Impact of single round of low dose CT lung cancer screening on cause of mortality in different socio-economic groups: a post-hoc analysis of long-term follow-up of the UKLS trial.

Background: Lower socioeconomic status, as measured by the Index of Multiple Deprivation (IMD), is associated with higher rates of smoking-related disease mortality, and with poor uptake of cancer screening. Here we explore whether socioeconomic status impacts the effectiveness of a single round of low-dose-CT screening, or impacts other causes of death, in the UKLS LDCT screening trial. Methods: IMD quintiles were defined according to UK-wide data, with the deprived group defined as the lower two quintiles (Q1-2) and the less deprived as Q3-5. Follow-up data was obtained for lung cancer diagnosis (median follow-up 9.1 years) and cause of death (median follow-up 9.9 years). Outcomes were compared based on IMD group and trial arm (CT or control). Findings: More deprived quintiles were less likely to respond to the questionnaire, but this population was more likely to be selected for screening by the LLP risk model. Lower IMD quintiles benefitted from low-dose-CT screening in terms of lung cancer survival (HR 1.89, 95% CI 1.16-3.08) to the same extent as upper quintiles (HR 1.87, 95% CI 1.07-3.26). However, there was a bigger impact on deaths due to COPD and emphysema in more deprived quintiles. Interpretation: Whilst LDCT screening benefit for lung cancer was similar, significant impact on the rates of death from other smoking-related diseases, notably COPD and emphysema, was seen primarily in lower socioeconomic groups. Future research is required to confirm how lung cancer screening benefits other disease outcomes. Funding: NIHR Health Technology Assessment Programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation.

Modification of extracellular matrix proteins by oxidants and electrophiles.

The extracellular matrix (ECM) is critical to biological architecture and determines cellular properties, function and activity. In many situations it is highly abundant, with collagens and elastin being some of the most abundant proteins in mammals. The ECM comprises of multiple different protein species and sugar polymers, with both different isoforms and post-translational modifications (PTMs) providing a large variety of microenvironments that play a key role in determining tissue structure and health. A number of the PTMs (e.g. cross-links) present in the ECM are critical to integrity and function, whereas others are deleterious to both ECM structure and associated cells. Modifications induced by reactive oxidants and electrophiles have been reported to accumulate in some ECM with increasing age. This accumulation can be exacerbated by disease, and in particular those associated with acute or chronic inflammation, obesity and diabetes. This is likely to be due to higher fluxes of modifying agents in these conditions. In this focused review, the role and effects of oxidants and other electrophiles on ECM are discussed, with a particular focus on the artery wall and atherosclerotic cardiovascular disease. Modifications generated on ECM components are reviewed, together with the effects of these species on cellular properties including adhesion, proliferation, migration, viability, metabolic activity, gene expression and phenotype. Increasing data indicates that ECM modifications are both prevalent in human and mammalian tissues and play an important role in disease development and progression.

Immunological and microbial shifts in the aging rhesus macaque lung during nontuberculous mycobacterial infection.

Nontuberculous mycobacteria (NTM) are environmentally ubiquitous organisms that predominately cause NTM pulmonary disease (NTMPD) in individuals over the age of 65. The incidence of NTMPD has increased in the U.S., exceeding that of Mycobacterium tuberculosis. However, the mechanisms leading to higher susceptibility and severity of NTMPD with aging are poorly defined in part due to the lack of animal models that accurately recapitulate human disease. Here, we compared bacterial load, microbial communities, and host responses longitudinally between three young (two female and one male) and two aged (two female) rhesus macaques inoculated with Mycobacterium avium subsp. hominissuis (MAH) in the right caudal lobe. Unilateral infection resulted in a low bacterial load in both young and aged animals confined to the infected side. Although a robust inflammatory response was only observed in the inoculated lung, immune cell infiltration and antigen-specific T cells were detected in both lungs. Computed tomography, gross pathology, and histopathology revealed increased disease severity and persistence of bacterial DNA in aged animals. Additional analyses showed the translocation of gut and oral-pharyngeal bacterial DNA into the lower respiratory microbiome. Finally, single-cell RNA sequencing revealed a heightened inflammatory response to MAH infection by alveolar macrophages in aged animals. These data are consistent with the model that increased disease severity in the aged is mediated by a dysregulated macrophage response that may be sustained through persistent antigen presence. IMPORTANCE: Nontuberculous mycobacteria (NTM) are emerging as pathogens of high consequence, as cases of NTM pulmonary disease (NTMPD) have exceeded those of Mycobacterium tuberculosis. NTMPD can be debilitating, particularly in patients over 65 years of age, as it causes chronic cough and fatigue requiring prolonged treatments with antibiotics. The underlying mechanisms of this increased disease severity with age are poorly understood, hampering the development of therapeutics and vaccines. Here, we use a rhesus macaque model to investigate the impact of age on host-NTM interactions. This work shows that aging is associated with increased disease severity and bacterial persistence in aged rhesus macaques, thus providing a preclinical model to develop and test novel therapeutics and interventions.

