Profibrotic monocyte-derived alveolar macrophages are expanded in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19.

Monocyte-derived alveolar macrophages drive lung injury and fibrosis in murine models and are associated with pulmonary fibrosis in humans. Monocyte-derived alveolar macrophages have been suggested to develop a phenotype that promotes lung repair as injury resolves. We compared single-cell and cytokine profiling of the alveolar space in a cohort of 35 patients with post-acute sequelae of COVID-19 who had persistent respiratory symptoms and abnormalities on a computed tomography scan of the chest that subsequently improved or progressed. The abundance of monocyte-derived alveolar macrophages, their gene expression programs, and the level of the monocyte chemokine CCL2 in bronchoalveolar lavage fluid positively associated with the severity of radiographic fibrosis. Monocyte-derived alveolar macrophages from patients with resolving or progressive fibrosis expressed the same set of profibrotic genes. Our findings argue against a distinct reparative phenotype in monocyte-derived alveolar macrophages, highlighting their utility as a biomarker of failed lung repair and a potential target for therapy.

Single Leg Hop Performance After Anterior Cruciate Ligament Reconstruction: Ready for Landing but Cleared for Take-Off?

CONTEXT: Understanding former professional football players engagement with health promoting behaviors (physical exercise, high quality diet, and good sleep hygiene) will be helpful for developing lifestyle interventions to improve their feelings of well-being, a relatively understudied facet of health among this population. OBJECTIVE: Examine associations among health-promoting behaviors and subjective outcomes related to well-being among former National Football League (NFL) players. DESIGN: Cross-sectional. SETTING: Online or hard-copy survey. PATIENTS OR OTHER PARTICIPANTS: Former NFL players. MAIN OUTCOME MEASURES: Self-reported health-promoting behaviors (exercise frequency, diet quality, sleep duration and disturbance) and factors related to well-being (PROMIS ® Meaning and Purpose [MP], Self-Efficacy [SE], Ability to Participate in Social Roles and Activities [SRA]). Multivariable linear regression models were fit for each well-being-related factor with health-promoting behaviors as explanatory variables alongside select demographic, behavioral, and functional covariates. Models were fit for the full sample and separately for individual age groups: <30 years; 30-39 years; 40-49 years; 50-59 years; 60-69 years; and 70+ years. RESULTS: A total of 1,784 former NFL players (aged 52.3±16.3 years) completed the survey. Lower sleep disturbance was associated with better MP (ß[standard error]=-0.196[0.024]), SE (ß[standard error]=-0.185[0.024]), and SRA (ß[standard error]=-0.137[0.017]) in the full sample and almost all the individual age groups. More frequent moderate-to-vigorous exercise was associated with higher MP (ß[standard error]=0.068[0.025]) and SRA (ß[standard error]=0.151[0.065]) in the full sample, and with better MP, SE, and SRA among select middle-aged groups (between 40-69 years old). Diet quality, resistance training exercise frequency, other wellness activity frequency, and sleep duration were not associated with well-being-related factors in the full-group and sparse significant associations were observed in individual age group models. CONCLUSIONS: Lower sleep disturbance and more frequent moderate-to-vigorous exercise frequency may be important targets for improving overall health and well-being among former NFL players.

A Machine Learning Approach to Concussion Risk Estimation Among Players Exhibiting Visible Signs in Professional Hockey.

