Tibial transverse transport combined with platelet-rich plasma sustained-release microspheres activates the VEGFA/VEGFR2 pathway to promote microcirculatory reconstruction in diabetic foot ulcer.

This study proposes to investigate the therapeutic efficacy and mechanism of combining tibial transverse transport (TTT) with platelet-rich plasma (PRP) for diabetic foot ulcer (DFU). The diabetic rabbit model was constructed with Streptozotocin, which was intervened with TTT and PRP. PRP injection combined with TTT significantly promoted vascularisation and enhanced CD31, VEGFA, and VEGFR2 expressions compared to traditional TTT. However, the VEGFR2 inhibitor suppressed these phenomena. In the in vitro injury model, PRP reversed the diminished human umbilical vein endothelial cells (HUVECs) function and vascularisation caused by high-glucose damage. Additionally, PRP reduced inflammation and oxidative stress (approximately 47% ROS level) and enhanced VEGFA and VEGFR2 expression in HUVECs. However, the knockdown of VEGFR2 reversed the effect of PRP. In conclusion, TTT combined with intraosseous flap injection of PRP sustained-release microspheres activated the VEGFA/VEGFR2 pathway to promote microcirculatory reconstruction in DFU. These findings may provide new potential therapeutic strategies for DFU.

Tibial transverse transport induces mobilization of endothelial progenitor cells to accelerate angiogenesis and ulcer wound healing through the VEGFA/CXCL12 pathway.

BACKGROUND: Tibial transverse transport (TTT) can promote the healing of chronic foot ulcers, but the specific cellular and molecular mechanisms by which TTT promotes wound healing remain unclear. METHODS: New Zealand White rabbits were selected to induce foot ulcer models. The treatment included unilateral TTT surgery and bilateral TTT surgery. Observation of tissue neovascularization structure by HE staining and CD31 immunofluorescence detection. Collagen fiber formation was detected through the Masson staining. The mobilization of endothelial progenitor cell (EPCs) were analyzed by VEGFR2 immunofluorescence detection and flow cytometry detection of the number of VEGFR2/Tie-2-positive cells in peripheral blood. ELISA and qPCR assay were performed to detect VEGFA and CXCL12 levels. RESULTS: The complete healing time of ulcer surfaces in sham, unilateral and bilateral TTT groups was about 22 days, 17 days and 13 days, respectively. TTT treatment significantly increased the deposition of granulation tissue and epithelialization of wounds. It also led to an increase in collagen fiber content and the level of the microvascular marker CD31. Furthermore, TTT treatment upregulated the levels of VEGFA and CXCL12 in peripheral blood and wound tissues, as well as increased the expression of VEGFR2 in wound tissues and the proportion of VEGFR2/Tie-2 in peripheral blood. Moreover, these effects of TTT treatment in the bilateral group was more significant than that in the unilateral group. CONCLUSIONS: TTT may facilitate wound fibroblasts to release VEGFA and CXCL12, causing EPC mobilization, thus promoting angiogenesis and ulcer wound healing.

Polyene phosphatidylcholine promotes tibial fracture healing in rats by stimulating angiogenesis dominated by the VEGFA/VEGFR2 signaling pathway.

One of the factors that predispose to fractures is liver damage. Interestingly, fractures are sometimes accompanied by abnormal liver function. Polyene phosphatidylcholine (PPC) is an important liver repair drug. We wondered if PPC had a role in promoting fracture healing. A rat model of tibial fracture was developed using the modified Einhorn model method. X-rays were used to detect the progression of fracture healing. Progress of ossification and angiogenesis at the fracture site were analyzed by Safranin O/fast green staining and CD31 immunohistochemistry. To investigate whether PPC has a direct angiogenesis effect, HUVECs were used. We performed MTT, wound healing, Transwell migration, and tube formation assays. Finally, RT-qPCR and Western blot analysis were used to study the underlying mechanism. The results showed that PPC significantly shortened the apparent recovery time of mobility in rats. PPC treatment significantly promoted the formation of cartilage callus, endochondral ossification, and angiogenesis at the fracture site. In vitro, PPC promoted the proliferative viability of HUVECs, their ability to heal wounds, and their ability to penetrate membranes in the Transwell apparatus and increased the tube formation of cells. The transcription of VEGFA, VEGFR2, PLCγ, RAS, ERK1/2 and MEK1/2 was significantly up regulated by PPC. Further, the protein level results demonstrated a significant increase in the expression of VEGFA, VEGFR2, MEK1/2, and ERK1/2 proteins. In conclusion, our findings suggest that PPC promotes angiogenesis by activating the VEGFA/VEGFR2 and downstream signaling pathway, thereby accelerating fracture healing.

Nitric oxide-mediated vasodilation in human bone.

