Improved microvascular imaging with optical coherence tomography using 3D neural networks and a channel attention mechanism.

Skin microvasculature is vital for human cardiovascular health and thermoregulation, but its imaging and analysis presents significant challenges. Statistical methods such as speckle decorrelation in optical coherence tomography angiography (OCTA) often require multiple co-located B-scans, leading to lengthy acquisitions prone to motion artefacts. Deep learning has shown promise in enhancing accuracy and reducing measurement time by leveraging local information. However, both statistical and deep learning methods typically focus solely on processing individual 2D B-scans, neglecting contextual information from neighbouring B-scans. This limitation compromises spatial context and disregards the 3D features within tissue, potentially affecting OCTA image accuracy. In this study, we propose a novel approach utilising 3D convolutional neural networks (CNNs) to address this limitation. By considering the 3D spatial context, these 3D CNNs mitigate information loss, preserving fine details and boundaries in OCTA images. Our method reduces the required number of B-scans while enhancing accuracy, thereby increasing clinical applicability. This advancement holds promise for improving clinical practices and understanding skin microvascular dynamics crucial for cardiovascular health and thermoregulation.

Patellofemoral Instability in Pediatric and Adolescent Athletes: A Review of Risk Factors and Treatments.

Pediatric patellar instability can impair function and restrict activity participation. If left untreated, it can lead to a degenerative knee. The incidence of patellar dislocations is highest in adolescents between 10 and 17 years of age; more than half of all first-time patellar dislocations occur during sports. This article reviews the evidence of risk factors for traumatic patellar instability, surgical interventions, and return-to-sport (RTS) considerations for pediatric and adolescent athletes. Anatomic risk factors for patellar instability in pediatric and adolescent patients include trochlear dysplasia, elevated tibial tuberosity-trochlear groove (TT-TG) distance, patella alta, genu valgum, femoral anteversion and tibial torsion, and hyperlaxity.

Concomitant Wilms tumor and autosomal dominant polycystic kidney disease.

BACKGROUND: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described. PROCEDURE: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. RESULTS: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT. CONCLUSION: Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies.

Evaluation of Tibial Slope on Radiographs in Pediatric Patients With Tibial Spine Fractures: An Age- and Sex-Matched Study.

Background: A recent study has reported that the radiographic measurement of posterior tibial slope (PTS) is larger in male pediatric patients with tibial spine fractures (TSF) than in controls. However, they found no difference in PTS between female patients and controls. Purpose: (1) To identify whether PTS is larger in female pediatric patients with TSF than in female controls and (2) to validate the relationship between PTS and pediatric TSF in male patients. Study Design: Cross-sectional study; Level of evidence, 3. Methods: After an a priori power analysis, 84 pediatric patients with TSF (50 female patients and 34 male patients) and 84 age- and sex-matched controls were enrolled in this study. Demographic information, including sex, age, and race, was recorded. Skeletal maturity was determined based on the stage of epiphyseal union on knee radiographs. PTS was defined as the angle between a line perpendicular to the longitudinal axis of the tibia and the posterior inclination of the medial tibial plateau on standard knee lateral radiographs. Results: The mean age when the TSF occurred was 11.2 ± 2.7 years for female patients and 12.9 ± 2.5 years for male patients. There was no significant difference in skeletal maturity between female patients and female controls or between male patients and male controls. The mean PTS was not significantly different between female patients (8.8°± 2.8°) and female controls (8.3°± 3.1°) (P = .366) or between male patients (9.0°± 2.8°) and male controls (9.3°± 2.6°) (P = .675). Those with a PTS >1 SD (2.9°) above the mean (8.8°) had no greater odds (1.0 [95% CI, 0.4-2.5]; P≥ .999) of having a TSF than others. Conclusion: PTS was not found to be a risk factor for pediatric TSF in female or male patients in this study.

Temporary hemi-epiphysiodesis with tension band plates in skeletally immature patients with genu valgum: Faster correction in patients with more than 2 years of expected time of growth remaining.

