Exploring Anti-Fibrotic Effects of Adipose-Derived Stem Cells: Transcriptome Analysis upon Fibrotic, Inflammatory, and Hypoxic Conditioning.

Autologous fat transfers show promise in treating fibrotic skin diseases, reversing scarring and stiffness, and improving quality of life. Adipose-derived stem cells (ADSCs) within these grafts are believed to be crucial for this effect, particularly their secreted factors, though the specific mechanisms remain unclear. This study investigates transcriptomic changes in ADSCs after in vitro fibrotic, inflammatory, and hypoxic conditioning. High-throughput gene expression assays were conducted on ADSCs exposed to IL1-ß, TGF-ß1, and hypoxia and in media with fetal bovine serum (FBS). Flow cytometry characterized the ADSCs. RNA-Seq analysis revealed distinct gene expression patterns between the conditions. FBS upregulated pathways were related to the cell cycle, replication, wound healing, and ossification. IL1-ß induced immunomodulatory pathways, including granulocyte chemotaxis and cytokine production. TGF-ß1 treatment upregulated wound healing and muscle tissue development pathways. Hypoxia led to the downregulation of mitochondria and cellular activity.

An Updated Systematic Review and Meta-analysis of the Impact of Graduated Compression Stockings in Addition to Pharmacological Thromboprophylaxis for Prevention of Venous Thromboembolism in Surgical Inpatients.

OBJECTIVE: To compare the rate of venous thromboembolism (VTE) in surgical inpatients with pharmacological thromboprophylaxis and additional graduated compression stockings (GCSs) versus pharmacological thromboprophylaxis alone. BACKGROUND: Surgical inpatients have elevated VTE risk; recent studies cast doubt on whether GCS confers additional protection against VTE, compared with pharmacological thromboprophylaxis alone. METHODS: The review followed "Preferred Reporting Items for Systematic Reviews and Meta-analyses" guidelines using a registered protocol (CRD42017062655). The MEDLINE and Embase databases were searched up to November 2022. Randomized trials reporting VTE rate after surgical procedures, utilizing pharmacological thromboprophylaxis, with or without GCS, were included. The rates of deep venous thrombosis (DVT), pulmonary embolism, and VTE-related mortality were pooled through fixed and random effects. RESULTS: In a head-to-head meta-analysis, the risk of DVT for GCS and pharmacological thromboprophylaxis was 0.85 (95% CI: 0.54-1.36) versus for pharmacological thromboprophylaxis alone (2 studies, 70 events, 2653 participants). The risk of DVT in pooled trial arms for GCS and pharmacological thromboprophylaxis was 0.54 (95% CI: 0.23-1.25) versus pharmacological thromboprophylaxis alone (33 trial arms, 1228 events, 14,108 participants). The risk of pulmonary embolism for GCS and pharmacological prophylaxis versus pharmacological prophylaxis alone was 0.71 (95% CI: 0.0-30.0) (27 trial arms, 32 events, 11,472 participants). There were no between-group differences in VTE-related mortality (27 trial arms, 3 events, 12,982 participants). CONCLUSIONS: Evidence from head-to-head meta-analysis and pooled trial arms demonstrates no additional benefit for GCS in preventing VTE and VTE-related mortality. GCS confer a risk of skin complications and an economic burden; current evidence does not support their use for surgical inpatients.

Single-Cell Analysis of ADSC Interactions with Fibroblasts and Endothelial Cells in Scleroderma Skin.