Age-dependent decline of B3AR agonist-mediated activation of FAP UCP-1 expression in murine models of chronic rotator cuff repair.

Amibegron, a ß3-adrenergic receptor (B3AR) agonist, has recently been shown to provide therapeutic effects for chronic rotator cuff (RC) tears by inducing the expression of uncoupling protein 1 (UCP-1), a marker of brown fat, in fibroadipogenic progenitors (FAPs). However, it remains to be seen if these beneficial effects hold true with age and in older, more clinically relevant populations. This study seeks to understand the impacts of aging on the efficacy of amibegron to treat chronic RC tears. Young (4-month-old) and aged (33-month-old) C57BL/6 mice underwent a RC injury procedure with delayed repair (DR). Mice were equally randomized to receive amibegron or dimethyl sulfoxide (DMSO) treatments after repair. Functional ability was measured at baseline and 6-weeks after DR. Wet muscle weight and histology of injured and contralateral supraspinatus were also analyzed 6-weeks post-DR. For in vitro histology and real-time quantitative PCR experiments, FAPs were isolated from young and aged mice via fluorescence-activated cell sorting. Young and aged FAPs were treated with amibegron or DMSO either immediately after seeding (early exposure) or 8-days after seeding (late exposure). In vitro results showed that amibegron-mediated FAP UCP-1 expression decreases with age. In vivo data demonstrated that aged mice have a decreased responsiveness to amibegron and decreased propensity for intramuscular FAP UCP-1 expression. Further, delayed amibegron treatment with RC repair did not lead to improvements in muscle atrophy and functional outcomes. Our findings demonstrate that age and the timing of interventions play a critical role in FAP-targeted therapeutics for chronic injuries.

Apoptosis Pathway-Associated Proteins Are Frequently Expressed in Melanoma: A Study of 32 Cases With Focus on Acral Lentiginous Melanoma.

ABSTRACT: Acral lentiginous melanoma (ALM) is an aggressive type of cutaneous melanoma (CM) that arises on palms, soles, and nail units. ALM is rare in White population, but it is relatively more frequent in dark-skinned populations. There is an unmet need to develop new personalized and more effective treatments strategies for ALM. Increased expression of antiapoptotic proteins (ie, BCL2, MCL1) has been shown to contribute to tumorigenesis and therapeutic resistance in multiple tumor types and has been observed in a subset of ALM and mucosal melanoma cell lines in vivo and in vitro. However, little is known about their expression and clinical significance in patients with ALM. Thus, we assessed protein expression of BCL2, MCL1, BIM, and BRAF V600E by immunohistochemistry in 32 melanoma samples from White and Hispanic populations, including ALM and non-ALM (NALM). BCL2, MCL1, and BIM were expressed in both ALM and NALM tumors, and no significant differences in expression of any of these proteins were detected between the groups, in our relatively small cohort. There were no significant associations between protein expression and BRAF V600E status, overall survival, or ethnicity. In summary, ALM and NALM demonstrate frequent expressions of apoptosis-related proteins BCL2, MCL1, and BIM. Our findings suggest that patients with melanoma, including ALM, may be potential candidates for apoptosis-directed therapies.

POLARIS: A phase 2 trial of encorafenib plus binimetinib evaluating high-dose and standard-dose regimens in patients with BRAF V600-mutant melanoma with brain metastasis.

Background: POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases. Methods: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined. Results: RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n = 10), 1 achieved complete response and 5 achieved partial responses (PR); the brain metastasis response rate (BMRR) was 60% (95% CI: 26.2, 87.8). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data. Conclusions: Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2, and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.

Assessment of Patient-Derived Xenograft Growth and Antitumor Activity: The NCI PDXNet Consensus Recommendations.