OBJECTIVE: Regulation of blood flow to bone is critical but poorly understood, particularly in humans. This study aims to determine whether nitric oxide (NO), a major regulator of vascular tone to other tissues, contributes also to the regulation of blood flow to bone. METHODS: In young healthy adults (n = 16, 8F, 8M), we characterized NO-mediated vasodilation in the tibia in response to sublingual nitroglycerin and contrasted it to lower leg. Blood flow responses were assessed in supine individuals by continuously measuring tibial total hemoglobin (tHb) via near-infrared spectroscopy and lower leg blood flow (LBF) as popliteal flow velocity via Doppler ultrasound in the same leg. RESULTS: LBF increased by Δ9.73 ± 0.66 cm/s and peaked 4.4 min after NO administration and declined slowly but remained elevated (Δ3.63 ± 0.60 cm/s) at 10 min. In contrast, time to peak response was longer and smaller in magnitude in the tibia as tHb increased Δ2.08 ± 0.22 µM and peaked 5.3 min after NO administration and declined quickly but remained elevated (Δ0.87±0.22 µM) at 10 min (p = .01). CONCLUSIONS: In young adults, the tibial vasculature demonstrates robust NO-mediated vasodilation, but tHb is delayed and diminishes faster compared to LBF, predominately reflective of skeletal muscle responses. Thus, NO-mediated vasodilation in bone may be characteristically different from other vascular beds.

Reduction of Overactive Bladder Medications in Spinal Cord Injury With Self-Administered Neuromodulation; a Randomized Trial.

PURPOSE: To evaluate if self-administered bladder neuromodulation with transcutaneous tibial nerve stimulation can safely replace overactive bladder medications in people with spinal cord injury. MATERIALS AND METHODS: We performed a 3-month, randomized, investigator-blinded, tibial nerve stimulation vs sham-control trial in adults with spinal cord injury and neurogenic bladder performing intermittent catheterization and taking overactive bladder medications. The primary outcome was a reduction in bladder medications while maintaining stable bladder symptoms and quality of life based on pre-post Neurogenic Bladder Symptom Score and the Incontinence-QOL questionnaire, respectively. Secondary outcomes included changes in pre-post cystometrogram, 2-day voiding diaries, and an anticholinergic medication side effect survey. RESULTS: Fifty people consented to the study, with 42 completing the trial. No dropouts were due to stimulation issues. All baseline demographics and surveys were comparable at baseline. Cystometrogram parameters were also comparable at baseline, except the stimulation group had a higher proportion of loss of bladder compliance compared to the control group. At the end of the trial, a significantly greater percentage of the tibial nerve stimulation group were able to reduce medications (95% v 68%), by a 26.2% difference in medication reduction (95% confidence interval 1.17%-51.2%). Function and quality of life surveys and cystometrograms at the end of the trial were alike between groups. Transcutaneous tibial nerve stimulation satisfaction surveys and adherence to protocol were high. CONCLUSIONS: In people with chronic spinal cord injury performing intermittent catheterization, transcutaneous tibial nerve stimulation can be an option to reduce or replace overactive bladder medications.

Effect of load reduction on the calcification of rat tibial tuberosity: Focus on calcification factors and chondrocyte mechanosensors.

The tibial tuberosity has a superficial patellar tendon-embedded portion and a deep uncalcified cartilage portion. Suppressed calcification of the tibial tuberosity leads to Osgood-Schlatter disease. The tibial tuberosity calcifies with age; load reduction degrades the cartilage matrix and promotes calcification, suggesting that reduced mechanical stimulation of the tibial tuberosity promotes calcification. However, this is yet to be clarified. Therefore, in this study, we aimed to investigate the effects of mechanical stimulation reduction on the tibial tuberosity tissue structure and calcification mechanism. Specifically, we examined the effect of load reduction on tibial tuberosity calcification in 20 male 7-week-old Wistar rats classified into two groups: hind-limb suspension (HS, n = 10) and control (CO, n = 10). We observed superficial and deep tibial tuberosities in both groups. The tibial tuberosity in the HS group had narrower areas of deep portions than did those in the CO group (p = 0.000539), and immature bone tissue and cartilage tissue were observed in the HS group. Enpp1 expression did not significantly differ between the groups (p = 0.804). In contrast, Alpl (p = 0.001) and Mmp3 (p = 0.006) expression increased whereas Timp3 expression decreased (p = 0.002) in the HS group. Thus, these results showed a maturing of bone ossification, and this gene expression trend was similar to that observed in a murine join instability model of osteoarthritis with articular cartilage calcification and ossification. The HS tibial tuberosity also showed immature bone tissue. In conclusion, reduced mechanical stimulation caused tibial tuberosity calcification and pathological changes. These findings highlight the importance of optimal exercise to avoid premature pathological structural changes in bones and joints.