BACKGROUND: The identification of concussion risk factors, such as visible signs and mechanisms of injury, improves concussion identification. Exploring individual risk factors, such as concussion history, may help to improve existing concussion risk models and algorithms. OBJECTIVES: The primary aim of the current study was to use machine learning techniques to develop a comprehensive, prospectively coded concussion risk model in professional hockey among players exhibiting visible signs. The secondary aim was to examine whether including concussion history improves model performance. METHODS: Data from the National Hockey League (NHL) spotter program, including coded visible signs and mechanisms of injury associated with possible concussive events, were extracted from the 2018-2019 to the 2021-2022 seasons. Each unique spotter event was matched with data extracted from the medical record to determine whether the event was associated with a subsequent physician diagnosed concussion. We compared the ability of three machine learning-based approaches to identify the likelihood of physician diagnosed concussion: conditional inference tree, conditional inference random forest, and logistic regression. RESULTS: A total of 1563 unique events with visible signs were identified by spotters (183 leading to a concussion diagnosis). A randomly selected training sample had 1250 events (146 concussions) and the remaining set-aside test sample had 313 events (37 concussions). The obtained models performed at a high level with large effects in the training [area under the receiver operating characteristic curve (AUC) = 0.79] and set-aside test data (AUC = 0.82). Concussion history was retained in the tree and logistic regression models, with each additional prior concussion associated with a 1.32 times increased odds of concussion diagnosis. CONCLUSIONS: We present simple tree and logistic algorithms for concussion screening and as diagnostic aids. Our results show that player concussion history can explain additional risk above and beyond that explained by visible signs and mechanisms of injury alone.

Continuous glucose monitoring metrics in people with liver glycogen storage disease and idiopathic ketotic hypoglycemia: A single-center, retrospective, observational study.

BACKGROUND: Cohort data on continuous glucose monitoring (CGM) metrics are scarce for liver glycogen storage diseases (GSDs) and idiopathic ketotic hypoglycemia (IKH). The aim of this study was to retrospectively describe CGM metrics for people with liver GSDs and IKH. PATIENTS AND METHODS: CGM metrics (descriptive, glycemic variation and glycemic control parameters) were calculated for 47 liver GSD and 14 IKH patients, categorized in cohorts by disease subtype, age and treatment status, and compared to published age-matched CGM metrics from healthy individuals. Glycemic control was assessed as time-in-range (TIR; ≥3.9 - ≤7.8 and ≥3.9 - ≤10.0 mmol/L), time-below-range (TBR; <3.0 mmol/L and ≥3.0 - ≤3.9 mmol/L), and time-above-range (TAR; >7.8 and >10.0 mmol/L). RESULTS: Despite all patients receiving dietary treatment, GSD cohorts displayed significantly different CGM metrics compared to healthy individuals. Decreased TIR together with increased TAR were noted in GSD I, GSD III, and GSD XI (Fanconi-Bickel syndrome) cohorts (all p < 0.05). In addition, all GSD I cohorts showed increased TBR (all p < 0.05). In GSD IV an increased TBR (p < 0.05) and decreased TAR were noted (p < 0.05). In GSD IX only increased TAR was observed (p < 0.05). IKH patient cohorts, both with and without treatment, presented CGM metrics similar to healthy individuals. CONCLUSION: Despite dietary treatment, most liver GSD cohorts do not achieve CGM metrics comparable to healthy individuals. International recommendations on the use of CGM and clinical targets for CGM metrics in liver GSD patients are warranted, both for patient care and clinical trials.

The transition to synchronization of networked systems.

We study the synchronization properties of a generic networked dynamical system, and show that, under a suitable approximation, the transition to synchronization can be predicted with the only help of eigenvalues and eigenvectors of the graph Laplacian matrix. The transition comes out to be made of a well defined sequence of events, each of which corresponds to a specific clustered state. The network's nodes involved in each of the clusters can be identified, and the value of the coupling strength at which the events are taking place can be approximately ascertained. Finally, we present large-scale simulations which show the accuracy of the approximation made, and of our predictions in describing the synchronization transition of both synthetic and real-world large size networks, and we even report that the observed sequence of clusters is preserved in heterogeneous networks made of slightly non-identical systems.

Clinical Features and Therapeutic Outcomes Comparing Primary Mediastinal Large B-cell Lymphoma to Mediastinal Hodgkin Disease.