Adipose-derived stem cells (ADSCs) as part of autologous fat grafting have anti-fibrotic and anti-inflammatory effects, but the exact mechanisms of action remain unknown. By simulating the interaction of ADSCs with fibroblasts and endothelial cells (EC) from scleroderma (SSc) skin in silico, we aim to unravel these mechanisms. Publicly available single-cell RNA sequencing data from the stromal vascular fraction of 3 lean patients and biopsies from the skin of 10 control and 12 patients with SSc were obtained from the GEO and analysed using R and Seurat. Differentially expressed genes were used to compare the fibroblast and EC transcriptome between controls and SSc. GO and KEGG functional enrichment was performed. Ligand-receptor interactions of ADSCs with fibroblasts and ECs were explored with LIANA. Pro-inflammatory and extracellular matrix (ECM) interacting fibroblasts were identified in SSc. Arterial, capillary, venous and lymphatic ECs showed a pro-fibrotic and pro-inflammatory transcriptome. Most interactions with both cell types were based on ECM proteins. Differential interactions identified included NTN1, VEGFD, MMP2, FGF2, and FNDC5. The ADSC secretome may disrupt vascular and perivascular inflammation hubs in scleroderma by promoting angiogenesis and especially lymphangiogenesis. Key phenomena observed after fat grafting remain unexplained, including modulation of fibroblast behaviour.

Refinement of the Superomedial Pedicle Technique: A New Approach to Breast Reshaping Following Reduction.

INTRODUCTION: We present an alteration of the superomedial pedicle technique in breast reduction to control lateral fullness and create a more natural and contoured breast during reshaping. This approach has been adopted by the senior author (NC) in 79 patients over the past 4 years. METHODS: A wise pattern skin incision is used, and the nipple-areola complex (NAC) is maintained on a de-epithelialized superomedial pedicle. Instead of fully releasing the pedicle from the lateral parenchyma for rotation and inset, a bridge of tissue between the pedicle on its most posterior aspect and the lateral pillar is maintained. Key holding sutures are subsequently placed in Scarpa's fascia for reshaping. RESULTS: We find that with this refinement, the connection with the lateral pillar pulls the lateral parenchyma medially and superiorly when the pedicle is rotated into its new position, adding a natural curve to the side. The superior medial pedicle is still attached in its postero-lateral aspect to the lateral pillar and theoretically, will provide an even more robust vascular supply to the NAC. In our series, three patients developed minor skin healing issues amenable to treatment with dressings. No one suffered from nipple loss or other serious complications, and no dog ear revisions were required. CONCLUSIONS: We present a simple alteration of the superomedial pedicle technique that we believe results in improved breast contouring. Our experience suggests that this simple adaptation is safe, effective, and reproducible. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Systematic Review and Meta-Analysis of the Pooled Rate of Post-Thrombotic Syndrome After Isolated Distal Deep Venous Thrombosis.

OBJECTIVE: To identify the rate of post-thrombotic syndrome (PTS) after isolated distal deep venous thrombosis (IDDVT) by performing a meta-analysis of the rate of PTS across randomised and observational studies. DATA SOURCES: MEDLINE, Embase, the Cochrane Controlled Trials Register, Clinicaltrials.gov, European Union Clinical Trials, International Standard Randomised Controlled Trial Number, and the Australian and New-Zealand Trials Registries. REVIEW METHODS: This review followed PRISMA guidelines using a registered protocol (CRD42021282136). Databases were searched up to December 2021 and prospective studies reporting the development of post-thrombotic syndrome were included; these were pooled with the meta-analysis. RESULTS: The results showed a post-thrombotic rate of 17% (95% CI 11 - 26%) (seven studies, 217 cases, 1 105 participants). Heterogeneity was high (I2 = 89%). On meta-regression, the rate of post-thrombotic syndrome was not correlated with the length of follow up (p = .71). Three studies (302 participants) reported the severity of post-thrombotic syndrome: 78% were mild (Villalta score 5 - 9); 11% were moderate (Villalta score 10 - 14), and 11% were severe (Villalta score ≥ 15). CONCLUSION: The risk of post-thrombotic syndrome after IDDVT was one in five and the risk of severe clinical manifestations, including ulceration, was one in 50. There was significant clinical, methodological, and statistical heterogeneity between studies and a substantial risk of bias from pooled studies. Randomised trials to support interventions for prevention of post-thrombotic syndrome are urgently needed.

Systematic review and meta-analysis of exercise therapy for venous leg ulcer healing and recurrence.