ENPP1 downregulation and FGF23 upregulation in growth-related calcification of the tibial tuberosity in rats.

During tibial tuberosity growth, superficial and deep portions can be observed; however, the deep portion is not observed after the growth period, as it develops into bone tissues. Calcification in vivo is known to be constitutively suppressed by ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) but promoted by tissue-nonspecific alkaline phosphatase (TNAP). FGF23 promotes calcification of enthesis. Gene expression of FGF23 increased rapidly at 13W in this study. Therefore, the tibial tuberosity is speculated to develop via Enpp1 downregulation and Tnap upregulation; however, the understanding of these processes remains unclear. Hence, in the present study, we aimed to explore the age-related structural changes and underlying gene expression changes in the tibial tuberosity of rats. Male Wistar rats were divided into three groups (3-, 7-, and 13-week-old; eight each). The tibial tuberosity superficial and deep portions were clearly observed in 3- and 7-week-old rats, but the presence of the deep portion was not confirmed in 13-week-old rats. The extracellular matrix of hypertrophic chondrocytes was calcified. Furthermore, the Enpp1 expression was the highest in 3-week-old rats and decreased with growth. The TNAP expression did not differ significantly among the groups. The deep portion area was significantly lower in 3-week-old rats than in 7-week-old rats. Generally, the extracellular matrix of the immature chondrocytes is not calcified. Therefore, we speculated that the cartilaginous tibial tuberosity calcifies and ossifies with growth. The Enpp1 expression decreased with growth, whereas the Tnap expression remained unchanged. Thus, we surmise that the tibial tuberosity calcifies with growth and that this process involves Enpp1 downregulation and FGF23 upregulation. As Osgood-Schlatter disease is closely related to the calcification of the tibial tuberosity, these findings may help clarify the pathogenesis of this disease.

Outcomes and predictors of amputation-free survival in patients undergoing below-knee popliteal-distal bypass.

OBJECTIVE: The infrageniculate popliteal artery is a potential source for inflow in lower extremity bypass surgery in patients with isolated tibial artery disease. The objective of our study was to assess the short- and long-term outcomes of popliteal-distal bypasses using data from the Vascular Quality Initiative (VQI). METHODS: The VQI registry was queried between 2003 and 2021 for patients undergoing surgical revascularizations with the below-knee popliteal artery serving as inflow. Demographics, comorbidities, intraoperative characteristics, and postoperative complications were analyzed. Kaplan-Meier models were used to estimate amputation-free survival, survival, and freedom from amputation. Cox regression analysis was conducted to determine factors associated with major amputation or death. RESULTS: A total of 1884 procedures were analyzed. The mean age of the included patients was 67.7 years. The most frequently observed preoperative comorbidities included insulin-dependent diabetes (52.3%), coronary disease (32.4%), and end-stage renal disease (14.4%). Of all the patients, 670 (35.6%) had a history of ipsilateral endovascular intervention. The procedures were performed for a variety of indications, including tissue loss (84.3%), rest pain (10.9%), and claudication (4.8%). Intraoperatively, the outflow targets were the dorsalis pedis (31.4%), the posterior tibial (24.4%), and the anterior tibial arteries (15.6%). Vein conduit was used in 92.1% of cases. The rate of perioperative myocardial infarction (MI) was 2.4%, and the 30-day mortality was 1.9%. The median length of follow up was 371 days. Amputation-free survival was found to be 85.6% (95% confidence interval [CI], 84.0%-87.2%) at 6 months and 78.6% (95% CI, 76.6%-80.4%) at 12 months. Survival was found to be 93.4% (95% CI, 92.2%-94.5%) at 6 months and 88.6% (95% CI, 87.1%-90.0%) at 12 months. Freedom from amputation was found to be 92.0% (95% CI, 90.7%-93.3%) at 6 months and 89.0% (95% CI, 87.3%-90.4%) at 12 months. Cox regression analysis demonstrated that age greater than 65 years, congestive heart failure, coronary artery disease, and end-stage renal disease were associated with a higher risk of major amputation or death (P < .05). CONCLUSIONS: Below-knee popliteal-distal bypass is a safe and effective approach to treat severe tibial vessel occlusive disease in this challenging patient cohort. Patients exhibited low perioperative complication rates and good amputation-free survival at 1 year.

Surgery or endovascular therapy for patients with chronic limb-threatening ischemia requiring infrapopliteal interventions.