Purpose: Hemi-epiphysiodesis procedures in skeletally immature patients are commonly done to correct genu valgum over time. This study seeks to demonstrate the average rate of deformity correction for genu valgum using hinged tension band plates, while examining different age groups and sex-related differences. Methods: A retrospective chart review of patients who underwent hemi-epiphysiodesis with hinged tension band plates for valgus knee deformity from 2012 to 2022 by one pediatric orthopaedic surgeon was performed. Expected time of growth remaining was calculated as the difference between age of skeletal maturity and bone age at time of surgery. The mechanical lateral distal femoral angle, mechanical medial proximal tibial angle, mechanical femoral tibia angle, screw divergence angle, and hinge angle were measured immediately after implant placement and prior to implant removal. Results: 54 skeletally immature patients were treated for pathologic genu valgum. The mean age at time of surgery was 12.5 ± 1.9 years. The radiographic measurement of the valgus deformity between the beginning and end of treatment showed significant correction (p = 0.002). The lower limb axis of the younger cohort corrected significantly faster (7.5 ± 4.6°/year) than the older cohort (5.3 ± 2.8°/year) (p = 0.030). The mechanical lateral distal femoral angle correction rate was also significantly different between the two cohorts (7.0 ± 4.7°/year vs. 4.8 ± 2.8°/year, respectively (p = 0.002)). The group with greater expected time of growth remaining demonstrated a significantly faster rate of correction than the group with less than 2 years of growth remaining (p < 0.001). Conclusion: This study reaffirms the finding that timing is essential when performing temporary hemi-epiphysiodesis for valgus knee deformity in skeletally immature patients.

The Number of Patellar Dislocation Events Is Associated With Increased Chondral Damage of the Trochlea.

BACKGROUND: Patellofemoral instability is associated with chondral injuries to the patella, trochlea, and lateral femoral condyle. Although studies have demonstrated an association between patellar dislocations and chondral injuries, the influence of the number of dislocations on chondrosis is not established. PURPOSE: To elucidate the precise association between the number of patellar dislocation events and the severity of chondral injuries in a multicenter cohort study at the time of patellar stabilization procedures. STUDY DESIGN: Cross-sectional study; Level of evidence, 2. METHODS: A prospective multicenter cohort study (JUPITER [Justifying Patellar Instability Treatment by Early Results]) database was queried for cases of primary patellofemoral instability procedures from December 2016 to September 2022. Cartilage lesions were classified using the International Cartilage Repair Society (ICRS) classification system during an arthroscopic or open evaluation (direct visualization), with grades 2 to 4 considered abnormal. The number of dislocations was categorized as 1, 2-5, and >5. Categorical variables were compared with the chi-square test, and binary logistic regression was performed to identify predictors of the presence of chondral lesions. RESULTS: A total of 938 knees (mean age, 16.2 ± 3.8 years; 61.4% female) were included, with 580 (61.8%) demonstrating a chondral injury. The most affected region was the patella (n = 498 [53.1%]), followed by the lateral femoral condyle (n = 117 [12.5%]) and trochlea (n = 109 [11.6%]). There were no differences in the presence (P = .17) or grade (P = .63) of patellar lesions by the number of dislocations. Patients with >5 dislocations more frequently had trochlear chondral lesions (19.8%) compared with those with fewer dislocations (1, 7.6%; 2-5, 11.0%; P < .001). More dislocations were also associated with a higher proportion of ICRS grade 2 to 4 trochlear lesions (>5, 15.3%; 2-5, 10.0%; 1, 6.9%; P = .015). Combined patellar and trochlear lesions were also more common in those with >5 dislocations (P = .001). In multivariable regression, >5 dislocations was the only variable predictive of a trochlear lesion (odds ratio, 3.03 [95% CI, 1.65-5.58]; P < .001). CONCLUSION: This large prospective cohort study demonstrated that recurrent patellar dislocations can lead to more severe chondral damage in specific locations in the knee. More than 5 dislocations was associated with a >3-fold increase in the incidence and severity of trochlear chondral injuries. There were no differences in the presence or grade of patellar lesions by the number of dislocations. These findings should caution surgeons regarding prolonged nonoperative treatment.

