Over the past two decades, increased research has highlighted the connection between endosomal trafficking defects and neurodegeneration. The endo-lysosomal network is an important, complex cellular ...system specialized in the transport of proteins, lipids, and other metabolites, essential for cell homeostasis. Disruption of this pathway is linked to a wide range of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and frontotemporal dementia. Furthermore, there is strong evidence that defects in this pathway create opportunities for diagnostic and therapeutic intervention. In this
piece, we concisely address the role of endo-lysosomal dysfunction in five neurodegenerative diseases and discuss how future research can investigate this intracellular pathway, including extracellular vesicles with a specific focus on exosomes for the identification of novel disease biomarkers. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.
Polatuzumab vedotin, marketed under the trade name POLIVY
, is a CD79b-targeted antibody-drug conjugate that preferentially delivers a potent anti-mitotic agent (monomethyl auristatin E) to B cells, ...resulting in anti-cancer activity against B-cell malignancies. In 2019, polatuzumab vedotin in combination with rituximab and bendamustine was approved by the United States Food and Drug Administration for the treatment of adult patients with diffuse large B-cell lymphoma who have received at least two prior therapies. Recent Health Authority guidance recommendations for submitting an Integrated Summary of Immunogenicity were followed including a comprehensive immunogenicity risk assessment, bioanalytical strategy, and immunogenicity data to support the registration of polatuzumab vedotin. Key components of the polatuzumab vedotin Integrated Summary of Immunogenicity and data are presented. Validated semi-homogeneous bridging enzyme-linked immunosorbent assays were used to detect anti-drug antibodies (ADA) to polatuzumab vedotin and characterize the immune response in patients with non-Hodgkin's lymphoma. The overall incidence of ADA observed for polatuzumab vedotin was low across seven clinical trials. The low incidence of ADA is likely due to the mechanism of action of polatuzumab vedotin that involves targeting and killing of B cells, thereby limiting the development to plasma cells and ADA secretion. Furthermore, patients are co-medicated with rituximab, which also targets B cells and results in B-cell depletion. Therefore, the immunogenicity risk is considered low and not expected to impact the polatuzumab vedotin benefit/risk profile.
Purpose
To systematically review and evaluate the current meta-analyses for the treatment of acute Achilles tendon rupture (AATR). This study can provide clinicians with a clear overview of the ...current literature to aid clinical decision-making and the optimal formulation of treatment plans for AATR.
Methods
Two independent reviewers searched PubMed and Embase on June 2, 2022 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Assessment of evidence was twofold: level of evidence (LoE) and quality of evidence (QoE). LoE was evaluated using published criteria by
The Journal of Bone and Joint Surgery
and the QoE by the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) scale. Pooled complication rates were highlighted for significance in favour of one treatment arm or no significance.
Results
There were 34 meta-analyses that met the eligibility criteria, with 28 studies of LoE 1, and the mean QoE was 9.8 ± 1.2. Significantly lower re-rupture rates were reported with surgical (2.3–5%) versus conservative treatment (3.9–13%), but conservative treatment was favoured in terms of lower complication rates. The re-rupture rates were not significantly different between percutaneous repair or minimally invasive surgery (MIS) compared to open repair, but MIS was favoured in terms of lower complication rates (7.5–10.4%). When comparing rehabilitation protocols following open repair (four studies), conservative treatment (nine studies), or combined (three studies), there was no significant difference in terms of re-rupture or obvious advantage in terms of lower complication rates between early versus later rehabilitation.
Conclusion
This systematic review found that surgical treatment was significantly favoured over conservative treatment for re-rupture, but conservative treatment had lower complication rates other than re-rupture, notably for infections and sural nerve injury. Open repair had similar re-rupture rates to MIS, but lower complication rates; however, the rate of sural nerve injuries was lower in open repair. When comparing earlier versus later rehabilitation, there was no difference in re-rupture rates or obvious advantage in complications between open repair, conservative treatment, or when combined. The findings of this study will allow clinicians to effectively counsel their patients on the postoperative outcomes and complications associated with different treatment approaches for AATR.
Level of evidence
IV.