OBJECTIVE: The recent publication of randomized trials comparing open bypass surgery to endovascular therapy in patients with chronic limb-threatening ischemia, namely, Best Endovascular vs Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) and Bypass versus Angioplasty in Severe Ischaemia of the Leg-2 (BASIL-2), has resulted in potentially contradictory findings. The trials differed significantly with respect to anatomical disease patterns and primary end points. We performed an analysis of patients in BEST-CLI with significant infrapopliteal disease undergoing open tibial bypass or endovascular tibial interventions to formulate a relevant comparator with the outcomes reported from BASIL-2. METHODS: The study population consisted of patients in BEST-CLI with adequate single segment saphenous vein conduit randomized to open bypass or endovascular intervention (cohort 1) who additionally had significant infrapopliteal disease and underwent tibial level intervention. The primary outcome was major adverse limb event (MALE) or all-cause death. MALE included any major limb amputation or major reintervention. Outcomes were evaluated using Cox proportional regression models. RESULTS: The analyzed subgroup included a total of 665 patients with 326 in the open tibial bypass group and 339 in the tibial endovascular intervention group. The primary outcome of MALE or all-cause death at 3 years was significantly lower in the surgical group at 48.5% compared with 56.7% in the endovascular group (P = .0018). Mortality was similar between groups (35.5% open vs 35.8% endovascular; P = .94), whereas MALE events were lower in the surgical group (23.3% vs 35.0%; P<.0001). This difference included a lower rate of major reinterventions in the surgical group (10.9%) compared with the endovascular group (20.2%; P = .0006). Freedom from above ankle amputation or all-cause death was similar between treatment arms at 43.6% in the surgical group compared with 45.3% the endovascular group (P = .30); however, there were fewer above ankle amputations in the surgical group (13.5%) compared with the endovascular group (19.3%; P = .0205). Perioperative (30-day) death rates were similar between treatment groups (2.5% open vs 2.4% endovascular; P = .93), as was 30-day major adverse cardiovascular events (5.3% open vs 2.7% endovascular; P = .12). CONCLUSIONS: Among patients with suitable single segment great saphenous vein who underwent infrapopliteal revascularization for chronic limb-threatening ischemia, open bypass surgery was associated with a lower incidence of MALE or death and fewer major amputation compared with endovascular intervention. Amputation-free survival was similar between the groups. Further investigations into differences in comorbidities, anatomical extent, and lesion complexity are needed to explain differences between the BEST-CLI and BASIL-2 reported outcomes.

Subchondral Bone Osteocyte Lacunae Morphology in End-Stage Osteoarthritis of the Human Tibial Plateau.

Subchondral bone remodeling, mediated by osteocytes within the lacuno-canalicular network, plays a crucial role in osteoarthritis (OA) progression. Following cell death, lacunae preserve integrity, offering insights into bone remodeling mechanisms. Limited and controversial data on osteocyte lacuna morphology in OA result from small sample sizes and two-dimensional (2D) techniques that have been used thus far. This study aimed to quantify three-dimensional (3D) osteocyte lacunar characteristics at well-defined tibial plateau locations, known to be differently affected by OA. Specifically, 11 tibial plateaus were obtained from end-stage knee-OA patients with varus deformity. Each plateau provided one sample from the less affected lateral compartment and two samples from the medial compartment, at minimum and maximum bone volume fraction (BV/TV) locations. High-resolution desktop micro-computed tomography (micro-CT) at 0.7 µm voxel resolution imaged the 33 samples. Lacuna number density (Lc.N/BV) and lacuna volume density (Lc.TV/BV) were significantly lower (p < 0.02) in samples from the medial side with maximum BV/TV compared to lateral side samples. In the medial compartment at maximum local BV/TV, mean lacuna volume (Lc.V), total lacuna volume (Lc.TV), and Lc.TV/BV were significantly (p < 0.001) lower than in the region with minimum BV/TV. Lc.N/BV was also significantly lower (p < 0.02) at the maximum local BV/TV location compared to the region with minimum BV/TV. Our findings suggest that subchondral bone lacunae adapt to the changing loads in end-stage OA.

Types of Short-Duration Electrical Stimulation-Induced Efficiency in the Axonal Regeneration and Recovery: Comparative in Vivo Study in Rat Model of Repaired Sciatic Nerve and its Tibial Branch after Transection Injury.

The restoration of adequate function and sensation in nerves following an injury is often insufficient. Electrical stimulation (ES) applied during nerve repair can promote axon regeneration, which may enhance the likelihood of successful functional recovery. However, increasing operation time and complexity are associated with limited clinical use of ES. This study aims to better assess whether short-duration ES types (voltage mode vs. current mode) are able to produce enhanced regenerative activity following peripheral nerve repair in rat models. Wistar rats were randomly divided into 3 groups: no ES (control), 30-minute ES with a current pulse, and 30-minute ES with a voltage pulse. All groups underwent sciatic nerve transection and repair using a silicone tube to bridge the 6-mm gap between the stumps. In the 2 groups other than the control, ES was applied after the surgical repair. Outcomes were evaluated using electrophysiology, histology, and serial walking track analysis. Biweekly walking tracks test over 12 weeks revealed that subjects that underwent ES experienced more rapid functional improvement than subjects that underwent repair alone. Electrophysiological analysis of the newly intratubular sciatic nerve at week 12 revealed strong motor function recovery in rats that underwent 30-minute ES. Histologic analysis of the sciatic nerve and its tibial branch at 12 weeks demonstrated robust axon regrowth in all groups. Both types of short-duration ES applied during nerve repair can promote axon regrowth and enhance the chances of successful functional recovery.

