Reduced protein kinase C delta in a high molecular weight complex in mitochondria and elevated creatine uptake into Barth syndrome B lymphoblasts.

Aim: Barth syndrome (BTHS) is a rare X-linked genetic disease in which mitochondrial oxidative phosphorylation is impaired due to a mutation in the TAFAZZIN gene. The protein kinase C delta (PKCδ) signalosome exists as a high molecular weight complex in mitochondria and controls mitochondrial oxidative phosphorylation. Method: Here, we examined PKCδ levels in mitochondria of aged-matched control and BTHS patient B lymphoblasts and its association with a higher molecular weight complex in mitochondria. Result: Immunoblot analysis of blue-native polyacrylamide gel electrophoresis mitochondrial fractions revealed an increase in total PKCδ protein expression in BTHS lymphoblasts compared to controls. In contrast, PKCδ associated with a higher molecular weight complex was markedly reduced in BTHS patient B lymphoblasts compared to controls. Given the decrease in PKCδ associated with a higher molecular weight complex in mitochondria, we examined the uptake of creatine, a compound whose utilization is enhanced upon high energy demand. Creatine uptake was markedly elevated in BTHS lymphoblasts compared to controls. Conclusion: We hypothesize that reduced PKCδ within this higher molecular weight complex in mitochondria may contribute to the bioenergetic defects observed in BTHS lymphoblasts and that enhanced creatine uptake may serve as one of several compensatory mechanisms for the defective mitochondrial oxidative phosphorylation observed in these cells.

Fundamental Body Composition Principles Provide Context for Fat-Free and Skeletal Muscle Loss With GLP-1 RA Treatments.

During weight loss, reductions in body mass are commonly described using molecular body components (eg, fat mass and fat-free mass [FFM]) or tissues and organs (eg, adipose tissue and skeletal muscle). While often conflated, distinctions between body components established by different levels of the 5-level model of body composition-which partitions body mass according to the atomic, molecular, cellular, tissue/organ, or whole-body level-are essential to recall when interpreting the composition of weight loss. A contemporary area of clinical and research interest that demonstrates the importance of these concepts is the discussion surrounding body composition changes with glucagon-like peptide-1 receptor agonists (GLP-1RA), particularly in regard to changes in FFM and skeletal muscle mass. The present article emphasizes the importance of fundamental principles when interpreting body composition changes experienced during weight loss, with a particular focus on GLP-1RA drug trials. The potential for obligatory loss of FFM due to reductions in adipose tissue mass and distribution of FFM loss from distinct body tissues are also discussed. Finally, selected countermeasures to combat loss of FFM and skeletal muscle, namely resistance exercise training and increased protein intake, are presented. Collectively, these considerations may allow for enhanced clarity when conceptualizing, discussing, and seeking to influence body composition changes experienced during weight loss.

Standardised reporting of burden of disease studies: the STROBOD statement.

BACKGROUND: The burden of disease (BOD) approach, originating with the Global Burden of Disease (GBD) study in the 1990s, has become a cornerstone for population health monitoring. Despite the widespread use of the Disability-Adjusted Life Year (DALY) metric, variations in methodological approaches and reporting inconsistencies hinder comparability across studies. To tackle this issue, we set out to develop guidelines for reporting DALY calculation studies to improve the transparency and comparability of BOD estimates. METHODS AND FINDINGS: The development of the STROBOD statement began within the European Burden of Disease Network, evolving from initial concepts discussed in workshops and training sessions focused on critical analysis of BOD studies. In 2021, a working group was formed to refine the preliminary version into the final Standardised Reporting of Burden of Disease studies (STROBOD) statement, consisting of 28 items structured across six main sections. These sections cover the title, abstract, introduction, methods, results, discussion, and open science, aiming to ensure transparency and standardization in reporting BOD studies. Notably, the methods section of the STROBOD checklist encompasses aspects such as study setting, data inputs and adjustments, DALY calculation methods, uncertainty analyses, and recommendations for reproducibility and transparency. A pilot phase was conducted to test the efficacy of the STROBOD statement, highlighting the importance of providing clear explanations and examples for each reporting item. CONCLUSIONS: The inaugural STROBOD statement offers a crucial framework for standardizing reporting in BOD research, with plans for ongoing evaluation and potential revisions based on user feedback. While the current version focuses on general BOD methodology, future iterations may include specialized checklists for distinct applications such as injury or risk factor estimation, reflecting the dynamic nature of this field.

