and the expression of the adiponectin receptor ADR2, in SC and VIS adipose tissue. DAPA increased AMP‐activated protein kinase activity and maximal mitochondrial respiratory function, especially in the SC depot. Furthermore, DAPA reduced cytokines and ceramide synthesis enzymes in SC and VIS depots. Conclusions: For the first time, to our knowledge, we identify mechanisms by which DAPA enhances adipose tissue function in regulating energy homeostasis in an insulin‐resistant canine model. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We used cultural neuropsychology‐informed procedures to derive and validate harmonized scores representing memory and language across population‐based studies in the United States and Mexico. METHODS: Data were from the Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS‐HCAP) and the Mexican Health and Aging Study (MHAS) Ancillary Study on Cognitive Aging (Mex‐Cog). We statistically co‐calibrated memory and language domains and performed differential item functioning (DIF) analysis using a cultural neuropsychological approach. We examined relationships among harmonized scores, age, and education. RESULTS: We included 3170 participants from the HRS‐HCAP (Mage = 76.6 [standard deviation (SD): 7.5], 60% female) and 2042 participants from the Mex‐Cog (Mage = 68.1 [SD: 9.0], 59% female). Five of seven memory items and one of twelve language items demonstrated DIF by study. Harmonized memory and language scores showed expected associations with age and education. DISCUSSION: A cultural neuropsychological approach to harmonization facilitates the generation of harmonized measures of memory and language function in cross‐national studies. HIGHLIGHTS: We harmonized memory and language scores across studies in the United States and Mexico.A cultural neuropsychological approach to data harmonization was used.Harmonized scores showed minimal measurement differences between cohorts.Future work can use these harmonized scores for cross‐national studies of Alzheimer's disease and related dementias. [ABSTRACT FROM AUTHOR]

Background: Obesity is a known risk factor for the development of hip osteoarthritis. The aim of this study was to investigate whether obesity is associated with the risk of undergoing total hip replacement (THR) in Australia. Methods: A cohort study was conducted comparing data from the Australian Bureau of Statistics and the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) from 2017 to 2018. Body mass index (BMI) data for patients undergoing primary total hip replacement and resurfacing for osteoarthritis were obtained from the AOANJRR. The distribution of THR patients by BMI category was compared to the general population, in age and sex sub‐groups. Results: During the study period, 32 495 primary THR were performed for osteoarthritis in Australia. Compared to the general population, there was a higher prevalence of Class I, II and III obesity in patients undergoing THR in both sexes aged 35–74 years. Class III obese females and males aged 55–64 years were 2.9 and 1.7 times more likely to undergo THR, respectively (P < 0.001). Class III obese females and males underwent THR on average 5.7 and 7.0 years younger than their normal weight counterparts, respectively. Conclusion: Obese Australians are at increased risk of undergoing THR, and at a younger age. [ABSTRACT FROM AUTHOR]

Antibody‐mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti‐donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti‐inflammatory therapy. Depletion or neutralization of anti‐pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG‐degrading enzymes do not deplete IgM. Despite the expression of human complement‐regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti‐C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell‐targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti‐inflammatory agents, anti‐IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti‐inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ‐source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD‐L1, HLA E, and/or HLA‐G. [ABSTRACT FROM AUTHOR]