Efficacy and safety of tibial nerve stimulation using a wearable device for overactive bladder.

OBJECTIVE: To evaluate the efficacy and safety of a wearable, smartphone-controlled, rechargeable transcutaneous tibial nerve stimulation (TTNS) device in patients with overactive bladder (OAB). PATIENTS AND METHODS: This multicentre, prospective, single-blind, randomised clinical trial included eligible patients with OAB symptoms who were randomly assigned to the stimulation group or sham group. The primary efficacy outcome was change from baseline in voiding frequency/24 h after 4 weeks of treatment. The secondary efficacy outcomes included changes in bladder diary outcomes (urgency score/void, nocturia episodes/day, micturition volume/void, and incontinence episodes/day), questionnaires on Overactive Bladder Symptom Score (OABSS), Patient Perception of Bladder Condition (PPBC), and American Urological Association Symptom Index Quality of Life Score (AUA-SI-QoL) at baseline and after 4 weeks of treatment. Device-related adverse events (AEs) were also evaluated. RESULTS: In the full analysis set (FAS), the mean (sd) change of voiding frequency/24 h in the stimulation group and sham group at 4 weeks were -3.5 (2.9) and -0.6 (2.4), respectively (P < 0.01). Similar results were obtained in the per-protocol set (PPS): -3.5 (2.9) vs -0.4 (2.3) (P < 0.01). In the FAS and PPS, micturition volume/void significantly improved at 4 weeks (P = 0.01 and P = 0.02). PPBC improvement almost reached significance in the FAS (P = 0.05), while it was significant in the PPS (P = 0.02). In the FAS and PPS, AUA-SI-QoL significantly improved at 4 weeks in the two groups (P < 0.01 and P < 0.01), whereas there were no significant differences in urgency score/void, nocturia episodes/day or OABSS between the groups. Also, no device-related serious AEs were reported. CONCLUSIONS: The non-invasive neuromodulation technique using the novel ambulatory TTNS device is effective and safe for treating OAB. Its convenience and easy maintenance make it a new potential home-based treatment modality. Future studies are warranted to confirm its longer-term efficacy.

Short Term Outcomes of a Prospective Registry in Popliteal and Infrapopliteal Endovascular Interventions for Chronic Limb Threatening Ischaemia.

OBJECTIVE: The prevalence of chronic limb threatening ischaemia (CLTI) is increasing worldwide, resulting in the need for more patients undergoing revascularisation, especially for below the knee pathology. Nevertheless, prospective data on below the knee endovascular interventions are lacking. The aim of the study was to provide large scale, real world data on procedural and short term outcomes of popliteal and infrapopliteal endovascular interventions in patients with CLTI. METHODS: This study is an analysis of the first 1 000 interventions of the Dutch Chronic Lower Limb-Threatening Ischemia Registry (THRILLER). It includes all patients with CLTI undergoing popliteal or infrapopliteal endovascular revascularisation in seven hospitals in the Netherlands. The primary outcomes were limb salvage and amputation free survival (AFS) at three months estimated with the Kaplan-Meier method. Secondary outcomes were procedural complications and primary patency. RESULTS: Between February 2021 and July 2023, 1 000 endovascular procedures were performed in 840 patients (947 limbs), treating 486 popliteal and 1 209 tibial lesions. Wound, Ischemia, and foot Infection (WIfI) stages 1 - 4 were present in 16.8%, 17.2%, 25.4%, and 40.6% of the limbs, respectively. Technical success was hampered by arterial perforation, acute thrombosis, and distal embolisation in 8.7%, 1.0%, and 2.3% of the interventions, respectively. Limb salvage was 100.0%, 96.9%, 94.9%, and 86.1% (p < .001), whereas AFS was 96.9%, 93.2%, 86.6%, and 76.4% for WIfI stages 1 - 4 at three months (p < .001), respectively. Primary patency at the 6 - 8 week visit was 86.4% for popliteal and 74.3% for tibial lesions, respectively. CONCLUSION: THRILLER presents a large prospective database on outcomes of CLTI endovascular interventions. Popliteal and infrapopliteal endovascular revascularisation for CLTI is safe. Interventions with initial technical success have high rates of limb salvage and survival at three months. The WIfI classification provides a reliable instrument to predict limb salvage and AFS independently at three months.