Liposomal delivery enhances absorption of vitamin C into plasma and leukocytes: a double-blind, placebo-controlled, randomized trial.

PURPOSE: L-Ascorbic acid (vitamin C) is an essential water-soluble vitamin that plays an important role in various physiological functions, including immune health. The stability of vitamin C in the gastrointestinal tract its bioavailability is limited. This study aimed to investigate if a liposomal form of vitamin C can increase absorption compared to standard vitamin C. METHODS: In a randomized, double-blind, placebo-controlled, crossover fashion, 19 males and 8 females (n = 27; 36.0 ± 5.1 years, 165.0 ± 6.9 cm, 70.6 ± 7.1 kg) ingested a single-dose of placebo (PLA), 500 mg vitamin C (VIT C), and 500 mg liposomal vitamin C (LV-VIT C, LipoVantage®, Specnova, LLC, Tyson Corner, VA, USA). Venous blood samples were collected 0, 0.5-, 1-, 1.5-, 2-, 3-, 4-, 6-, 8-, 12-, and 24-hours after ingestion and were analyzed for plasma and leukocyte vitamin C concentration. RESULTS: VIT C and LV-VIT C demonstrated significantly greater Cmax and AUC0 - 24 in plasma and in leukocytes compared to placebo (p < 0.001). Additionally, LV-VIT C had significantly higher Cmax (plasma + 27%, leukocytes + 20%, p < 0.001) and AUC0 - 24 (plasma + 21%, leukocytes + 8%, p < 0.001) values as compared to VIT C. CONCLUSION: Liposomal formulation of vitamin C increases absorption into plasma and leukocytes. TRIAL REGISTRATION: Clinical Trials Registry - India (CTRI/2023/04/051789).

Prevalence of Medical Mistrust and Its Impact on Patient Satisfaction in Pediatric Caregivers.

Racial minorities report lower perceived quality of care received compared to non-Hispanic White Americans, resulting in racial disparities in patient satisfaction. Medical mistrust, defined as a lack of confidence in the medical establishment and the intentions of medical personnel, is more prevalent among racial minority groups and is associated with poorer health outcomes. This study examines the prevalence and racial differences of patient/caregiver medical mistrust and its relationship to patient satisfaction among the pediatric patient population at a large urban academic medical center. A cross-sectional anonymous survey was conducted for caregivers of pediatric families seen at an urban tertiary care facility, including demographic information, the Patient Satisfaction Questionnaire (PSQ), and the Group-Based Medical Mistrust Scale (GBMMS). Linear regressions and mediation analyses were performed, examining race-based medical mistrust and associations with patient satisfaction. Sixty-seven surveys (67% Black/African American, 24% White) were completed. Black/African American participants reported higher levels of medical mistrust (M = 2.29, SD = 0.88 vs. M = 1.37, SD = 0.50; p < .001), which was associated with lower patient satisfaction (p < .001). In a parallel mediation analysis, disaggregating the GBMMS into three subscales, a significant indirect relationship emerged between race and patient satisfaction via the subscale lack of support from healthcare providers (95% CI [- 1.52, - .02], p < .05). Black/African American participants were more likely to have medical mistrust, and greater medical mistrust was significantly associated with lower patient satisfaction. Black/African American participants were significantly more likely to perceive lower support from healthcare providers which, in turn, was associated with lower patient satisfaction. These findings identify potential areas for intervention to improve Black/African American patients' experience with healthcare.

In the presence of death and dying: death attitudes and compassion fatigue among certified nursing assistants in skilled care.