A Recess Is Observed Between the Posterior Knee Capsule and the Meniscotibial Ligament Complex in Pediatric Specimens.

Purpose: To define the surgical anatomy of the meniscotibial ligament complex of the pediatric medial and lateral menisci and their relation to the proximal tibial physis and posterior joint capsule. Methods: Fourteen pediatric cadaveric knee specimens (aged 3 months to 11 years) were dissected to clarify the relation of the posterior knee capsule, the meniscus, and the meniscotibial ligament complex. Metallic markers were placed marking the meniscotibial ligament capsular attachment on the proximal tibia. Specimens underwent computed tomography scanning to evaluate pin placement and relation to the physis. A digital measurement tool was used to measure the distances between the proximal tibial physis and the pins (placed at 5 points on both the lateral and medial menisci). Results: In each specimen, clear separation was noted between the posterior joint capsule from the meniscus and meniscotibial ligament complex in the medial and lateral compartments. There was an increase in the distance between the proximal tibial physis and the insertion points of the meniscotibial ligament complex with increasing specimen age. For both the medical and lateral menisci in group 1, the median meniscotibial ligament insertion points were often less than 7 mm (interquartile range, 0.00-7.8 mm) away from the physis. The median meniscotibial ligament insertion points in group 2 tended to be farther from the physis but always less than 20 mm (interquartile range, 2.5-17.5 mm)-and as close as less than 5 mm (lateral posterior root). Conclusions: In this anatomic study of pediatric knees, we observed a distinct recess/cul-de-sac space between the posterior knee capsule and meniscal attachments in all specimens. This defines a distinct plane between the posterior knee capsule and the meniscotibial ligament complex, with a distance between the physis and meniscotibial ligament capsular attachments that increases with age. Clinical Relevance: The anatomic parameters evaluated in our study should be considered as future meniscal repair and transplantation techniques aim to restore the meniscal anatomy, stability, and mobility provided by the meniscotibial ligament complex and capsule structures.

Quadriceps Tendon Anterior Cruciate Ligament Reconstruction in Skeletally Immature Patients: 3-Year Clinical and Patient-Reported Outcomes.

BACKGROUND: The rate of anterior cruciate ligament (ACL) rupture in active, skeletally immature patients is increasing. Although hamstring tendon autograft (HTA) was previously deemed the gold standard, recent studies have shown HTA to have a high failure rate in this high-risk population of young competitive athletes, and quadriceps tendon autograft (QTA) has yielded excellent preliminary outcomes in some studies examining this population. PURPOSE: To evaluate 3-year clinical and patient-reported functional outcomes of primary ACL reconstruction (ACLR) with soft tissue QTA in skeletally immature patients. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Skeletally immature patients who underwent ACLR with a full-thickness soft tissue QTA were included. Preoperative patient and surgical data were collected. The ACLR technique was selected predicated upon skeletal age and included all-epiphyseal and complete transphyseal techniques. Patients were followed for a minimum of 2 years with successive clinical visits or were contacted via telephone. Patients who did not have minimum 2-year follow-up after 3 contact attempts via telephone were excluded. Information regarding return to sports (RTS) and concomitant or subsequent surgical procedures was collected. Pediatric International Knee Documentation Committee (Pedi-IKDC), Hospital for Special Surgery Functional Activity Brief Scale (HSS Pedi-FABS), and Single Assessment Numeric Evaluation (SANE) scores were collected. RESULTS: Of 85 adolescent patients aged 11.1 to 17.6 years (mean age, 14.1 ± 1.2 years), 2 patients were determined to be lost to follow-up after 3 failed contact attempts. Of the patients included in this study (N = 83), 26 patients (31%) underwent all-epiphyseal and 57 patients (69%) underwent complete transphyseal ACLR. Additionally, 48 patients (58%) underwent concomitant lateral extra-articular tenodesis using the iliotibial band with a modified Lemaire technique. The mean follow-up time was 3.7 ± 1.2 years (range, 2-7 years). Twenty (24%) patients had subsequent surgical procedures, of which 3 (4%) were due to graft failures. At a mean 3-year follow-up, the mean Pedi-IKDC, HSS Pedi-FABS, and SANE scores were 90, 23, and 94 respectively; the RTS rate was 100%; and the rate of RTS at the previous level of performance was 93%. CONCLUSION: Use of a soft tissue QTA for ALCR in a high-risk skeletally immature population of athletes resulted in excellent postoperative outcomes with low rates of graft failure and high return to sport rates.