Introduction: Expression of human complement pathway regulatory proteins (hCPRP's) such as CD46 or CD55 has been associated with improved survival of pig organ xenografts in multiple different models. Here we evaluate the hypothesis that an increased human CD46 gene dose, through homozygosity or additional expression of a second hCPRP, is associated with increased protein expression and with improved protection from injury when GTKO lung xenografts are perfused with human blood. Methods: Twenty three GTKO lungs heterozygous for human CD46 (GTKO.heteroCD46), 10 lungs homozygous for hCD46 (GTKO.homoCD46), and six GTKO.homoCD46 lungs also heterozygous for hCD55 (GTKO.homoCD46.hCD55) were perfused with human blood for up to 4 h in an ex vivo circuit. Results: Relative to GTKO.heteroCD46 (152 min, range 5–240; 6/23 surviving at 4 h), survival was significantly improved for GTKO.homoCD46 (>240 min, range 45–240, p =.034; 7/10 surviving at 4 h) or GTKO.homoCD46.hCD55 lungs (>240 min, p =.001; 6/6 surviving at 4 h). Homozygosity was associated with increased capillary expression of hCD46 (p <.0001). Increased hCD46 expression was associated with significantly prolonged lung survival (p =.048),) but surprisingly not with reduction in measured complement factor C3a. Hematocrit, monocyte count, and pulmonary vascular resistance were not significantly altered in association with increased hCD46 gene dose or protein expression. Conclusion: Genetic engineering approaches designed to augment hCPRP activity — increasing the expression of hCD46 through homozygosity or co‐expressing hCD55 with hCD46 — were associated with prolonged GTKO lung xenograft survival. Increased expression of hCD46 was associated with reduced coagulation cascade activation, but did not further reduce complement activation relative to lungs with relatively low CD46 expression. We conclude that coagulation pathway dysregulation contributes to injury in GTKO pig lung xenografts perfused with human blood, and that the survival advantage for lungs with increased hCPRP expression is likely attributable to improved endothelial thromboregulation. [ABSTRACT FROM AUTHOR]

Introduction: Stakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain—organized in a separate work package—included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project. Methods: Stakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses. Results: Consortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders. Conclusion: Stakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities. Public Contribution: Patient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration. [ABSTRACT FROM AUTHOR]

Heart and lung transplant recipients require care provided by clinicians from multiple different specialties, each contributing unique expertise and perspective. The period the patient spends in the intensive care unit is one of the most critical times in the perioperative trajectory. Various organizational models of intensive care exist, including those led by intensivists, surgeons, transplant cardiologists, and pulmonologists. Coordinating timely efficient intensive care is an essential and logistically difficult goal. The present work product of the American Society of Transplantation's Thoracic and Critical Care Community of Practice, Critical Care Task Force outlines operational guidelines and principles that may be applied in different organizational models to optimize the delivery of intensive care for the cardiothoracic organ recipient. [ABSTRACT FROM AUTHOR]

Introduction: One‐year health‐care costs associated with delirium in older hospitalized patients with and without Alzheimer's disease and related dementias (ADRD) have not been examined previously. Methods: Medicare costs were determined prospectively at discharge, and at 30, 90, and 365 days in a cohort (n = 311) of older adults after hospital admission. Results: Seventy‐six (24%) patients had ADRD and were more likely to develop delirium (51% vs. 24%, P < 0.001) and die within 1 year (38% vs. 21%, P = 0.002). In ADRD patients with versus without delirium, adjusted mean difference in costs associated with delirium were $34,828; most of the excess costs were incurred between 90 and 365 days (P = 0.03). In non‐ADRD patients, delirium was associated with increased costs at all timepoints. Excess costs associated with delirium in ADRD patients increased progressively over 1 year, whereas in non‐ADRD patients the increase was consistent across time periods. Discussion: Our findings highlight the complexity of health‐care costs for ADRD patients who develop delirium, a potentially preventable source of expenditures. Highlights: Novel examination of health‐care costs of delirium in persons with and without Alzheimer's disease and related dementias (ADRD).Increased 1‐year costs of $34,828 in ADRD patients with delirium (vs. without).Increased costs for delirium in ADRD occur later during the 365‐day study period.For ADRD patients, cost differences between those with and without delirium increased over 1 year.For non‐ADRD patients, the parallel cost differences were consistent over time. [ABSTRACT FROM AUTHOR]