OBJECTIVES: Certified Nursing Assistants (CNAs) are responsible for 80-90% of direct-to-resident care in skilled nursing facilities (SNFs), and may develop close, family-like relationships with their residents. With SNFs becoming a common place of death for older adults, CNAs now find themselves engaging in end-of-life caregiving with limited training and institutional support for emotional outcomes. This study aimed to understand and evaluate the relations between bereavement, death exposure, and compassion fatigue among CNAs, hypothesizing that (a) experiential avoidance moderates the relation between death exposure and negative death attitudes and (b) death attitudes moderate the relation between death exposure and compassion fatigue. METHOD: One hundred and ten CNAs across all shifts from four skilled nursing facilities in the southeastern United States participated in surveys and, potentially, focus groups. RESULTS: Results failed to find support for death exposure being related either to experiential avoidance or negative death attitudes. However, results supported the relation between negative death attitudes and compassion fatigue. CONCLUSION: Implications highlight the need to develop interventions focusing on palliative skills-based training and emotional support of CNAs in their role as end-of-life caregivers. By reducing compassion fatigue, it may be possible to decrease job turnover and increase quality-of-care for residents.

The Film Room: Using Artificial Intelligence to Facilitate Video Review for Urology Trainees.

Video-based educational programs offer a promising avenue to augment surgical preparation, allow for targeted feedback delivery, and facilitate surgical coaching. Recently, developments in surgical intelligence and computer vision have allowed for automated video annotation and organization, drastically decreasing the manual workload required to implement video-based educational programs. In this article, we outline the development of a novel AI-assisted video forum and describe the early use in surgical education at our institution.

The American Cancer Society National Lung Cancer Roundtable strategic plan: Implementation of high-quality lung cancer screening.

More than a decade has passed since researchers in the Early Lung Cancer Action Project and the National Lung Screening Trial demonstrated the ability to save lives of high-risk individuals from lung cancer through regular screening by low dose computed tomography scan. The emergence of the most recent findings in the Dutch-Belgian lung-cancer screening trial (Nederlands-Leuvens Longkanker Screenings Onderzoek [NELSON]) further strengthens and expands on this evidence. These studies demonstrate the benefit of integrating lung cancer screening into clinical practice, yet lung cancer continues to lead cancer mortality rates in the United States. Fewer than 20% of screen eligible individuals are enrolled in lung cancer screening, leaving millions of qualified individuals without the standard of care and benefit they deserve. This article, part of the American Cancer Society National Lung Cancer Roundtable (ACS NLCRT) strategic plan, examines the impediments to successful adoption, dissemination, and implementation of lung cancer screening. Proposed solutions identified by the ACS NLCRT Implementation Strategies Task Group and work currently underway to address these challenges to improve uptake of lung cancer screening are discussed. PLAIN LANGUAGE SUMMARY: The evidence supporting the benefit of lung cancer screening in adults who previously or currently smoke has led to widespread endorsement and coverage by health plans. Lung cancer screening programs should be designed to promote high uptake rates of screening among eligible adults, and to deliver high-quality screening and follow-up care.

A Comparative Genomic Study of Conventional and Undifferentiated Melanoma.

Undifferentiated melanoma, defined as melanoma which has lost all usual phenotypic and immunohistochemical characteristics of conventional melanoma, can pose significant diagnostic challenges. Molecular studies have advanced our understanding of undifferentiated melanoma by demonstrating that a subset of these tumors harbor known melanoma driver alterations in genes such as BRAF, NRAS, and NF1. However, there is a paucity of data describing genetic alterations which may distinguish undifferentiated melanoma from conventional melanoma. In this study, we directly compared the genomic profiles of undifferentiated melanoma to a cohort of conventional melanomas, including 14 undifferentiated melanoma cases (comprised of two primary cases, two cutaneous recurrences and 10 metastases) and a cohort of 127 conventional melanomas including primary, recurrent, and metastatic cases. Targeted sequencing of 447 cancer-associated genes was performed, including identification of mutations and copy number alterations (CNAs). NRAS was the most frequent melanoma driver in undifferentiated melanoma (8/14 cases, 57%), although notably only one undifferentiated melanoma harbored an NRAS Q61R mutation. Compared to the conventional melanoma cohort, undifferentiated melanoma demonstrated statistically significant enrichment of pathogenic activating RAC1 mutations (6/14 total cases, 43%), including P29S (4/6 cases), P29L (1/6 cases) and D11E (1/6 cases). In addition to providing insight into the molecular pathogenesis of undifferentiated melanoma, these findings also suggest that RAS Q61R immunohistochemistry may have limited utility for its diagnosis. The presence of recurrent RAC1 mutations in undifferentiated melanoma is also notable as these alterations may contribute to mitogen-activated protein (MAP) kinase pathway targeted therapy resistance. Furthermore, the RAC1 alterations identified in this cohort have been shown to drive a melanocytic to mesenchymal switch in melanocytes, offering a possible explanation for the undifferentiated phenotype of these melanomas.