OBJECTIVE: National guidelines in the United Kingdom have recommended regular exercise for individuals with venous leg ulceration. However, data on the effects of exercise on ulcer healing and recurrence are sparse. In the present study, we aimed to quantify the evidence for exercise regarding venous ulcer healing with respect to the primary outcomes of the proportion of healed ulcers and rate of ulcer recurrence. The secondary outcomes were improvement in ulcer symptoms, ulcer healing time, quality of life, compliance, and adverse events reported. METHODS: The review followed PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines using a registered protocol (CRD42021220925). The MEDLINE and Embase databases and Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, European Union Clinical Trials, and International Standard Randomised Controlled Trial Number registries were searched up to April 6, 2022 and included studies comparing exercise therapy and compression vs compression alone. Data for the proportion of healed ulcers were pooled using a fixed effects meta-analysis. RESULTS: After screening 1046 reports, 7 were included, with 121 participants allocated to exercise therapy and 125 to compression alone. All the reports were of randomized controlled trials and had reported ulcer healing at 12 weeks, with a pooled relative risk of ulcer healing of 1.38 for exercise vs compression (95% confidence interval, 1.11-1.71). Only one study had reported on recurrence; thus, data pooling was not performed. No differences between exercise and usual care were demonstrated. Compliance with exercise ranged from 33% to 81%. The included studies demonstrated low enrollment and a high risk of bias. Also, most of the trials had failed to demonstrate any differences in activity completed between the intervention and control arms. CONCLUSIONS: A paucity of studies has examined leg ulcer recurrence after exercise programs, with no evidence to show that exercise is beneficial. Furthermore, the quality of evidence supporting exercise as an adjunct to ulcer healing is very low, and the trials demonstrated serious methodologic flaws, chiefly in recording the activity undertaken by the participants in the intervention arm. Future randomized controlled trials should implement activity monitoring and standardize the reporting of key patient, ulcer, and reflux characteristics to enable future meaningful meta-analyses to determine the role of exercise as an adjunct to venous leg ulceration healing.

Systematic Review and Meta-analysis of the Additional Benefit of Pharmacological Thromboprophylaxis for Endovenous Varicose Vein Interventions.

OBJECTIVE: The primary objective of this systematic review and meta-analysis was to elucidate the rate of venous thromboembolism (VTE) after endovenous interventions for varicose veins in the presence of pharmacological and mechanical thromboprophylaxis versus mechanical thromboprophylaxis alone. BACKGROUND: The VTE rate after endovenous procedures for varicose veins is higher than other day-case procedures and could be reduced with pharmacological thromboprophylaxis. METHODS: The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines with a registered protocol (PROSPERO: CRD42021274963). Studies of endovenous intervention for superficial venous incompetence reporting the predefined outcomes with at least 30 patients were eligible. Data were pooled with a fixed effects model. RESULTS: There were 221 trials included in the review (47 randomized trial arms, 105 prospective cohort studies, and 69 retrospective studies). In randomized trial arms, the rate of deep venous thrombosis with additional pharmacological thromboprophylaxis was 0.52% (95% CI, 0.23%-1.19%) (9 studies, 1095 patients, 2 events) versus 2.26% (95% CI, 1.81%-2.82%) (38 studies, 6951 patients, 69 events) with mechanical thromboprophylaxis alone. The rate of pulmonary embolism in randomized trial arms with additional pharmacological thromboprophylaxis was 0.45% (95% CI, 0.09-2.35) (5 studies, 460 participants, 1 event) versus 0.23% (95% CI, 0.1%-0.52%) (28 studies, 4834 participants, 3 events) for mechanical measures alone. The rate of EHIT grade III to IV was 0.35% (95% CI, 0.09-1.40) versus 0.88% (95% CI, 0.28%-2.70%). There was 1 VTE-related mortality and 1 instance of major bleeding, with low rates of minor bleeding. CONCLUSIONS: There is a significant reduction in the rate of DVT with additional pharmacological thromboprophylaxis and routine prescription of anticoagulation after endovenous varicose vein intervention should be considered. VTE risk for individual study participants is heterogeneous and risk stratification in future randomized interventional studies is critical to establish the clinical effectiveness and safety of additional pharmacological thromboprophylaxis.