Although patient-derived xenografts (PDXs) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and access to a suite of analytical tools will enhance information exchange and facilitate identification of promising novel therapies and biomarkers for guiding cancer therapy.

Hierarchical cluster analysis and nonlinear mixed-effects modelling for candidate biomarker detection in preclinical models of cancer.

BACKGROUND: Preclinical models of cancer can be of translational benefit when assessing how different biomarkers are regulated in response to particular treatments. Detection of molecular biomarkers in preclinical models of cancer is difficult due inter-animal variability in responses, combined with limited accessibility of longitudinal data. METHODS: Nonlinear mixed-effects modelling (NLME) was used to analyse tumour growth data based on expected tumour growth rates observed 7 days after initial doses (DD7) of Radiotherapy (RT) and Combination of RT with DNA Damage Response Inhibitors (DDRi). Cox regression was performed to confirm an association between DD7 and survival. Hierarchical Cluster Analysis (HCA) was then used to identify candidate biomarkers impacting responses to RT and RT/DDRi and these were validated using NLME. RESULTS: Cox regression confirmed significant associations between DD7 and survival. HCA of RT treated samples, combined with NLME confirmed significant associations between DD7 and Cluster specific CD8+ Ki67 MFI, as well as DD7 and cluster specific Natural Killer cell density in RT treated mice. CONCLUSION: Application of NLME, as well as HCA of candidate biomarkers may provide additional avenues to assess the effect of RT in MC38 syngeneic tumour models. Additional studies would need to be conducted to confirm association between DD7 and biomarkers in RT/DDRi treated mice.

Clomiphene citrate administered in peri-conception phase causes fetal loss and developmental impairment in mice.

Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated in mice the consequences for fetal development and pregnancy outcome of peri-conception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 h after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in three independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and ∼30% of fetuses exhibited delayed development and/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30 h average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed post-weaning growth and development comparable to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can inhibit implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the peri-conception phase unless its use is well-supervised.

Elevated levels of iodide promote peroxidase-mediated protein iodination and inhibit protein chlorination.

At inflammatory sites, immune cells generate oxidants including H2O2. Myeloperoxidase (MPO), released by activated leukocytes employs H2O2 and halide/pseudohalides to form hypohalous acids that mediate pathogen killing. Hypochlorous acid (HOCl) is a major species formed. Excessive or misplaced HOCl formation damages host tissues with this linked to multiple inflammatory diseases. Previously (Redox Biology, 2020, 28, 101331) we reported that iodide (I⁻) modulates MPO-mediated protein damage by decreasing HOCl generation with concomitant hypoiodous acid (HOI) formation. HOI may however impact on protein structure, so in this study we examined whether and how HOI, from peroxidase/H2O2/I⁻ systems ± Cl⁻, modifies proteins. Experiments employed MPO and lactoperoxidase (LPO) and multiple proteins (serum albumins, anastellin), with both chemical (intact protein and peptide mass mapping, LC-MS) and structural (SDS-PAGE) changes assessed. LC-MS analyses revealed dose-dependent iodination of anastellin and albumins by LPO/H2O2 with increasing I⁻. Incubation of BSA with MPO/H2O2/Cl⁻ revealed modest chlorination (Tyr286, Tyr475, ∼4 %) and Met modification. Lower levels of these species, and extensive iodination at specific Tyr and His residues (>20 % modification with ≥10 µM I⁻) were detected with increasing I⁻. Anastellin dimerization was inhibited by increasing I⁻, but less marked changes were observed with albumins. These data confirm that I⁻ competes with Cl⁻ for MPO and is an efficient HOCl scavenger. These processes decrease protein chlorination and oxidation, but result in extensive iodination. This is consistent with published data on the presence of iodinated Tyr on neutrophil proteins. The biological implications of protein iodination relative to chlorination require further clarification.

Participatory Causal Loop Diagrams Building for Supporting Decision-Makers Integrating Flood Risk Management in an Urban Regeneration Process.