Background: Older surgical patients have an increased risk for postoperative complications, driving up healthcare costs. We determined if postoperative co‐management of older surgery patients is associated with postoperative outcomes and hospital costs. Methods: Retrospective data were collected for patients ≥70 years old undergoing colorectal surgery at a community teaching hospital. Patient outcomes were compared between those receiving postoperative surgery co‐management care through the Optimization of Senior Care and Recovery (OSCAR) program and controls who received standard of care. Main outcome measures were postoperative complications and hospital charges, 30‐day readmission rate, length of stay (LOS), and transfer to intensive care during hospitalization. Multivariable linear regression was used to model total charge and multivariable logistic regression to model complications, adjusted for multiple variables (e.g., age, sex, race, body mass index, Charlson Comorbidity Index [CCI], American Society of Anesthesiologists score, surgery duration). Results: All 187 patients in the OSCAR and control groups had a similar mean CCI score of 2.7 (p = 0.95). Compared to the control group, OSCAR recipients experienced less postoperative delirium (17% vs. 8%; p = 0.05), cardiac arrhythmia (12% vs. 3%; p = 0.03), and clinical worsening requiring transfer to intensive care (20% vs. 6%; p < 0.005). OSCAR group patients had a shorter mean LOS among high‐risk patients (CCI ≥3) (−1.8 days; p = 0.09) and those ≥80 years old (−2.3 days; p = 0.07) compared to the control group. Mean total hospital charge was $10,297 less per patient in the OSCAR group (p = 0.01), with $17,832 less per patient with CCI ≥3 (p = 0.01), than the control group. Conclusions: A co‐management care approach after colorectal surgery in older patients improves outcomes and decreases costs, with the most benefit going to the oldest patients and those with higher comorbidity scores. [ABSTRACT FROM AUTHOR]

Introduction: Research focusing on cognitive aging and dementia is a global endeavor. However, cross‐national differences in cognition are embedded in other sociocultural differences, precluding direct comparisons of test scores. Such comparisons can be facilitated by co‐calibration using item response theory (IRT). The goal of this study was to explore, using simulation, the necessary conditions for accurate harmonization of cognitive data. Method: Neuropsychological test scores from the US Health and Retirement Study (HRS) and the Mexican Health and Aging Study (MHAS) were subjected to IRT analysis to estimate item parameters and sample means and standard deviations. These estimates were used to generate simulated item response patterns under 10 scenarios that adjusted the quality and quantity of linking items used in harmonization. IRT‐derived factor scores were compared to the known population values to assess bias, efficiency, accuracy, and reliability of the harmonized data. Results: The current configuration of HRS and MHAS data was not suitable for harmonization, as poor linking item quality led to large bias in both cohorts. Scenarios with more numerous and higher quality linking items led to less biased and more accurate harmonization. Discussion: Linking items must possess low measurement error across the range of latent ability for co‐calibration to be successful. HIGHLIGHTS: We developed a statistical simulation platform to evaluate the degree to which cross‐sample harmonization accuracy varies as a function of the quality and quantity of linking items.Two large studies of aging—one in Mexico and one in the United States—use three common items to measure cognition.These three common items have weak correspondence with the ability being measured and are all low in difficulty.Harmonized scores derived from the three common linking items will provide biased and inaccurate estimates of cognitive ability.Harmonization accuracy is greatest when linking items vary in difficulty and are strongly related to the ability being measured. [ABSTRACT FROM AUTHOR]

Introduction: Morel‐Lavallée lesions (MLL), also referred to as closed degloving injuries, result from traumatic shearing forces with separation of the subcutaneous fat from the underlying fascia. The aim of this study was to determine the incidence and treatment of MLLs at a level 1 trauma centre. Methods: Single‐centre retrospective cross‐sectional study of consecutive patients with an imaging diagnosis of a Morel‐Lavallee lesion from 1/1/2010–31/12/2019. Demographic data, mechanism of injury, volume of lesion, management and outcome data were collated. Results: Sixty‐six MLLs were identified in 63 patients (64% Male) with a median age of 49.5 years (19–94 years). Mechanism of injury were road traffic accidents in the majority (66%). Median injury severity score (ISS) was 17 (range 1–33). Patients on oral anti‐coagulants had significantly larger lesions (181.9 cc v 445.5 cc, P = 0.044). The most common lesion location was the thigh (60.5%). Patients that underwent imaging within 72 h of injury had significantly larger lesions than those imaged more than 72 h after the inciting trauma (65 cc v 167 cc, P < 0.05). Management data were documented in 59% of lesions (39/66) in which 66.6% (n = 26) had invasive treatment. In the 31 patients where follow‐up was available, 64.5% (n = 20) were persistent but decreasing in size. There was no significant difference in follow‐up size for those who had invasive compared to conservative treatment (P = 0.3). Conclusion: The diagnosis of MLL should be considered for soft‐tissue swelling in the context of shearing trauma. A variety of management options have been employed, with good overall outcomes. [ABSTRACT FROM AUTHOR]