Currently, there is limited data available comparing Primary Mediastinal Large B-cell Lymphoma (PMBL) and mediastinal Hodgkin disease, nodular sclerosis type (HDNS). This is a retrospective cohort study that compares the clinical features, histology through immunohistochemistry (IHC) and treatment outcomes of 19 cases of PMBL and 39 cases of HDNS diagnosed over 13 years at a single institution in San Juan, PR. Superior Vena Cava syndrome (SVCS) and elevated Lactate Dehydrogenase (LDH) levels were more frequently seen in the PMBL cohort. At the median follow-up visit, of 74 months, no significant difference was seen in overall survival or progression free survival between PMBL and HDNS. Almost all of the relapses in the PMBL group occurred within 12 months of diagnosis. Our data suggests that PMBL and HDNS differ in their clinical presentation and have a favorable prognosis.

Reverse Shoulder Arthroplasty versus Non-Operative Treatment of Three-Part and Four-Part Proximal Humerus Fractures in the Elderly Patient: A Pooled Analysis and Systematic Review.

Background: The treatment of complex proximal humerus fractures in elderly patients is not yet fully elucidated. Of all treatment options, reverse shoulder arthroplasty (RSA) and non-operative treatment (NOT) appear to provide the best results. Evidence to guide the choice between the two is sparse. Therefore, this review provides an overview of the available evidence on RSA versus NOT. Methods: Studies comparing complex proximal humerus fractures in patients aged >65 years treated either with RSA or NOT were included for systematic review and direct comparison via pooled analysis of patient-rated outcome and range of motion. Indirect comparison of case series and non-comparative studies on either treatment was performed separately. Results: Three comparative studies including 77 patients treated with RSA and 81 treated non-operatively were analysed. The RSA group scored better for both the Constant-Murley score (mean difference 6 points) and DASH score (mean difference 8 points). No differences were detected in ASES, PENN score, pain scores, or range of motion between treatment groups. The most common complications for RSA were infection (3%), nerve injury (2%), and dislocation (2%). Reoperation was required in 5%. In the NOT group, common complications included malunion (42%), osteonecrosis (25%), and non-union (3%); no reoperation was required. Patient satisfaction was equal in both groups. Conclusions: The functional outcomes and range of motion after RSA seemed satisfactory and potentially superior to NOT in elderly patients. Patient satisfaction was comparable despite a high malunion and osteonecrosis rate in the non-operative treatment group, which did not require re-interventions.

Longitudinal Characterization of Pain Interference and Influential Factors in Former National Football League (NFL) Players Over a 19-Year Period: An NFL-LONG Study.

Previous studies on pain experiences in retired contract sport athletes have been cross-sectional, leaving gaps in our understanding of the evolution of pain interference (PI) and factors that influence trajectories decades after sport discontinuation. This study investigated the longitudinal course of PI in former male National Football League (NFL) players over a 19-year period following sport discontinuation and examined factors influencing overall levels and trajectories of PI. Former NFL players completed health surveys in 2001, 2010, and 2019, with PI ratings measured using the 36-Item Short Form Health Survey (2001 and 2010) and the Patient-Reported Outcomes Measurement Information System (2019). Unconditional latent growth curve models analyzed overall PI severity and trajectories. Conditional latent growth curve models explored the influence of musculoskeletal injuries, osteoarthritis (OA), and depression diagnosis on PI. Over 19 years (N = 338; mean age = 48.96 ± 9.35), PI significantly increased (slope = .179, P < .001; mean Patient-Reported Outcomes Measurement Information System PI t-scores 2001 = 54.19, 2010 = 54.64, 2019 = 57.38). Cumulative musculoskeletal injuries (B = .092, P < .001) and baseline depression diagnosis (B = 4.463, P < .001) were associated with overall PI levels but not change over time. OA was significantly associated with overall PI levels (B = 6.536, P < .001) and trajectory (B = -.253, P < .001); those endorsing OA in 2001 had lower PI increases over 19 years. The body region of injury and level of play during injuries mirrored overall injury effects. PI mildly increased over 19 years, with multiple factors independently influencing overall PI levels. Enhancing former contact sport athletes' daily functionality may be achieved through holistic biopsychosocial interventions addressing musculoskeletal injuries, OA, and depression. Future research should identify factors influencing elevated trajectories of long-term PI post-sport discontinuation. PERSPECTIVE: This study assessed PI in former NFL athletes over 2 decades, revealing notable interindividual variability in trajectories over time. Musculoskeletal injuries, depression, and OA correlated with overall PI. Prevention and intervention in these 3 areas present the potential to improve disruptions in daily living due to pain in former athletes.