Several modeling tools commonly used for supporting flood risk assessment and management are highly effective in representing physical phenomena, but provide a rather limited understanding of the multiple implications that flood risk and flood risk reduction measures have on highly complex systems such as urban areas. In fact, most of the available modeling tools do not fully account for this complexity-and related uncertainty-which heavily affects the interconnections between urban systems evolution and flood risk, ultimately resulting in an ineffective flood risk management. The present research proposes an innovative methodological framework to support decision-makers involved in an urban regeneration process at a planning/strategic level, accounting for the multi-dimensional implications of flood risk and of different flood risk management strategies. The adopted approach is based on the use of System Thinking principles and participatory System Dynamics modeling techniques, and pursues an integration between scientific and stakeholder knowledge. Reference is made to one of the case studies of the CUSSH and CAMELLIA projects, namely Thamesmead (London), a formerly inhospitable marshland currently undergoing a process of urban regeneration, and perceived as being increasingly vulnerable to flooding. It represents an interesting opportunity for building a replicable modeling approach to integrate urban development dynamics with flood risk, ultimately supporting policy and decision-makers in identifying mitigation/prevention measures and understanding how they could help achieve multi-dimensional benefits (e.g., environmental, social and economic).

Randomized controlled trial of the CMR immersive virtual reality (IVR) headset training compared to e-learning for operating room configuration of the CMR versius robot.

Robotic surgery offers potential advantages over laparoscopic procedures, but the training for configuring robotic systems in the operating room remains underexplored. This study seeks to validate immersive virtual reality (IVR) headset training for setting up the CMR Versius in the operating room. This single-blinded randomized control trial randomised medical students with no prior robotic experience using an online randomiser. The intervention group received IVR headset training, and the control group, e-learning modules. Assessors were blinded to participant group. Primary endpoint was overall score (OS): Likert-scale 1-5: 1 reflecting independent performance, with increasing verbal prompts to a maximum score of 5, requiring physical assistance to complete the task. Secondary endpoints included task scores, time, inter-rater reliability, and concordance with participant confidence scores. Statistical analysis was performed using IBM SPSS Version 27. Of 23 participants analysed, 11 received IVR and 12 received e-learning. The median OS was lower in the IVR group than the e-learning group 53.5 vs 84.5 (p < 0.001). VR recipients performed tasks independently more frequently and required less physical assistance than e-learning participants (p < 0.001). There was no significant difference in time to completion (p = 0.880). Self-assessed confidence scores and assessor scores differed for e-learning participants (p = 0.008), though not IVR participants (p = 0.607). IVR learning is more effective than e-learning for preparing robot-naïve individuals in operating room set-up of the CMR Versius. It offers a feasible, realistic, and accessible option in resource-limited settings and changing dynamics of operating theatre teams. Ongoing deliberate practice, however, is still necessary for achieving optimal performance. ISCRTN Number 10064213.

Beta-Hydroxybutyrate Levels and Risk of Diabetic Ketoacidosis in Adults with Type 1 Diabetes Treated with Sotagliflozin.

Introduction: Sodium glucose cotransporter inhibitors may increase beta-hydroxybutyrate (BHB) in insulin-requiring patients. We determined factors associated with BHB changes from baseline (ΔBHB) and diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) receiving sotagliflozin as an insulin adjunct. Research Design and Methods: This post hoc analysis compared ΔBHB levels in adults with T1D receiving sotagliflozin 400 mg or placebo for 6 months. We evaluated clinical and metabolic factors associated with ΔBHB and used logistic regression models to determine predictors associated with BHB values >0.6 and >1.5 mmol/L (inTandem3 population; N = 1402) or with DKA events in a pooled analysis (inTandem1-3; N = 2453). Results: From baseline (median, 0.13 mmol/L), median fasting BHB increased by 0.04 mmol/L (95% confidence interval, 0.03-0.05; P < 0.001) at 24 weeks with sotagliflozin versus placebo; 67% of patients had no or minimal changes in BHB over time. Factors associated with on-treatment BHB >0.6 or >1.5 mmol/L included baseline BHB and sotagliflozin use. Age, insulin pump use, sotagliflozin use, baseline BHB, and ΔBHB were significantly associated with DKA episodes. Independent of treatment, DKA risk increased by 18% with each 0.1-mmol/L increase in baseline BHB and by 8% with each 0.1-mmol/L increase from baseline. Conclusion: Incremental increases in baseline BHB and ΔBHB were associated with a higher DKA risk independent of treatment. Adding sotagliflozin to insulin increased median BHB over 24 weeks in patients with T1D and was associated with increased DKA events. These results highlight the importance of BHB testing and monitoring and individualizing patient education on DKA risk, mitigation, identification, and treatment.