Infrapopliteal Peripheral Vascular Interventions for Claudication are Performed Frequently in the USA and Are Associated with Poor Long Term Outcomes.

OBJECTIVE: Infrapopliteal peripheral vascular interventions (PVIs) for claudication are still performed in the USA. This study aimed to evaluate whether infrapopliteal PVI is associated with worse long term outcomes than isolated femoropopliteal PVI for treatment of claudication. METHODS: A retrospective analysis of fee for service claims in a national administrative database was conducted using 100% of the Medicare fee for service claims between 2017 and 2019 to capture all Medicare beneficiaries who underwent an index infra-inguinal PVI for claudication. Hierarchical Cox proportional hazards models were performed to assess the association of infrapopliteal PVI with conversion to chronic limb threatening ischaemia (CLTI), repeat PVI, and major amputation. RESULTS: In total, 36 147 patients (41.1% female; 89.7% age ≥ 65 years; 79.0% non-Hispanic White ethnicity) underwent an index PVI for claudication, of whom 32.6% (n = 11 790) received an infrapopliteal PVI. Of these, 61.4% (n = 7 245) received a concomitant femoropopliteal PVI and 38.6% (n = 4 545) received an isolated infrapopliteal PVI. The median follow up time was 3.5 years (interquartile range 2.7, 4.3). Patients receiving infrapopliteal PVI had a higher three year cumulative incidence of conversion to CLTI (26.0%; 95% confidence interval [CI] 24.9 - 27.2% vs. 19.9%; 95% CI 19.1 - 20.7%), repeat PVI (56.0%; 95% CI 54.8 - 57.3% vs. 45.7%; 95% CI 44.9 - 46.6%), and major amputation (2.2%; 95% CI 1.8 - 2.6% vs. 1.3%; 95% CI 1.1 - 1.5%) compared with patients receiving isolated femoropopliteal PVI. After adjusting for patient and physician level characteristics, the risk of conversion to CLTI (adjusted hazard ratio [aHR] 1.31, 95% CI 1.23 - 1.39), repeat PVI (aHR 1.12, 95% CI 1.05 - 1.20), and major amputation (aHR 1.72, 95% CI 1.42 - 2.07) remained significantly higher for patients receiving infrapopliteal PVI. An increasing number of infrapopliteal vessels treated during the index intervention was associated with increasingly poor outcomes (p < .001 for trend). CONCLUSION: Infrapopliteal PVI for claudication is associated with worse long term outcomes relative to isolated femoropopliteal PVI.

T2-weighted spoiled gradient echo MRI for forensic age estimation: a study on knee growth plates.

The timing of growth plate fusion is a key indicator for age estimation and is primarily used in forensic investigations. On the other hand, non-ionizing techniques such as MRI are being developed to provide safer and more ethical evaluations in forensic casework. This study aims to evaluate the closure process of growth plates in the distal femoral and proximal tibial epiphyses using Multiple Echo Recombined Gradient Echo (MERGE) MRI sequences and provide age estimation data based on staging methods for forensic purposes. We retrospectively analyzed 559 patients (294 males, 265 females, aged 8-25 years) diagnosed with trauma and knee pain at Tepecik Training and Research Hospital from 2016 to 2019. MRI scans were performed using a 1.5-T system with MERGE sequences and evaluated by two observers using a new staging system. Observer agreement was assessed using Cohen's κ test, yielding high agreement values (κ > 0.8). Positive correlations were found between age and ossification stages (p < 0.001). Minimum age thresholds for stages 5a and 5b of the distal femoral epiphysis were 16 and 18 years for females and 17 and 19 years for males, respectively. For the proximal tibial epiphysis, the minimum ages for stages 5a and 5b were 15 years for females and 17 years for males. The MERGE sequence provides a viable method for assessing skeletal maturity in living individuals with significant ethical advantages due to non-ionizing radiation. This study supports the potential application of the MERGE sequence in forensic age estimation, demonstrating high observer agreement and consistency. Future research should focus on comparing different sequences and populations to enhance the methodology's applicability.

Effects of posterior tibial nerve stimulation (PTNS) on lower urinary tract dysfunction: An umbrella review.