A multi-method exploration of a cardiac rehabilitation service delivered by registered Clinical Exercise Physiologists in the UK: key learnings for current and new services.

BACKGROUND: Cardiac rehabilitation has been identified as having the most homogenous clinical exercise service structure in the United Kingdom (UK), but inconsistencies are evident in staff roles and qualifications within and across services. The recognition of Clinical Exercise Physiologists (CEPs) as a registered health professional in 2021 in the UK, provides a potential solution to standardise the cardiac rehabilitation workforce. This case study examined, in a purposefully selected cardiac exercise service that employed registered CEPs, (i) how staff knowledge, skills and competencies contribute to the provision of the service, (ii) how these components assist in creating effective service teams, and (iii) the existing challenges from staff and patient perspectives. METHODS: A multi-method qualitative approach (inc., semi-structured interviews, observations, field notes and researcher reflections) was employed with the researcher immersed for 12-weeks within the service. The Consolidated Framework for Implementation Research was used as an overarching guide for data collection. Data derived from registered CEPs (n = 5), clinical nurse specialists (n = 2), dietitians (n = 1), service managers/leads (n = 2) and patients (n = 7) were thematically analysed. RESULTS: Registered CEPs delivered innovative exercise prescription based on their training, continued professional development (CPD), academic qualifications and involvement in research studies as part of the service. Exposure to a wide multidisciplinary team (MDT) allowed skill and competency transfer in areas such as clinical assessments. Developing an effective behaviour change strategy was challenging with delivery of lifestyle information more effective during less formal conversations compared to timetabled education sessions. CONCLUSIONS: Registered CEPs have the specialist knowledge and skills to undertake and implement the latest evidence-based exercise prescription in a cardiac rehabilitation setting. An MDT service structure enables a more effective team upskilling through shared peer experiences, observations and collaborative working between healthcare professionals.

Establishment of clinical exercise physiology as a regulated healthcare profession in the UK: a progress report.

In 2021, a 'call to action' was published to highlight the need for professional regulation of clinical exercise physiologists to be established within UK healthcare systems to ensure patient safety and align training and regulation with other health professions. This manuscript provides a progress report on the actions that Clinical Exercise Physiology UK (CEP-UK) has undertaken over the past 4 years, during which time clinical exercise physiologists have implemented regulation and gained formal recognition as healthcare professionals in the UK. An overview of the consultation process involved in creating a regulated health profession, notably the development of policies and procedures for both individual registration and institutional master's degree (MSc) accreditation is outlined. Additionally, the process for developing an industry-recognised scope of practice, a university MSc-level curriculum framework, the Academy for Healthcare Science Practitioner standards of proficiency and Continuing Professional Development opportunities is included. We outline the significant activities and milestones undertaken by CEP-UK and provide insight and clarity for other health professionals to understand the training and registration process for a clinical exercise physiologist in the UK. Finally, we include short, medium and long-term objectives for the future advocacy development of this workforce in the UK.

Transosseous Repair of Isolated Posterior Medial Meniscal Root Injuries in Children and Adolescents.

The meniscal roots are critically important for maintaining knee stability, functional load distribution, and proper knee kinematics. Although adult meniscal root injuries have been a topic of increasing research, medial meniscus injuries also occur in pediatric and adolescent patients, with up to 2% of meniscal injuries involving root attachments. The purpose of this Technical Note is to demonstrate the transosseous repair of isolated posterior medial meniscal root injuries in children and adolescents, including tear visualization on magnetic resonance imaging and during arthroscopy, operative technique, and postoperative management.