Safety and feasibility of colonoscopy in nonagenarians: A systematic review, meta-analysis and meta-regression analysis.

AIM: The aim of this work was to evaluate the safety and feasibility of performing colonoscopy in patients aged 90 years or over. METHOD: In compliance with PRISMA statement standards, a systematic review of studies reporting the outcomes of colonoscopy in patients aged ≥90 years was conducted. A proportional meta-analysis model was constructed to quantify the risk of outcomes and a direct comparison meta-analysis model was constructed to compare outcomes between nonagenarians and patients aged between 50 and 89 years via random-effects models. RESULTS: Seven studies enrolling 1304 patients (1342 colonoscopies) were included. Analyses showed that complications related to bowel preparation occurred in 0.7% (95% CI 0.1%-1.6%), procedural complications in 0.6% (0.00%-1.7%), 30-day complications in 1.5% (0.6%-2.7%), procedural mortality in 0.3% (0.0%-1.1%) and 30-day mortality in 1.1% (0.3%-2.2%). Adequate bowel preparation and colonoscopy completion were achieved in 81.3% (73.8%-87.9%) and 92.1% (86.7%-96.3%), respectively. No difference was found in bowel preparation-related complications [risk difference (RD) 0.00, p = 0.78], procedural complications (RD 0.00, p = 0.60), 30-day complications (RD 0.01, p = 0.20), procedural mortality (RD 0.00, p = 1.00) or 30-day mortality (RD 0.01, p = 0.34) between nonagenarians and patients aged between 50 and 89 years. The colorectal cancer detection rate was 14.3% (9.8%-19.5%), resulting in therapeutic intervention in 65.9% (54.5%-76.6%). CONCLUSIONS: Although the evidence is limited to a selected group of nonagenarians, it may be fair to conclude that if a colonoscopy is indicated in a nonagenarian with good performance status (based on initial less-invasive investigations), the level 2 evidence supports its safety and feasibility. Age on its own should not be a reason for failing to offer colonoscopy to a nonagenarian.

Co-producing knowledge on the use of urban natural space: Participatory system dynamics modelling to understand a complex urban system.

Decision-makers are increasingly asked to act differently in how they respond to complex urban challenges, recognising the value in bringing together and integrating cross-disciplinary, cross-sectoral knowledge to generate effective solutions. Participatory modelling allows to bring stakeholders together, enhance knowledge and understanding of a system, and identify the impacts of interventions to a given problem. This paper uses an interdisciplinary and systems approach to investigate a complex urban problem, using a participatory System Dynamics modelling process as an approach to facilitate learning and co-produce knowledge on the factors influencing the use of urban natural space. Stakeholders used a Systems Dynamics model and interface, as a tool to collectively identify pathways for improving the use of space and simulating their impacts. Under the lens of knowledge co-production, the paper reflects how such mechanisms can lead to the co-production of knowledge and social learning. The findings also contribute to identify ways of increasing the value of urban natural space focusing on urban areas undergoing physical and social transformation, such as the Thamesmead case study, London, UK.

Defining Endogenous Mitochondrial Transfer in Muscle After Rotator Cuff Injury.