BACKGROUND: Lower urinary tract dysfunction (LUTD) is a common, troublesome condition that often negatively affects patients' quality of life. Current literature has long been interested in how posterior tibial nerve stimulation (PTNS) can affect this condition. AIM: To extensively and systematically explore how PTNS affects LUTD based on the most recent systematic reviews. METHODS: A systematic search was conducted in PubMed, Scopus, Web of Science, and Embase according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All the systematic reviews, with or without meta-analysis that assessed the effects of PTNS on LUTD were retrieved. The quality of the included studies was assessed using the Joanna Briggs Institute tool, and analysis was conducted using the Comprehensive Meta-Analysis version 3 tool. RESULTS: From a total of 3077 citations, 20 systematic reviews entered this study, and 13 of them included meta-analysis. The population of studies varied vastly, for instance, some studies included only children or women while other focused on a specific pathology like multiple sclerosis-induced neurogenic LUTD. The majority of included studies reported an overall improvement in LUTD following percutaneous PTNS, although admitting that these results were derived from moderate to low-quality evidence. CONCLUSION: The findings of this thorough umbrella review showed that the positive benefits of PTNS in treating LUTD are currently supported by low-quality evidence, and it is crucial to interpret them with great care.

Identification of brain functional connectivity during acute transcutaneous tibial nerve stimulation: A 3T fMRI study.

OBJECTIVES: A feasibility proof-of-concept study was conducted to assess the effects of acute tibial nerve stimulation (TNS) on the central nervous system in healthy volunteers using functional magnetic resonance imaging (fMRI). MATERIALS AND METHODS: Fourteen healthy volunteers were included in a prospective, single-site study conducted on a clinical 3T MRI scanner. Four scans of functional MRI, each lasting 6 min, were acquired: two resting-state fMRI scans (prior and following the TNS intervention) and in-between two fMRI scans, both consisting of alternating rest periods and noninvasive acute transcutaneous TNS (TTNS). Whole brain seed-based functional connectivity (FC) correlation analysis was performed comparing TTNS stimulation with rest periods. Cluster-level familywise error (FWE) corrected p and a minimal cluster size of 200 voxels were used to explore FC patterns. RESULTS: Increased FC is reported between inferior frontal gyrus, posterior cingulate gyrus, and middle temporal gyrus with the precuneus as central receiving node. In addition, decreased FC in the cerebellum, hippocampus, and parahippocampal areas was observed. CONCLUSIONS: Altered FC is reported in areas which have been described to be also involved in lower urinary tract control. Although conducted with healthy controls, the assumption that the underlying therapeutic effect of TNS involves the central nervous system is supported and has to be further examined in patients with incomplete spinal cord injury.

Shifts in patient preference of third-line overactive bladder therapy after introduction of the implantable tibial nerve stimulator.

INTRODUCTION: Third-line therapies for overactive bladder (OAB) that are currently recommended include intravesical Onabotulinumtoxin-A injections (BTX-A), percutaneous tibial nerve stimulation (PTNS), and sacral neuromodulation (SNM). The implantable tibial nerve stimulator (ITNS) is a novel therapy that is now available to patients with OAB. OBJECTIVE: The objective of this study was to analyze shifts in patient preference of third-line therapies for OAB after introducing ITNS as an option among the previously established therapies for non-neurogenic OAB. METHODS: A survey was designed and distributed via SurveyMonkey to the platform's audience of U.S. adults of age 18 and older. Screening questions were asked to include only subjects who reported symptoms of OAB. Descriptions of current AUA/SUFU guideline-approved third-line therapies (BTX-A, PTNS, and SNM) were provided, and participants were asked to rank these therapies in order of preference (stage A). Subsequently, ITNS was introduced with a description, and participants were then asked to rank their preferences amongst current guideline-approved therapies and ITNS (stage B). Absolute and relative changes in therapy preferences between stage A and stage B were calculated. Associations between ultimate therapy choice in stage B and participant characteristics were analyzed. RESULTS: A total of 485 participants completed the survey (62.5% female). The mean age was 49.1 ± 36.5 years (SD). The most common OAB symptoms reported were urgency urinary incontinence (UUI) (73.0%) and urinary urgency (68.0%). 29.2% of patients had tried medication for OAB in the past, and 8.0%-10.3% of patients were previously treated with a third-line therapy for OAB. In stage A, participants ranked their first choice of third-line therapy as follows: 28% BTX-A, 27% PTNS, and 13.8% SNM. 26.6% of participants chose no therapy, and 4.5% chose all three equally. In stage B, participants ranked their first choice as follows: 27.6% BTX-A, 19.2% PTNS, 7.8% SNM, and 19.2% ITNS. 21.9% of participants chose no therapy and 4.3% chose all four equally as their first choice. There were both absolute and relative declines in proportions of patients interested in BTX-A, SNM, and PTNS as their first choice of third-line therapy with the introduction of ITNS. Patients originally interested in PTNS in stage A had the greatest absolute change after the introduction of ITNS with 7.8% of participants opting for ITNS in stage B. Those interested in SNM in stage A had the largest relative change in interest, with 43.5% of those originally interested in SNM opting for ITNS in stage B. Finally, with the introduction of ITNS, the number of participants initially not interested in any third-line therapy declined by an absolute change of 4.7% and relative change of 17.6%. Participants experiencing concurrent stress urinary incontinence (SUI) symptoms were more likely to choose a current guideline-approved third-line therapy than ITNS or no therapy at all (p = 0.047). Those who had prior experience with third-line therapies were more likely to choose a third-line therapy other than ITNS as their ultimate choice of therapy in stage B. Of those who had chosen a guideline-approved third-line therapy in stage B (not ITNS), 13.6% had prior experience with BTX-A, 14.7% with PTNS, and 32 (11.2%) with SNM (p < 0.001, p < 0.001, p = 0.009, respectively). CONCLUSION: From our study, it appears that ITNS may attract a subset of patients who would not have otherwise pursued current guideline-approved third-line therapies for OAB. When patients are provided with descriptions of third-line OAB therapies including ITNS as an option, ITNS appears to compete with SNM and PTNS. It is possible that ITNS will provide patients with a different phenotype of neuromodulation therapy that can appeal to a niche OAB population. Given that ITNS devices have been introduced relatively recently to the market, their application will largely depend on cost and payer coverage, provider bias, and patient comorbidities. Further study is needed to understand how these factors interact with and influence patient preference of advanced OAB therapy to understand which patients will most benefit from this treatment modality.