Femorotibial rotation is linearly associated with tibial tubercle-trochlear groove distance: A cadaveric study.

OBJECTIVES: A tibial tubercle-trochlear groove (TT-TG) distance of 20 millimeters (mm) is typically used when determining whether tibial tubercle medialization is performed for the surgical treatment of patellar instability. Without knowledge of how the variability of an individual's TT-TG distance is influenced by through-the-knee femorotibial rotation, the use of a specific TT-TG distance during preoperative planning for patellar instability may lead to incorrect decisions on the use of tibial tubercle medialization. We hypothesized that knee joint internal/external (IE) rotation is related to the TT-TG distance. METHODS: Eight independent human cadaveric knee specimens (age: 32 â€‹± â€‹6 years; 4 males, 4 females) were utilized. A robotic manipulator (ZX165U, Kawasaki Robotics, Wixom, MI, USA) instrumented with a universal force/moment sensor was used to determine knee joint IE rotation under applied moments of ±5 newton-meters (Nm) at full extension. Two independent reviewers selected the trochlear groove and tibial tuberosity points on computerized tomography (CT) images of each specimen to define TT-TG. To determine the influence of knee joint IE rotation on TT-TG distance, three-dimensional (3D) models generated from CT scans were registered to tibiofemoral kinematics. Linear regression was performed to determine the relationship between knee joint IE rotation and TT-TG distance. The regression coefficient, standard error of measurement (α â€‹= â€‹0.05), and coefficient of determination (r2) were reported. RESULTS: At 0° of rotation, the mean TT-TG distance was 14.2 â€‹± â€‹5.0 â€‹mm. Knee joint IE rotation averaged 23.0 â€‹± â€‹4.2°. For every degree of knee joint IE rotation, TT-TG distance changed by 0.52 â€‹mm. CONCLUSION: TT-TG distance was linearly dependent on knee joint IE rotation, changing by 0.52 â€‹mm for every degree of knee joint IE rotation. Thus, an offset of IE rotation of 10° would lead to a change in TT-TG distance of 5.2 â€‹mm, enough to alter the surgical decision-making for/or against tibial tubercle medialization. LEVEL OF EVIDENCE: IV: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Osseous and Cartilaginous Trochlear Development in the Pediatric Knee: A Cadaveric Computed Tomography Study.

Background: The anatomy of the trochlea plays a significant role in patellar stability. The developmental anatomy of the trochlea and its relationship to patellar stability remains poorly understood. Purpose: To describe the developmental changes of the osseous and cartilaginous trochlear morphology in skeletally immature specimens. Study Design: Descriptive laboratory study. Methods: A total of 65 skeletally immature cadaveric knees between the ages of 2 months and 11 years were evaluated using computed tomography scans. The measurements in the axial plane of both cartilage and bone include medial, central, and lateral trochlear height; sulcus height; medial and later trochlear facet length; trochlear sulcus angle; patellar sulcus angle; condylar height asymmetry; and trochlear facet asymmetry. Additional measurements included trochlear depth and lateral trochlear inclination angle. In the sagittal plane, measurements included curvilinear trochlear length, direct trochlear length, condylar height, and patellar sulcus angle. Results: Analysis of trochlear morphology using condylar height, condylar height asymmetry, and trochlear depth all increased with increasing age. The osseous and cartilaginous sulcus angles became deeper with age until age 8 and then plateaued. This corresponded with an increase in trochlear depth that also plateaued around age 8. Osseous condylar asymmetry increased with age but flipped from a larger medial condyle to a larger lateral condyle around age 8. The continued growth of the trochlea with age was further demonstrated in all measures in the sagittal view. Conclusion: This cadaveric analysis demonstrated that there is an increase in condylar height as age increased by all measurements analyzed. These changes in condylar height continued to be seen through age 11, suggesting a still-developing trochlea past this age. By age 8, a plateau in sulcus angle, and sulcus depth suggests more proportionate growth after this point. Similar changes in trochlear and patellar shape with age suggests that the 2 structures may affect each other during development. Clinical Relevance: This information can help design, develop, and determine timing of procedures that may alter the anatomy and stabilize the trochlear and patellofemoral joint.