Systematic review of exercise therapy in the management of post-thrombotic syndrome.

OBJECTIVES: Exercise improves haemodynamic parameters in patients with chronic venous disease. There is a paucity of evidence on its effect in post-thrombotic syndrome (PTS). The aim of this systematic review is to assess the impact of exercise in PTS. METHODS: Adhering to PRISMA guidelines and following PROSPERO registration (CRD42021220924), MEDLINE, Cochrane Library, EMBASE database, and trial registries were searched on 19th May 2022. RESULTS: One article met the inclusion criteria and a narrative synthesis was carried out. The included randomised controlled trial reported a between-group mean difference of 4.6 points (p = .027) in the VEINES-QOL score and -2.0 points (p = .14) in the Villalta score, in favour of exercise therapy. The statistical significance threshold was not reached. CONCLUSION: Data on exercise in PTS remains sparse but exercise appears to be a safe intervention. In the context of this literature, a potential future trial and outcome reporting measures are suggested.

Anterior Urethroplasty for the Management of Urethral Strictures in Males: A Systematic Review.

OBJECTIVE: To identify the currently utilised techniques of anterior urethroplasty described in literature for treatment of urethral strictures, assess the effectiveness of the identified techniques based on re-stricture and complication rates, evaluate, and suggest treatment options based on current evidence for urethral strictures at different locations and of different lengths. METHODS: A systematic review of the MEDLINE, EMBASE, Scopus and Cochrane Library databases from conception up to September 2020 was performed. Primary outcomes included success rates measured via re-stricture rates and the post-operative maximum urinary flow rate (Qmax). Secondary outcomes included patient reported complication rates. RESULTS: A total of 52 papers, including 7 RCTs, met the inclusion criteria. Forty studies described the use of free graft urethroplasty with a median success rate of 86.5% (IQR = 8.1). The best outcomes were found in dorsal onlay buccal mucosa grafting in the penile urethra (86.6%). Twelve described the use of pedicled flap urethroplasty with a median success rate of 76% (IQR = 14.4). Excision and Primary Anastomosis results were reported in 5 studies and showed an overall highest success rate of 89.7% (IQR = 7.0) but involved the shortest strictures of median lengths of 2.1 cm (IQR = 0.48). CONCLUSION: Graft urethroplasty showed optimal outcomes when utilised in penile and bulbar strictures, with dorsal onlay buccal mucosa grafting presenting with the largest evidence base and best outcomes overall. Flap urethroplasty had the highest success rates in panurethral and bulbar strictures, while anastomotic urethroplasty had the greatest success in bulbar and penobulbar strictures.

Aortic stenosis of a bicuspid aortic valve in a patient with Klippel-Feil syndrome: a case report.

BACKGROUND: Klippel-Feil syndrome (KFS) is a rare congenital anomaly of the cervical spine, which is associated with a number of cardiovascular malformations, including coarctation of the aorta, bicuspid aortic valve (BAoV), and aortic aneurysm. Operative management of aortic stenosis of a BAoV in a patient with KFS has not been previously reported. CASE SUMMARY: A 54-year-old Caucasian woman with known KFS presented to her local hospital for elective cholecystectomy. An ejection systolic murmur was found incidentally on preoperative workup, which was confirmed to be due to a severely stenosed BAoV. The cholecystectomy was cancelled, and the patient was referred to our centre and accepted for surgical aortic valve replacement (AVR) based on symptomatic and prognostic grounds. Anaesthetic review of cervical spine imaging showed fusion of the C2-C6 vertebral bodies and a desiccated bulging disc at C4-C5 but no significant foraminal narrowing in the lower cervical spine. Valve replacement with a mechanical aortic prosthesis resulted in an uneventful recovery and the patient was discharged home to follow-up. DISCUSSION: We report the first case of severe aortic valve stenosis requiring AVR in a Klippel-Feil patient, in whom the aortic valve was confirmed to be bicuspid. This report provides further evidence of an association of KFS with BAoV and strengthens the case for screening and follow-up of KFS patients for BAoV and other cardiovascular pathologies, the consequences of which may be serious.