Range of trait variation in prey determines evolutionary contributions to predator growth rates.

Evolutionary and ecological dynamics can occur on similar timescales and thus influence each other. While it has been shown that the relative contribution of ecological and evolutionary change to population dynamics can vary, it still remains unknown what influences these differences. Here, we test whether prey populations with increased variation in their defence and competitiveness traits will have a stronger impact on evolution for predator growth rates. We controlled trait variation by pairing distinct clonal lineages of the green alga Chlamydomonas reinhardtii with known traits as prey with the rotifer Brachionus calyciforus as predator and compared those results with a mechanistic model matching the empirical system. We measured the impact of evolution (shift in prey clonal frequency) and ecology (shift in prey population density) for predator growth rate and its dependency on trait variation using an approach based on a 2-way ANOVA. Our experimental results indicated that higher trait variation, i.e., a greater distance in trait space, increased the relative contribution of prey evolution to predator growth rate over 3-4 predator generations, which was also observed in model simulations spanning longer time periods. In our model, we also observed clone-specific results, where a more competitive undefended prey resulted in a higher evolutionary contribution, independent of the trait distance. Our results suggest that trait combinations and total prey trait variation combine to influence the contribution of evolution to predator population dynamics, and that trait variation can be used to identify and better predict the role of eco-evolutionary dynamics in predator-prey systems.

Drosophila in the study of hTBP protein interactions in the development and modeling of SCA17.

BACKGROUND: Protein interactions participate in many molecular mechanisms involved in cellular processes. The human TATA box binding protein (hTBP) interacts with Antennapedia (Antp) through its N-terminal region, specifically via its glutamine homopeptides. This PolyQ region acts as a binding site for other transcription factors under normal conditions, but when it expands, it generates spinocerebellar ataxia 17 (SCA17), whose protein aggregates in the brain prevent its correct functioning. OBJECTIVE: To determine whether the hTBP glutamine-rich region is involved in its interaction with homeoproteins and the role it plays in the formation of protein aggregates in SCA17. MATERIAL AND METHODS: We characterized hTBP interaction with other homeoproteins using BiFC, and modeled SCA17 in Drosophila melanogaster by targeting hTBPQ80 to the fly brain using UAS/GAL4. RESULTS: There was hTBP interaction with homeoproteins through its glutamine-rich region, and hTBP protein aggregates with expanded glutamines were found to affect the locomotor capacity of flies. CONCLUSIONS: The study of hTBP interactions opens the possibility for the search for new therapeutic strategies in neurodegenerative pathologies such as SCA17.

ANTECEDENTES: Las interacciones proteicas participan en una gran cantidad de mecanismos moleculares que rigen los procesos celulares. La proteína de unión a la caja TATA humana (hTBP) interacciona con Antennapedia (Antp) a través de su extremo N-terminal, específicamente a través de sus homopéptidos de glutaminas. Esta región PolyQ sirve como sitio de unión a factores de transcripción en condiciones normales, pero cuando se expande genera la ataxia espinal cerebelosa 17 (SCA17), cuyos agregados proteicos en el cerebro impiden su funcionamiento correcto. OBJETIVO: Determinar si la región rica en glutaminas de hTBP interviene en su interacción con homeoproteínas y el papel que tiene en la formación de agregados proteicos en SCA17. MATERIAL Y MÉTODOS: Se caracterizó la interacción de hTBP con otras homeoproteínas usando BiFC y se modeló SCA17 en Drosophila melanogaster dirigiendo hTBPQ80 al cerebro de las moscas usando UAS/GAL4. RESULTADOS: Existió interacción de hTBP con homeoproteínas a través de su región rica en glutaminas. Los agregados proteicos de hTBP con las glutaminas expandidas afectaron la capacidad locomotriz de las moscas. CONCLUSIONES: El estudio de las interacciones de hTBP abre la posibilidad para la búsqueda de nuevas estrategias terapéuticas en patologías neurodegenerativas como SCA17.

Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin.

Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen. SGLT2 inhibitors act on apical glucose reabsorption of renal proximal tubular cells. The purpose of this study was to retrospectively describe the first experiences with repurposing the SGLT2 inhibitor empagliflozin to treat the generalized tubulopathy in Fanconi-Bickel syndrome. A case series was conducted of seven persons from five families (five males, two females; three children, who were 14y5m, 2y9m, and 1y6m old) with genetically confirmed Fanconi-Bickel syndrome, off-label treated with empagliflozin. Median (range) age at start of empagliflozin was 27 years (1y6m - 61y) and duration of follow-up under empagliflozin treatment was 169 days (57-344). Under empagliflozin (up to 25 mg/d), biochemical parameters of tubular cell integrity (urinary N-acetyl-glucosaminidase) and/or tubular functions (including urinary α1-microglobulin) improved in all persons with Fanconi-Bickel syndrome, albeit to varying degrees. Clinically, supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children, whereas results in the four adult patients were more variable and not as significant. Empagliflozin was well-tolerated and no symptomatic hypoglycemia was observed. In conclusion, SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi-Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood.

Structure-specific rigid dose accumulation dosimetric analysis of ablative stereotactic MRI-guided adaptive radiation therapy in ultracentral lung lesions.

BACKGROUND: Definitive local therapy with stereotactic ablative radiation therapy (SABR) for ultracentral lung lesions is associated with a high risk of toxicity, including treatment related death. Stereotactic MR-guided adaptive radiation therapy (SMART) can overcome many of the challenges associated with SABR treatment of ultracentral lesions. METHODS: We retrospectively identified 14 consecutive patients who received SMART to ultracentral lung lesions from 10/2019 to 01/2021. Patients had a median distance from the proximal bronchial tree (PBT) of 0.38 cm. Tumors were most often lung primary (64.3%) and HILUS group A (85.7%). A structure-specific rigid registration approach was used for cumulative dose analysis. Kaplan-Meier log-rank analysis was used for clinical outcome data and the Wilcoxon Signed Rank test was used for dosimetric data. RESULTS: Here we show that SMART dosimetric improvements in favor of delivered plans over predicted non-adapted plans for PBT, with improvements in proximal bronchial tree DMax of 5.7 Gy (p = 0.002) and gross tumor 100% prescription coverage of 7.3% (p = 0.002). The mean estimated follow-up is 17.2 months and 2-year local control and local failure free survival rates are 92.9% and 85.7%, respectively. There are no grade ≥ 3 toxicities. CONCLUSIONS: SMART has dosimetric advantages and excellent clinical outcomes for ultracentral lung tumors. Daily plan adaptation reliably improves target coverage while simultaneously reducing doses to the proximal airways. These results further characterize the therapeutic window improvements for SMART. Structure-specific rigid dose accumulation dosimetric analysis provides insights that elucidate the dosimetric advantages of SMART more so than per fractional analysis alone.

Stereotactic MR-guided Adaptive Radiation Therapy (SMART) is a type of radiation therapy for cancer. With SMART, treatment can be adapted based on daily changes in the body seen via imaging. SMART can safely deliver radiation to lung tumors near the center of the body which are risky to treat, due to potential damage to nearby organs. We looked at 14 patients who received SMART to determine how much changing the radiation plan each day improved our ability to safely deliver high doses. We found that SMART not only improved our ability to cover the entirety of the tumor with the dose originally intended, but also reduced dose to nearby organs. Treatment resulted in excellent control of the tumor with few side effects. SMART shows promise for safer and more effective treatment for lung tumors in this part of the body.