Racism from one's partner is a highly sensitive phenomenon that has received little research attention. The current research introduces the concept of "intimate racism" to refer to racism from close others. The manifestation of intimate racism in intercultural romantic relationships was explored with a sample of 92 racialized minorities who were currently, or previously, in an intercultural relationship. An online survey enquired about the experience of racism from their partner, and responses were coded and analyzed using thematic content analysis. More than 50 different manifestations of intimate racism emerged and these were grouped into eight categories: explicit racism, microinsults, microinvalidations, positive stereotypes, racial fetishization, partner abuse, defensiveness, and others. Co‐occurrence analyses revealed links between intimate racism with negative, neutral and positive experiences, which were connected to participants' responses to racism (e.g., confronting, disengaging) and to stressful identity experiences. The present work opens a new field of study to examine intimate racism and its implications. [ABSTRACT FROM AUTHOR]

We present immunoassay‐based desorption electrospray ionization mass spectrometry imaging (immuno‐DESI‐MSI) to visualize functional macromolecules such as drug targets and cascade signaling factors. A set of boronic acid mass tags (BMTs) were synthesized to label antibodies as MSI probes. The boronic ester bond is employed to cross‐link the BMT with the galactosamine‐modified antibody. The BMT can be released from its tethered antibody by ultrafast cleavage of the boronic ester bond caused by the acidic condition of sprayed DESI microdroplets containing water. The fluorescent moiety enables the BMT to work in both optical and MS imaging modes. The positively charged quaternary ammonium group enhances the ionization efficiency. The introduction of the boron element also makes mass tags readily identified because of its unique isotope pattern. Immuno‐DESI‐MSI provides an appealing strategy to spatially map macromolecules beyond what can be observed by conventional DESI‐MSI, provided antibodies are available to the targeted molecules of interest. [ABSTRACT FROM AUTHOR]

Objective: Haemorrhagic shock is a life-threatening complication of trauma, but remains a preventable cause of death. Early recognition of retroperitoneal haemorrhage (RPH) is crucial in preventing deleterious outcomes including mortality. Injury to the 9-11th intercostal arteries (i.e. arteries of the lower thoracic region) are complicit in RPH. However, the associated injuries, implications and management of such bleeds remain poorly characterised. Methods: We performed a retrospective review of the medical records of patients diagnosed with RPH who presented to our level-1 trauma centre (2009-2019). We described the associated injuries, management and outcomes relating to RPH of the lower thoracic region (the 9-11th intercostal arteries) from this cohort to identify potential predictors and evaluate the impact of early identification and management of non-cavitary bleeds. Results: Haemorrhage of the lower intercostal arteries (LIA) into the retroperitoneal space is associated with an increased number of posterior lower rib fractures and pneumothorax/haemothorax. A higher proportion of patients in the LIA group required massive transfusion, angioembolisation or surgical ligation when compared to other causes of RPH. Conclusion: The present study highlights the importance of injury patterns, particularly posterior lower rib fractures, as predictors for early recognition and management of RPH in the prevention of deleterious patient outcomes. RPH secondary to bleeding of the LIA may require early and aggressive management of haemorrhage through massive transfusion, and angioembolisation or surgical ligation when compared to RPH because of other causes. [ABSTRACT FROM AUTHOR]