Effect of low-volume combined aerobic and resistance high-intensity interval training on vascular health in people with type 2 diabetes: a randomised controlled trial.

PURPOSE: We compared the effects of low-volume combined aerobic and resistance high-intensity interval training (C-HIIT), combined moderate-intensity continuous training (C-MICT) and waitlist control (CON) on vascular health after 8-weeks of supervised training, and an additional 10-months of self-directed training, in adults with type 2 diabetes (T2D). METHODS: Sixty-nine low active adults with T2D were randomised to 8-weeks of supervised C-HIIT (3 times/week, 78-min/week), C-MICT (current exercise guidelines, 4 times/week, 210-min/week) or CON. CON underwent usual care for 8-weeks before being re-randomised to C-HIIT or C-MICT. This was followed by 10-months of self-directed training for participants in C-HIIT and C-MICT. Vascular outcomes were evaluated at baseline, 8-weeks, and 12-months. RESULTS: After 8-weeks, supervised C-HIIT significantly improved relative flow-mediated dilation (FMD) compared with CON (mean difference [MD] 0.8% [0.1, 1.4], p = 0.025). Although not significantly different from CON, the magnitude of change in relative FMD following 8-weeks of supervised C-MICT was similar (MD 0.8% [-0.1, 1.7], p = 0.080). There were no differences in haemodynamic indices, carotid-femoral pulse wave velocity (cfPWV), or aortic reservoir pressure between groups at 8-weeks. After 12-months, there was a significant reduction in haemodynamic indices (time effect, p < 0.05) for both C-HIIT and C-MICT, with no between-group difference. The reduction in cfPWV over 12-months was significantly greater in C-MICT than C-HIIT (group × time effect, p = 0.018). There was no difference in FMD over time or between groups at 12-months. CONCLUSIONS: Short-term supervised C-HIIT and C-MICT both increased brachial artery FMD compared with CON. Long-term C-HIIT and C-MICT were beneficial for improving haemodynamic indices, but not brachial artery FMD. C-MICT was superior to C-HIIT for improving cfPWV at 12-months. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Identifier ACTRN12615000475549.

Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis.

OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER: NCT03202498.

Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage-fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis.

Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition?

This narrative review highlights the degree to which new antiobesity medications based on gut-derived nutrient-stimulated hormones (incretins) cause loss of lean mass, and the importance of resistance exercise to preserve muscle. Glucagon-like peptide 1 receptor agonists (GLP-1RA) induce substantial weight loss in randomized trials, effects that may be enhanced in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. Liraglutide and semaglutide (GLP-1RA), tirzepatide (GLP-1 and GIP receptor dual agonist), and retatrutide (GLP-1, GIP, and glucagon receptor triple agonist) are peptides with incretin agonist activity that induce ∼15-24% weight loss in adults with overweight and obesity, alongside beneficial impacts on blood pressure, cholesterol, blood glucose, and insulin. However, these agents also cause rapid and significant loss of lean mass (∼10% or ∼6 kg), comparable to a decade or more of aging. Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality. Studies indicate that supervised resistance exercise training interventions with a duration >10 weeks can elicit large increases in lean mass (∼3 kg) and strength (∼25%) in men and women. After a low-calorie diet, combining aerobic exercise with liraglutide improved weight loss maintenance compared with either alone. Retaining lean mass during incretin therapy could blunt body weight (and fat) regain on cessation of weight loss pharmacotherapy. We propose that tailored resistance exercise training be recommended as an adjunct to incretin therapy to optimize changes in body composition by preserving lean mass while achieving fat loss.

Comparing the Impacts of Testosterone and Exercise on Lean Body Mass, Strength and Aerobic Fitness in Aging Men.