Operating Properties of Disease Activity Indices in Pediatric Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND: Accurate, reliable, and responsive disease activity indices are important to streamline drug approval and treatment modalities for pediatric inflammatory bowel disease (pIBD). We aimed to identify all scoring indices used in pIBD randomized controlled trials (RCTs) and to evaluate their operating properties. METHODS: MEDLINE, EMBASE, and CENTRAL were searched on December 6, 2022, to identify studies evaluating clinical, endoscopic, imaging, or patient-reported outcome measures (PROMs) in pIBD including Crohn's disease (CD) and ulcerative colitis (UC). Validity, reliability, responsiveness, and feasibility were summarized. RESULTS: Seventy RCTs evaluating pIBD indices were identified. Forty-one studies reported on the operating properties of 14 eligible indices (n = 9 CD, n = 5 UC). The Pediatric Crohn's Disease Activity Index (PCDAI) varied widely in terms of validity and reliability and was less feasible overall. In contrast, the Mucosal Inflammation Noninvasive Index, which includes fecal calprotectin, had better operating properties than the PCDAI. The Simplified Endoscopic Mucosal Assessment of Crohn's Disease appears more feasible and had similar operating properties than the longer Simple Endoscopic Score for Crohn's Disease. The Pediatric Ulcerative Colitis Activity Index was feasible, valid, and reliable, but responsiveness needs to be evaluated further. The Endoscopic Mayo score and the Ulcerative Colitis Endoscopic Index of Severity were reliable, but validity and responsiveness need to be evaluated further. Imaging and PROMs/quality of life indices need further evaluation. CONCLUSIONS: The operating properties of pIBD clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices.

The operating properties of pediatric inflammatory bowel disease clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices in this population.

Precise infliximab exposure and pharmacodynamic control to achieve deep remission in paediatric Crohn's disease (REMODEL-CD): study protocol for a multicentre, open-label, pragmatic clinical trial in the USA.

INTRODUCTION: The only biologic therapy currently approved to treat moderate to severe Crohn's disease in children (<18 years old) are those that antagonise tumour necrosis factor-alpha (anti-TNF). Therefore, it is critically important to develop novel strategies that maximise treatment effectiveness in this population. There is growing evidence that rates of sustained corticosteroid-free clinical remission, endoscopic healing and drug durability considerably improve when patients receive early anti-TNF dose optimisations guided by reactive or proactive therapeutic drug monitoring and pharmacodynamic monitoring. In response, our team has developed a personalised and scalable infliximab dosing intervention that starts with dose selection and continues throughout maintenance to optimise drug exposure. We hypothesise that a precision dosing strategy starting from induction and targeting dose-specific pharmacokinetic and pharmacodynamic endpoints throughout therapy will significantly improve outcomes compared with a conventional dosing strategy. METHODS AND ANALYSIS: Conduct a clinical trial to assess rates of deep remission between Crohn's disease patients receiving infliximab with precision dosing (n=90) versus conventional care (n=90). Patients (age 6-22 years) will be recruited from 10 medical centres in the USA. Each centre has been selected to provide either precision dosing or conventional care dosing. Precision dosing includes the use of a clinical decision support tool (RoadMAB) from the start of infliximab to achieve specific (personalised) trough concentrations and specific pharmacodynamic targets (at doses 3, 4 and 6). Conventional care includes the use of a modified infliximab starting dose (5 or 7.5 mg/kg based on the pretreatment serum albumin) with a goal to achieve maintenance trough concentrations of 5-10 µg/mL. The primary endpoint is year 1 deep remission defined as a combination of clinical remission (paediatric Crohn's disease activity index<10 (child) or a Crohn's disease activity index<150 (adults)), off prednisone>8 weeks and endoscopic remission (simple endoscopic severity-Crohn's disease≤2). ETHICS AND DISSEMINATION: ). The study protocol has been approved by the Cincinnati Children's Hospital Medical Centre Institutional Review Board. Study results will be disseminated in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05660746.