Purpose: Infection is a major complication following joint replacement (JR) surgery. However, little data exist regarding antibiotic utilisation following primary JR and how use changes with subsequent revision surgery. This study aimed to examine variation in antibiotic utilisation rates before and after hip replacement surgery in those revised for infection, revised for other reasons and those without revision. Methods: This retrospective cohort analysis used linked data from the Australian Orthopaedic Association National Joint Replacement Registry and Australian Government Pharmaceutical Benefits Scheme. Patients were included if undergoing total hip replacement (THR) for osteoarthritis in private hospitals between 2002 and 2017. Three groups were examined: primary THR with no subsequent revision (n = 102 577), primary THR with a subsequent revision for reasons other than periprosthetic joint infection (PJI) (n = 3156) and primary THR with a subsequent revision for PJI (n = 520). Monthly antibiotic utilisation rates and prevalence rate ratios (PRRs) with 95% confidence intervals (CIs) were calculated in the 2 years pre‐ and post‐THR. Results: Prior to primary THR antibiotic utilisation was 9%–10%. After primary THR, antibiotic utilisation rates were higher among patients revised for PJI (PRR 1.69, 95% CI 1.60–1.79) compared to non‐revised patients, while the utilisation rate was lower in patients revised for reasons other than infection (PRR 0.96, 95% CI 0.93–0.98). For those revised for infection, antibiotic utilisation post‐revision surgery was two times higher than those revised for other reasons (PRR 2.16, 95% CI 2.08–2.23). Utilisation of injectable antibiotics including, vancomycin, flucloxacillin and cephazolin was higher in those revised for PJI patients 0–2 weeks following surgery but not in those revised for other reasons compared to the non‐revised group. Conclusions: Ongoing antibiotic utilisation after primary surgery may be an early signal of problems with the THR and should be a prompt for primary care physicians to refer patients to specialists for further appropriate investigations and management. [ABSTRACT FROM AUTHOR]

Background: The Successful Aging after Elective Surgery (SAGES) II study was designed to increase knowledge of the pathophysiology and linkages between delirium and dementia. We examine novel biomarkers potentially associated with delirium, including inflammation, Alzheimer's disease (AD) pathology and neurodegeneration, neuroimaging markers, and neurophysiologic markers. The goal of this paper is to describe the study design and methods for the SAGES II study. Methods: The SAGES II study is a 5‐year prospective observational study of 400–420 community dwelling persons, aged 65 years and older, assessed prior to scheduled surgery and followed daily throughout hospitalization to observe for development of delirium and other clinical outcomes. Delirium is measured with the Confusion Assessment Method (CAM), long form, after cognitive testing. Cognitive function is measured with a detailed neuropsychologic test battery, summarized as a weighted composite, the General Cognitive Performance (GCP) score. Other key measures include magnetic resonance imaging (MRI), transcranial magnetic stimulation (TMS)/electroencephalography (EEG), and Amyloid positron emission tomography (PET) imaging. We describe the eligibility criteria, enrollment flow, timing of assessments, and variables collected at baseline and during repeated assessments at 1, 2, 6, 12, and 18 months. Results: This study describes the hospital and surgery‐related variables, delirium, long‐term cognitive decline, clinical outcomes, and novel biomarkers. In inter‐rater reliability assessments, the CAM ratings (weighted kappa = 0.91, 95% confidence interval, CI = 0.74–1.0) in 50 paired assessments and GCP ratings (weighted kappa = 0.99, 95% CI 0.94–1.0) in 25 paired assessments. We describe procedures for data quality assurance and Covid‐19 adaptations. Conclusions: This complex study presents an innovative effort to advance our understanding of the inter‐relationship between delirium and dementia via novel biomarkers, collected in the context of major surgery in older adults. Strengths include the integration of MRI, TMS/EEG, PET modalities, and high‐quality longitudinal data. [ABSTRACT FROM AUTHOR]

Objective: To preliminary evaluate the clinical effects of probiotics in individuals with symptomatic oral lichen planus and the possible mechanisms of action. Subjects and Methods: A group of 30 individuals with symptomatic oral lichen planus were recruited in a randomised double‐blind parallel group controlled (1:1) proof‐of‐concept pilot trial of probiotic VSL#3 vs placebo. Efficacy outcomes included changes in pain numeric rating scale, oral disease severity score and the chronic oral mucosal disease questionnaire. Adverse effects, home diary and withdrawals were assessed as feasibility outcomes. Mechanistic outcomes included changes in salivary and serum levels of CXCL10 and IFN‐γ and in oral microbial composition. Results: The probiotic VSL#3 was safe and well tolerated. We observed no statistically significant change in pain, disease activity, quality of life, serum/salivary CXCL10 or oral microbial composition with respect to placebo. Salivary IFN‐γ levels demonstrate a trend for a reduced level in the active group (p = 0.082) after 30 days of probiotic consumption. Conclusions: The present proof‐of‐concept study provides some weak not convincing indication of biological and clinical effects of probiotic VSL#3 in individuals with painful oral lichen planus. Further research in this field is needed, with the current study providing useful information to the design of future clinical trials. [ABSTRACT FROM AUTHOR]