Aortic valve replacement with sutureless Perceval S valve: A case report of aortic root homograft failure in the setting of Streptococcus constellatus endocarditis.

BACKGROUND: Surgery for failed homograft aortic root replacement with extensive calcification in the setting of endocarditis alone is very challenging. CASE SUMMARY: We report the case of redo aortic valve replacement and mitral valve replacement, in a 39 years old presenting with a rare Streptococcus constellatus endocarditis of a previously implanted homograft root and native mitral valve, where conventional valve replacement proved nonfeasible. S. constellatus had caused severe tissue destruction and the extensive calcification in the homograft prevented conventional valve replacement with sutures. In this case, a sutureless valve provided a useful alternative surgical strategy. DISCUSSION: We consider heavily calcified failed homografts to be a good indication for sutureless (rapid deployment) valves.

Development and content validation of the Urethroplasty Training and Assessment Tool (UTAT) for dorsal onlay buccal mucosa graft urethroplasty.

OBJECTIVES: To develop and validate the Urethroplasty Training and Assessment Tool (UTAT) using Healthcare Failure Mode and Effect Analysis (HFMEA) for training and assessment of urology trainees learning this urethral reconstruction technique, as urethroplasty is the 'gold standard' treatment for long and recurrent urethral strictures and with a variety of techniques and a lack of standardised reconstructive curricula, there is a need for procedure-specific training tools to improve surgeon training and patient safety. MATERIALS AND METHODS: This international observational study was performed over an 11-month period. The HFMEA was used to identify and evaluate hazardous stages of urethroplasty to develop the UTAT. Hazard scores were calculated for the included steps of urethroplasty. Content validation was performed by 12 expert surgeons and multidisciplinary teams from international tertiary centres. RESULTS: The HFMEA process resulted in an internationally validated UTAT. Hazard scores ≥4 and single point weaknesses were included to implement actions and outcome measures. Content validation was achieved by circulating the process map, hazard analysis table, and developed tools. Changes were implemented based on the feedback received from expert surgeons. The content validated dorsal onlay buccal mucosa graft bulbar UTAT contained five phases, 10 processes and 23 sub-processes. CONCLUSIONS: The modular UTAT offers a comprehensive validated training tool developed via a detailed HFMEA protocol. This may be utilised to standardise the training and assessment of urology trainees.

Redo-urethroplasty for the management of recurrent urethral strictures in males: a systematic review.

PURPOSE: Redo-urethroplasty is a challenge for any genitourethral surgeon, with a number of techniques previously described. This systematic review aims to identify the surgical techniques described in the literature and evaluate the evidence for their effectiveness in managing recurrent urethral strictures. MATERIALS AND METHODS: A systematic review of the MEDLINE and EMBASE databases from 1945 to July 2018 was performed and the urethroplasty procedures were classified according to the site and surgical technique. Primary outcomes included success rates measured via re-stricture rates and the post-op maximum urinary flow rate. Secondary outcomes included complication rates and patient-reported quality of life. RESULTS: A total of 39 identified studies met the inclusion criteria. Twenty-two studies described the use of excision and primary anastomotic urethroplasty with success rates showing wide variability (58-100%). Success rates reported according to the site of the stricture also varied: bulbar (58-100%) and posterior (69-100%) recurrent strictures. One-stage substitution urethroplasty was described in 25 studies with success rates of 18-100%, with the best outcomes reported for bulbar (58-100%) and hypospadias-related (78.6-82%) strictures. Two-stage substitution urethroplasty was described in 12 studies with the success rates of 20-100%, with the best evidence related to hypospadias-related and posterior urethral strictures. The buccal mucosa graft was the graft source with the best evidence for substitution urethroplasty (18-100%). CONCLUSIONS: Trends of effectiveness were identified for redo-urethroplasty modalities in different locations. However, the current levels of evidence are limited to small observational studies, highlighting the need for further larger prospective data to evaluate different techniques used for recurrent urethral strictures.