Optimization of cardiopulmonary bypass prime fluid to preserve microcirculatory perfusion during on-pump coronary artery bypass graft surgery: PRIME study protocol for a double-blind randomized trial.

BACKGROUND: Acute microcirculatory perfusion disturbances and organ edema are important factors leading to organ dysfunction during cardiac surgery with cardiopulmonary bypass (CPB). Priming of the CPB system with crystalloid or colloid fluids, which inevitably leads to hemodilution, could contribute to this effect. However, there is yet no optimal evidence-based strategy for this type of priming. Hence, we will investigate different priming strategies to reduce hemodilution and preserve microcirculatory perfusion. METHODS: The PRIME study is a single-center double-blind randomized trial. Patients undergoing elective coronary artery bypass graft surgery with CPB will be randomized into three groups of prime fluid strategy: (1) gelofusine with crystalloid, (2) albumin with crystalloid, or (3) crystalloid and retrograde autologous priming. We aim to include 30 patients, 10 patients in each arm. The primary outcome is the change in microcirculatory perfusion. Secondary outcomes include colloid oncotic pressure; albumin; hematocrit; electrolytes; fluid balance and requirements; transfusion rates; and endothelial-, glycocalyx-, inflammatory- and renal injury markers. Sublingual microcirculatory perfusion will be measured using non-invasive sidestream dark field video microscopy. Microcirculatory and blood measurements will be performed at five consecutive time points during surgery up to 24 h after admission to the intensive care unit. DISCUSSION: PRIME is the first study to assess the effect of different prime fluid strategies on microcirculatory perfusion in cardiac surgery with CPB. If the results suggest that a specific crystalloid or colloid prime fluid strategy better preserves microcirculatory perfusion during on-pump cardiac surgery, the current study may help to find the optimal pump priming in cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT05647057. Registered on 04/25/2023. CLINICALTRIALS: gov PRS: Record Summary NCT05647057, all items can be found in the protocol.

Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

Drosophila en el estudio de las interacciones proteicas de hTBP en el desarrollo y modelaje de SCA17 / Drosophila in the study of hTBP protein interactions in the development and modeling of SCA17

Resumen Antecedentes: Las interacciones proteicas participan en una gran cantidad de mecanismos moleculares que rigen los procesos celulares. La proteína de unión a la caja TATA humana (hTBP) interacciona con Antennapedia (Antp) a través de su extremo N-terminal, específicamente a través de sus homopéptidos de glutaminas. Esta región PolyQ sirve como sitio de unión a factores de transcripción en condiciones normales, pero cuando se expande genera la ataxia espinal cerebelosa 17 (SCA17), cuyos agregados proteicos en el cerebro impiden su funcionamiento correcto. Objetivo: Determinar si la región rica en glutaminas de hTBP interviene en su interacción con homeoproteínas y el papel que tiene en la formación de agregados proteicos en SCA17. Material y métodos: Se caracterizó la interacción de hTBP con otras homeoproteínas usando BiFC y se modeló SCA17 en Drosophila melanogaster dirigiendo hTBPQ80 al cerebro de las moscas usando UAS/GAL4. Resultados: Existió interacción de hTBP con homeoproteínas a través de su región rica en glutaminas. Los agregados proteicos de hTBP con las glutaminas expandidas afectaron la capacidad locomotriz de las moscas. Conclusiones: El estudio de las interacciones de hTBP abre la posibilidad para la búsqueda de nuevas estrategias terapéuticas en patologías neurodegenerativas como SCA17.