People with HIV exhibit spectrally distinct patterns of rhythmic cortical activity serving cognitive flexibility.

Despite effective antiretroviral therapy, cognitive impairment remains prevalent among people with HIV (PWH) and decrements in executive function are particularly prominent. One component of executive function is cognitive flexibility, which integrates a variety of executive functions to dynamically adapt one's behavior in response to changing contextual demands. Though substantial work has illuminated HIV-related aberrations in brain function, it remains unclear how the neural oscillatory dynamics serving cognitive flexibility are affected by HIV-related alterations in neural functioning. Herein, 149 participants (PWH: 74; seronegative controls: 75) between the ages of 29-76 years completed a perceptual feature matching task that probes cognitive flexibility during high-density magnetoencephalography (MEG). Neural responses were decomposed into the time-frequency domain and significant oscillatory responses in the theta (4-8 Hz), alpha (10-16 Hz), and gamma (74-98 Hz) spectral windows were imaged using a beamforming approach. Whole-brain voxel-wise comparisons were then conducted on these dynamic functional maps to identify HIV-related differences in the neural oscillatory dynamics supporting cognitive flexibility. Our findings indicated group differences in alpha oscillatory activity in the cingulo-opercular cortices, and differences in gamma activity were found in the cerebellum. Across all participants, alpha and gamma activity in these regions were associated with performance on the cognitive flexibility task. Further, PWH who had been treated with antiretroviral therapy for a longer duration and those with higher current CD4 counts had alpha responses that more closely resembled those of seronegative controls, suggesting that optimal clinical management of HIV infection is associated with preserved neural dynamics supporting cognitive flexibility.

Emulating Low-Dose PCCT Image Pairs with Independent Noise for Self-Supervised Spectral Image Denoising.

Photon counting CT (PCCT) acquires spectral measurements and enables generation of material decomposition (MD) images that provide distinct advantages in various clinical situations. However, noise amplification is observed in MD images, and denoising is typically applied. Clean or high-quality references are rare in clinical scans, often making supervised learning (Noise2Clean) impractical. Noise2Noise is a self-supervised counterpart, using noisy images and corresponding noisy references with zero-mean, independent noise. PCCT counts transmitted photons separately, and raw measurements are assumed to follow a Poisson distribution in each energy bin, providing the possibility to create noise-independent pairs. The approach is to use binomial selection to split the counts into two low-dose scans with independent noise. We prove that the reconstructed spectral images inherit the noise independence from counts domain through noise propagation analysis and also validated it in numerical simulation and experimental phantom scans. The method offers the flexibility to split measurements into desired dose levels while ensuring the reconstructed images share identical underlying features, thereby strengthening the model's robustness for input dose levels and capability of preserving fine details. In both numerical simulation and experimental phantom scans, we demonstrated that Noise2Noise with binomial selection outperforms other common self-supervised learning methods based on different presumptive conditions.

Evolving through multiple, co-existing pressures to change: a case study of self-organization in primary care during the COVID-19 pandemic in Canada.

BACKGROUND: Primary care is often described as slow to change. But conceptualized through complexity theory, primary care is continually changing in unpredictable, non-linear ways through self-organization processes. Self-organization has proven hard to study directly. We aimed to develop a methodology to study self-organization and describe how a primary care clinic self-organizes over time. METHODOLOGY: We completed a virtual case study of an urban primary care clinic from May-Nov 2021, applying methodological insights from actor-network theory to examine the complexity theory concept of self-organization. We chose to focus our attention on self-organization activities that alter organizational routines. Data included fieldnotes of observed team meetings, document collection, interviews with clinic members, and notes from brief weekly discussions to detect actions to change clinical and administrative routines. Adapting schema analysis, we described changes to different organizational routines chronologically, then explored intersecting changes. We sought feedback on results from the participating clinic. FINDINGS: Re-establishing equilibrium remained challenging well into the COVID-19 pandemic. The primary care clinic continued to self-organize in response to changing health policies, unintended consequences of earlier adaptations, staff changes, and clinical care initiatives. Physical space, technologies, external and internal policies, guidelines, and clinic members all influenced self-organization. Changing one created ripple effects, sometimes generating new, unanticipated problems. Member checking confirmed we captured most of the changes to organizational routines during the case study period. CONCLUSIONS: Through insights from actor-network theory, applied to studying actions taken that alter organizational routines, it is possible to operationalize the theoretical construct of self-organization. Our methodology illuminates the primary care clinic as a continually changing entity with co-existing and intersecting processes of self-organization in response to varied change pressures.