BACKGROUND: Rotator cuff muscle degeneration leads to poor clinical outcomes for patients with rotator cuff tears. Fibroadipogenic progenitors (FAPs) are resident muscle stem cells with the ability to differentiate into fibroblasts as well as white and beige adipose tissue. Induction of the beige adipose phenotype in FAPs has been shown to improve muscle quality after rotator cuff tears, but the mechanisms of how FAPs exert their beneficial effects have not been fully elucidated. PURPOSE: To study the horizontal transfer of mitochondria from FAPs to myogenic cells and examine the effects of ß-agonism on this novel process. STUDY DESIGN: Controlled laboratory study. METHODS: In mice that had undergone a massive rotator cuff tear, single-cell RNA sequencing was performed on isolated FAPs for genes associated with mitochondrial biogenesis and transfer. Murine FAPs were isolated by fluorescence-activated cell sorting and treated with a ß-agonist versus control. FAPs were stained with mitochondrial dyes and cocultured with recipient C2C12 myoblasts, and the rate of transfer was measured after 24 hours by flow cytometry. PdgfraCreERT/MitoTag mice were generated to study the effects of a rotator cuff injury on mitochondrial transfer. PdgfraCreERT/tdTomato mice were likewise generated to perform lineage tracing of PDGFRA+ cells in this injury model. Both populations of transgenic mice underwent tendon transection and denervation surgery, and MitoTag-labeled mitochondria from Pdgfra+ FAPs were visualized by fluorescent microscopy, spinning disk confocal microscopy, and 2-photon microscopy; overall mitochondrial quantity was compared between mice treated with ß-agonists and dimethyl sulfoxide. RESULTS: Single-cell RNA sequencing in mice that underwent rotator cuff tear demonstrated an association between transcriptional markers of adipogenic differentiation and genes associated with mitochondrial biogenesis. In vitro cocultures of murine FAPs with C2C12 cells revealed that treatment of cells with a ß-agonist increased mitochondrial transfer compared to control conditions (17.8% ± 9.9% to 99.6% ± 0.13% P < .0001). Rotator cuff injury in PdgfraCreERT/MitoTag mice resulted in a robust increase in MitoTag signal in adjacent myofibers compared with uninjured mice. No accumulation of tdTomato signal from PDGFRA+ cells was seen in injured fibers at 6 weeks after injury, suggesting that FAPs do not fuse with injured muscle fibers but rather contribute their mitochondria. CONCLUSION: The authors have described a novel process of endogenous mitochondrial transfer that can occur within the injured rotator cuff between FAPs and myogenic cells. This process may be leveraged therapeutically with ß-agonist treatment and represents an exciting target for improving translational therapies available for rotator cuff muscle degeneration. CLINICAL RELEVANCE: Promoting endogenous mitochondrial transfer may represent a novel translational strategy to address muscle degeneration after rotator cuff tears.

Distinct human stem cell subpopulations drive adipogenesis and fibrosis in musculoskeletal injury.

Fibroadipogenic progenitors (FAPs) maintain healthy skeletal muscle in homeostasis but drive muscle degeneration in chronic injuries by promoting adipogenesis and fibrosis. To uncover how these stem cells switch from a pro-regenerative to pro-degenerative role we perform single-cell mRNA sequencing of human FAPs from healthy and injured human muscles across a spectrum of injury, focusing on rotator cuff tears. We identify multiple subpopulations with progenitor, adipogenic, or fibrogenic gene signatures. We utilize full spectrum flow cytometry to identify distinct FAP subpopulations based on highly multiplexed protein expression. Injury severity increases adipogenic commitment of FAP subpopulations and is driven by the downregulation of DLK1. Treatment of FAPs both in vitro and in vivo with DLK1 reduces adipogenesis and fatty infiltration, suggesting that during injury, reduced DLK1 within a subpopulation of FAPs may drive degeneration. This work highlights how stem cells perform varied functions depending on tissue context, by dynamically regulating subpopulation fate commitment, which can be targeted improve patient outcomes after injury.

Transferring laparoscopic skills to robotic-assisted surgery: a systematic review.

Robotic-Assisted Surgery (RAS) is experiencing rapid expansion, prompting the integration of robotic technical skills training into surgical education programs. As access to robotic training platforms remains limited, it is important to investigate the transferability of laparoscopic skills to RAS. This could potentially support the inclusion of early years laparoscopic training to mitigate the learning curve associated with robotic surgery. This study aims to assess the transferability of laparoscopic skills to robotic surgery. A systematic search was conducted using the PRISMA checklist to identify relevant articles. PubMed, MEDLINE, Embase, and Cochrane databases were searched, and inclusion and exclusion criteria were applied to collate eligible articles. Included were original articles comparing the performance of comparable tasks on both laparoscopic and robotic platforms written in English. Non-peer reviewed papers, conference abstracts, reviews, and case series were excluded. Seventeen articles met the inclusion criteria. Among these, 10 studies (59%) demonstrated skill transferability from laparoscopic surgery (LS) to robotic surgery (RS); while one study (5.8%) showed no significant transferability. Four studies highlighted the positive impact of prior laparoscopic training on robotic skill, whereas six papers suggested no significant difference between laparoscopic novices and experienced laparoscopists when utilizing a robotic simulator. Five studies evaluated advanced surgical skills such as intracorporeal knot tying and suturing, revealing superior robotic performance among experienced laparoscopists compared to novice learners. Laparoscopic skills appear to be transferrable to robotic surgery, particularly in complex surgical techniques. Robotic simulators demonstrate a significant reduction in the learning curve for surgical novices, albeit to a lesser extent for experienced laparoscopists.