Abstract Background: Protein interactions participate in many molecular mechanisms involved in cellular processes. The human TATA box binding protein (hTBP) interacts with Antennapedia (Antp) through its N-terminal region, specifically via its glutamine homopeptides. This PolyQ region acts as a binding site for other transcription factors under normal conditions, but when it expands, it generates spinocerebellar ataxia 17 (SCA17), whose protein aggregates in the brain prevent its correct functioning. Objective: To determine whether the hTBP glutamine-rich region is involved in its interaction with homeoproteins and the role it plays in the formation of protein aggregates in SCA17. Material and methods: We characterized hTBP interaction with other homeoproteins using BiFC, and modeled SCA17 in Drosophila melanogaster by targeting hTBPQ80 to the fly brain using UAS/GAL4. Results: There was hTBP interaction with homeoproteins through its glutamine-rich region, and hTBP protein aggregates with expanded glutamines were found to affect the locomotor capacity of flies. Conclusions: The study of hTBP interactions opens the possibility for the search for new therapeutic strategies in neurodegenerative pathologies such as SCA17.

ER stress and the unfolded protein response in gastrointestinal stem cells and carcinogenesis.

Endoplasmic reticulum (ER) stress and the adaptive response that follows, termed the unfolded protein response (UPR), are crucial molecular mechanisms to maintain cellular integrity by safeguarding proper protein synthesis. Next to being important in protein homeostasis, the UPR is intricate in cell fate decisions such as proliferation, differentiation, and stemness. In the intestine, stem cells are critical in governing epithelial homeostasis and they are the cell of origin of gastrointestinal malignancies. In this review, we will discuss the role of ER stress and the UPR in the gastrointestinal tract, focusing on stem cells and carcinogenesis. Insights in mechanisms that connect ER stress and UPR with stemness and carcinogenesis may broaden our understanding in the development of cancer throughout the gastrointestinal tract and how we can exploit these mechanisms to target these malignancies.

Let's Agree to Disagree on Operative Versus Nonoperative Treatment for Distal Radius Fractures in Older People: Protocol for a Prospective International Multicenter Cohort Study.

BACKGROUND: Distal radius fractures are the most frequently encountered fractures in Western societies, typically affecting patients aged 50 years and older. Although this is a common injury, the best treatment for these fractures in older patients is still under debate. OBJECTIVE: This prospective study aims to compare the outcome of operatively and nonoperatively treated distal radius fractures in the older population. Only patients with distal radius fractures for which equipoise regarding the optimal treatment exists will be included. METHODS: This prospective international multicenter observational cohort study will be designed as a natural experiment. Natural experiments are observational studies in which treatment allocation is determined by factors outside the control of the investigators but also (largely) independent of patient characteristics. Patients aged 65 years and older with an acute distal radius fracture will be considered for inclusion. Treatment allocation (operative vs nonoperative) will be based on the local preferences of the treating hospital either in Switzerland or the Netherlands. Hence, the process governing treatment allocation resembles that of randomization. Patients will be identified after treatment has been initiated. Based on the radiographs and baseline information of the patient, an expert panel of 6 certified trauma surgeons from 2 regions will provide their treatment recommendation. Only patients for whom the experts disagree on treatment recommendations will ultimately be included in the study (ie, for whom there is a clinical equipoise). For these patients, both operative and nonoperative treatment of distal radius fractures are viable, and treatment choice is predominantly determined by personal or local preference. The primary outcome will be the Patient-Rated Wrist Evaluation score at 12 weeks. Secondary outcomes will include the Physical Activity Score for the Elderly, the EQ questionnaire, pain, the living situation, range of motion, complications, and radiological outcomes. By including outcomes such as living situation and the Physical Activity Score for the Elderly, which are not relevant for younger cohorts, valuable information to tailor treatment to the needs of the older population can be gained. According to the sample size collection, which was based on the minimal important clinical difference of the Patient-Rated Wrist Evaluation, 92 patients will have to be included, with at least 46 patients in each treatment group. RESULTS: Enrollment began in July 2023 and is expected to continue until summer 2024. The final follow-up will be 2 years after the last patient is included. CONCLUSIONS: Although many trials on this topic have previously been published, there remains an ongoing debate regarding the optimal treatment for distal radius fractures in older patients. This observational study, which will use a fairly new methodological study design, will provide further information on treatment outcomes for older patients with distal radius fractures for which to date equipoise exists regarding the optimal treatment. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52917.