A synthetic cell-free pathway for biocatalytic upgrading of one-carbon substrates.

Biotechnological processes hold tremendous potential for the efficient and sustainable conversion of one-carbon (C1) substrates into complex multi-carbon products. However, the development of robust and versatile biocatalytic systems for this purpose remains a significant challenge. In this study, we report a hybrid electrochemical-biochemical cell-free system for the conversion of C1 substrates into the universal biological building block acetyl-CoA. The synthetic reductive formate pathway (ReForm) consists of five core enzymes catalyzing non-natural reactions that were established through a cell-free enzyme engineering platform. We demonstrate that ReForm works in a plug-and-play manner to accept diverse C1 substrates including CO2 equivalents. We anticipate that ReForm will facilitate efforts to build and improve synthetic C1 utilization pathways for a formate-based bioeconomy.

Application of the wildland fire emissions inventory system to estimate fire emissions on forest lands of the United States.

BACKGROUND: Forests are significant terrestrial biomes for carbon storage, and annual carbon accumulation of forest biomass contributes offsets affecting net greenhouse gases in the atmosphere. The immediate loss of stored carbon through fire on forest lands reduces the annual offsets provided by forests. As such, the United States reporting includes annual estimates of direct fire emissions in conjunction with the overall forest stock and change estimates as a part of national greenhouse gas inventories within the United Nations Framework Convention on Climate Change. Forest fire emissions reported for the United States, such as the 129 Tg CO2 reported for 2022, are based on the Wildland Fire Emissions Inventory System (WFEIS). Current WFEIS estimates are included in the Inventory of U.S. Greenhouse Gas Emissions and Sinks: 1990-2022 published in 2024 by the United States Environmental Protection Agency. Here, we describe WFEIS the fire emissions inventory system we used to address current information needs, and an analysis to confirm compatibility of carbon mass between estimated forest fire emissions and carbon in forest stocks. RESULTS: The summaries of emissions from forests are consistent with previous reports that show rates and interannual variability in emissions and forest land area burned are generally greater in recent years relative to the 1990s. Both emissions and interannual variability are greater in the western United States. The years with the highest CO2 emissions from forest fires on the 48 conterminous states plus Alaska were 2004, 2005, and 2015. In some years, Alaska emissions exceed those of the 48 conterminous states, such as in 2022, for example. Comparison of forest fire emission to forest carbon stocks indicate there is unlikely any serious disconnect between inventory and fire emissions estimates. CONCLUSIONS: The WFEIS system is a user-driven approach made available via a web browser. Model results are compatible with the scope and reporting needs of the annual national greenhouse gas inventories.

Improving wood carbon fractions for multiscale forest carbon estimation.

BACKGROUND: Wood carbon fractions (CFs)-the proportion of dry woody biomass comprised of elemental carbon (C)-are a key component of forest C estimation protocols and studies. Traditionally, a wood CF of 50% has been assumed in forest C estimation protocols, but recent studies have specifically quantified differences in wood CFs across several different forest biomes and taxonomic divisions, negating the need for generic wood CF assumptions. The Intergovernmental Panel on Climate Change (IPCC), in its 2006 "Guidelines for National Greenhouse Gas Inventories", published its own multitiered system of protocols for estimating forest C stocks, which included wood CFs that (1) were based on the best available literature (at the time) and (2) represented a significant improvement over the generic 50% wood CF assumption. However, a considerable number of new studies on wood CFs have been published since 2006, providing more accurate, robust, and spatially- and taxonomically- specific wood CFs for use in forest C estimation. MAIN TEXT: We argue that the IPCC's recommended wood CFs and those in many other forest C estimation models and protocols (1) differ substantially from, and are less robust than, wood CFs derived from recently published data-rich studies; and (2) may lead to nontrivial errors in forest C estimates, particularly for countries that rely heavily on Tier 1 forest C methods and protocols (e.g., countries of the Global South with large expanses of tropical forests). Based on previous studies on this topic, we propose an alternative set of refined wood CFs for use in multiscale forest C estimation, and propose a novel decision-making framework for integrating species- and location-specific wood CFs into forest C estimation models. CONCLUSION: The refined wood CFs that we present in this commentary may be used by the IPCC to update its recommended wood CFs for use in forest C estimation. Additionally, we propose a novel decision-making framework for integrating data-driven wood CFs into a wider suite of multitiered forest C estimation protocols, models, and studies.