BACKGROUND: Based on the largely untested premise that it is a restorative hormone that may reverse the detrimental impacts of aging, prescription of testosterone (T) has increased in recent decades despite no new clinical indications. It is apparent that middle-aged and older men with low-normal serum T levels are considering T supplementation as an anti-aging strategy. At the same time, there is evidence that physical activity (PA) is at historical lows in the Western world. In this review, we compare the impacts of T treatment aimed at achieving physiological T concentrations in middle-aged and older men, alongside the impacts of ecologically relevant forms of exercise training. The independent, and possible combined, effects of T and exercise therapy on physiological outcomes such as aerobic fitness, body composition and muscular strength are addressed. MAIN BODY: Our findings suggest that both T treatment and exercise improve lean body mass in healthy older men. If improvement in lean body mass is the primary aim, then T treatment could be considered, and the combination of T and exercise may be more beneficial than either in isolation. In terms of muscle strength in older age, an exercise program is likely to be more beneficial than T treatment (where the dose is aimed at achieving physiological concentrations), and the addition of such T treatment does not provide further benefit beyond that of exercise alone. For aerobic fitness, T at doses aimed at achieving physiological concentrations has relatively modest impacts, particularly in comparison to exercise training, and there is limited evidence as to additive effects. Whilst higher doses of T, particularly by intramuscular injection, may have larger impacts on lean body mass and strength, this must be balanced against potential risks. CONCLUSION: Knowing the impacts of T treatment and exercise on variables such as body composition, strength and aerobic fitness extends our understanding of the relative benefits of physiological and pharmacological interventions in aging men. Our review suggests that T has impacts on strength, body composition and aerobic fitness outcomes that are dependent upon dose, route of administration, and formulation. T treatment aimed at achieving physiological T concentrations in middle-aged and older men can improve lean body mass, whilst exercise training enhances lean body mass, aerobic fitness and strength. Men who are physically able to exercise safely should be encouraged to do so, not only in terms of building lean body mass, strength and aerobic fitness, but for the myriad health benefits that exercise training confers.

Simultaneous MPFL reconstruction and guided growth result in low rates of recurrent patellofemoral instability.

PURPOSE: Implant-mediated guided growth (IMGG) is used to address coronal plane deformity in skeletally immature patients. Few studies have reported on IMGG and simultaneous medial patellofemoral ligament (MPFL) reconstruction for paediatric patients with concurrent genu valgum and patellofemoral instability (PFI). This study aimed to report on the outcomes of these simultaneous procedures. MATERIALS AND METHODS: This was a retrospective review of paediatric patients undergoing simultaneous MPFL reconstruction and IMGG between 2016 and 2023. Mechanical lateral distal femoral angle (mLDFA), hip-knee-ankle angle (HKA) and mechanical axis deviation (MAD) were measured on full-length hip-to-ankle plain radiographs. Measurements were taken preoperatively, prior to implant removal and/or at final follow-up with minimum 1-year clinical follow-up. RESULTS: A total of 25 extremities in 22 patients (10 female) underwent simultaneous IMGG and MPFL reconstruction. The mean age at surgery was 12.6 ± 1.7 years. The mean duration of implant retention was 18.6 ± 11.3 months. Nineteen extremities (76%) underwent implant removal by final follow-up. Preoperative HKA corrected from a mean of 5.8 ± 2.3° to -0.8 ± 4.5° at implant removal or final follow-up (p < 0.001), with mLDFA and MAD similarly improving (both p < 0.001). HKA corrected a mean of 0.7 ± 0.9° per month, while mLDFA and MAD corrected a mean of 0.5 ± 0.6°/month and 2 ± 3 mm/month, respectively. At the time of implant removal or final follow-up, 88% of patients demonstrated alignment within 5° of neutral. Only one extremity experienced subsequent PFI (4%). For 14 patients who underwent implant removal with further imaging at a mean of 7.8 ± 4.9 months, only one patient (7%) had a valgus rebound to an HKA > 5°. CONCLUSION: Simultaneous MPFL reconstruction and IMGG provided successful correction of lower extremity malalignment with only one recurrence of PFI. This approach is a reliable surgical option for skeletally immature patients with genu valgum and PFI. LEVEL OF EVIDENCE: Level 4 case series.