Response to tibial and sacral nerve modulation in overactive bladder: Is there any correlation?

OBJECTIVES: To assess the correlation between the response to transcutaneous tibial nerve stimulation (TTNS) and subsequent response to sacral nerve modulation (SNM) to treat overactive bladder (OAB). MATERIALS AND METHODS: All patients who consecutively received TTNS followed by a two-stage SNM between January 2016 and June 2022 to treat OAB in two university hospital centers were included. The response to each therapy was evaluated with success defined by a 50% or greater improvement in one or more bothersome urinary symptoms from baseline. The primary endpoint was the statistical relationship between the response to TTNS and the response to SNM, assessed by logistic regression. Secondary endpoints were the statistical relationship between the response to TTNS and the response to SNM when controlling for gender, age (<57 years vs. >57 years), presence of an underlying neurological disease, and presence of DO, adding the factor and interaction to the previous regression model. RESULTS: Among the 92 patients enrolled in the study, 68 of them were women (73.9%), and the median age was 57.0 [41.0-69.0] years. The success was reported in 22 patients (23.9%) under TTNS and 66 patients (71.7%) during the SNM test phase. There was no statistical correlation between response to TTNS and response to SNM in the overall population (confidence interval: 95% [0.48-4.47], p = 0.51). Similarly, there was no statistical correlation when controlling for age <57 years or ≥57 years, with p = 1.0 and p = 0.69, respectively. No statistical study could be conducted for the other subpopulations due to small sample sizes. CONCLUSION: The response to TTNS does not predict the response to SNM in the treatment of OAB. TTNS and SNM should be considered as separate therapies, and the decision-making process for OAB treatment should take this into account.

Percutaneous tibial neuromodulation initial therapy compliance and subsequent third-line treatment patterns.

PURPOSE: Percutaneous Tibial Neuromodulation (PTNM) is used to treat Overactive Bladder (OAB). This analysis summarizes patient adherence to PTNM treatment and examines trends of other third-line therapy use during and after PTNM. METHODS: Optum's deidentified Clinformatics® Data Mart Database (CDM) and CMS Research Identifiable Files were queried for adults with OAB symptoms and who underwent PTNM treatment (2019-2020). We evaluated the proportion of patients who completed 12 visits within 1 year, and defined patients as treatment compliant if 12 PTNM visits were completed within 12 weeks. We then identified the proportion of patients who used other third-line therapies after PTNM and stratified these patients based on their PTNM therapy compliance status. RESULTS: 2302 patients met selection criteria from CDM and 16,473 patients from CMS. The proportion of patients completing a full PTNM treatment course increased over time; from 16% at week 12% to 42% by week 52 (CDM) and 24% to 38% (CMS). Other third-line therapy use increased over time and was higher for PTNM noncompliant versus compliant patients at 52 weeks: onabotulinumtoxinA was 6.5% versus 5.7% for noncompliant versus compliant (CMS, p = 0.0661) and 6.4% versus 4.9% (CDM, p = 0.035), SNM trial procedure was 6.5% versus 2.5% (CDM, p = 0.002) and 4.2% versus 2.0% (CMS, p = 0.010). CONCLUSIONS: Most patients are noncompliant with recommended PTNM treatment regimen. Albeit low, third-line therapy was pursued more frequently by noncompliant patients. Given low compliance, the effectiveness of PTNM may be compromised. Alternative implantable technologies may be needed to assure effectiveness of neuromodulation.