Miniature linear and split-belt treadmills reveal mechanisms of adaptive motor control in walking Drosophila.

To navigate complex environments, walking animals must detect and overcome unexpected perturbations. One technical challenge when investigating adaptive locomotion is measuring behavioral responses to precise perturbations during naturalistic walking; another is that manipulating neural activity in sensorimotor circuits often reduces spontaneous locomotion. To overcome these obstacles, we introduce miniature treadmill systems for coercing locomotion and tracking 3D kinematics of walking Drosophila. By systematically comparing walking in three experimental setups, we show that flies compelled to walk on the linear treadmill have similar stepping kinematics to freely walking flies, while kinematics of tethered walking flies are subtly different. Genetically silencing mechanosensory neurons altered step kinematics of flies walking on the linear treadmill across all speeds. We also discovered that flies can maintain a forward heading on a split-belt treadmill by specifically adapting the step distance of their middle legs. These findings suggest that proprioceptive feedback contributes to leg motor control irrespective of walking speed and that the fly's middle legs play a specialized role in stabilizing locomotion.

Assessing Relative Linguistic Impairment With Model-Based Item Selection.

PURPOSE: A picture naming test is presented that reveals impairment to specific mechanisms involved in the naming process, using accuracy scores on curated item sets. A series of psychometric validation experiments are reported. METHOD: Using a computational model that enables estimation of item difficulty at the lexical and sublexical stages of word retrieval, two complimentary sets of items were constructed that challenge the respective psycholinguistic levels of representation. The difference in accuracy between these item sets yields the relative linguistic impairment (RLI) score. In a cohort of 91 people with chronic left-hemisphere stroke who enrolled in a clinical trial for anomia, we assessed psychometric properties of the RLI score and then used the new scale to make predictions about other language behaviors, lesion distributions, and functional activation during naming. RESULTS: RLI scores had adequate psychometric properties for clinical significance. RLI scores contained predictive information about spontaneous speech fluency, over and above accuracy. A dissociation was observed between performance on the RLI item sets and performance on the subtests of an independent language battery. Sublexical RLI was significantly associated with apraxia of speech and with lesions encompassing perisylvian regions, while lexical RLI was associated with lesions to deep white matter. The RLI construct was reflected in functional brain activity during naming, independent of overall accuracy, with a respective shift of activation between dorsal and ventral networks responsible for different aspects of word retrieval. CONCLUSION: The RLI assessment satisfies the psychometric requirements to serve as a useful clinical measure.

Race and ethnicity moderate the associations between lifetime psilocybin use and past year hypertension.

Background: Hypertension is a major source of morbidity and mortality worldwide, particularly for racial and ethnic minorities who face higher rates of hypertension and worse health-related outcomes. Recent research has reported on protective associations between classic psychedelics and hypertension; however, there is a need to explore how race and ethnicity may moderate such associations. Methods: We used data from the National Survey on Drug Use and Health (2005-2014) to assess whether race and ethnicity moderate the associations between classic psychedelic use - specifically psilocybin - and past year hypertension. Results: Hispanic identity moderated the associations between psilocybin use and past year hypertension. Furthermore, individuals who used psilocybin and identified as Non-Hispanic White had reduced odds of hypertension (aOR: 0.83); however, these associations were not observed for any other racial or ethnic groups in our study for individuals who used psilocybin. Conclusion: Overall, our results demonstrate that the associations between psychedelics and hypertension may vary by race and ethnicity. Longitudinal studies and clinical trials can further advance this research and determine whether such differences exist in causal contexts. Project registration: https://osf.io/xsz2p/?view_only=0bf7b56749034c18abb2a3f8d3d4bc0b.