Category:
Ankle; Sports
Introduction/Purpose:
Chronic ankle instability occurs in 15-20% of patients with ankle sprains who do not recover following conservative management and typically requires ...surgical intervention. There is recent interest in Anterior Talofibular Ligament (ATFL) Repair techniques that may improve outcomes and expedite recovery. Evidence for the use of suture-tape as an internal in ATFL Repair is limited in the literature. The purpose of this study was to retrospectively assess outcomes and return to sport following ATFL Repair with and without suture-tape (ST) augmentation at greater than 1-year follow-up.
Methods:
Chart review was conducted to identify patients who underwent Anterior Talofibular Ligament (ATFL) Repair with a minimum of 1-year follow-up. Data collected and assessed included: patient demographics, pathological characteristics, treatment characteristics, Foot and Ankle Outcome Score (FAOS), visual analog scale (VAS) scores, return to sport (RTS), complications, and failures. Linear regression was performed to identify potential predictors of outcomes.
Results:
Eighteen cases of ATFL repair augmented with suture-tape (ST) and 20 cases of ATFL repair alone were included. The mean follow-up in the ST cohort was 20.8 ± 7.9 months and the mean follow-up time in the ATFL repair alone cohort was 25.3 ± 13.2 months. Improvements in FAOS and VAS scores were observed in both cohorts at final follow-up (p < 0.01). No statistically significant difference in FAOS and VAS scores at final follow up was found between the 2 cohorts. The mean time to RTS was 8.6 ± 3.3 weeks in the ST cohort and 13.3 ± 2.7 weeks in the ATFL repair alone cohort (p < 0.01). No statistically significant difference in complication rates nor failure rates was observed between the 2 cohorts.
Conclusion:
This retrospective study found that ATFL Repair with and without suture-tape augmentation produced comparable subjective clinical outcomes, complication rates and failure rates at short-term follow-up. A superior mean time to RTS was found in the ST cohort. The early results of this surgical technique are promising, but further studies with larger patient cohorts and longer follow-up times are needed to determine the optimal role of suture-tape augmentation of ATFL repair.
Category:
Midfoot/Forefoot; Other
Introduction/Purpose:
The purpose of this systematic review was to evaluate outcomes following intra-articular 1st MTPJ hyaluronic acid injection for the management ...of hallux rigidus.
Methods:
During January 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies evaluating outcomes in patients who underwent intra-articular 1st MTPJ hyaluronic acid injection for the management of hallux rigidus. Data regarding injection characteristics, subjective clinical outcomes, failure rates and complications were extracted and analysed.
Results:
In total, 5 studies were included in this review. In total, 209 patients underwent intra-articular 1st MTPJ hyaluronic acid injection for the management of hallux rigidus at a weighted mean follow-up of 4.4 ± 1.4 months. The weighted mean VAS improved from a pre-injection score of 6.4 ± 0.3 to a post-injection score of 2.8 ± 0.4. A 10.1% complication rate was noted, the most common of which was transient 1st MTPJ swelling. One infection (0.5%) was reported. A symptomatic recurrence rate of 18.6% was observed at a weighted mean time of 7.3 ± 4.2 months
Conclusion:
This systematic review demonstrated that intra-articular 1st MTPJ hyaluronic acid injection for the management of hallux rigidus led to a reduction in pain and a moderate complication rate at short-term follow-up. In addition, intra-articular 1st MTPJ hyaluronic acid injection for the management of hallux rigidus produced a symptomatic recurrence rate of 18.6% at approximately 7.3 months, suggesting that HA provides short-term relief. The lack of quality comparative studies limits the generation of robust conclusions, reinforcing the need for further research to identify the optimal role of HA in the management of hallux rigidus.
Category:
Midfoot/Forefoot; Other
Introduction/Purpose:
The purpose of this systematic review was to evaluate outcomes following polyvinyl alcohol hydrogel implant for the management of hallux ...rigidus.
Methods:
During January 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies evaluating outcomes in patients who underwent polyvinyl alcohol hydrogel implant for the management of hallux rigidus. Data regarding surgical characteristics, subjective clinical outcomes, radiographic outcomes, failure rates and complications were extracted and analysed. In total, 15 studies were included in this review.
Results:
In total, 1536 patients (1578 feet) underwent polyvinyl alcohol hydrogel implant for the management of hallux rigidus at a weighted mean follow-up of 39.4 ± 17.3 months. The weighted mean VAS score improved from a pre-operative score of 6.2 ± 1.3 to a post-operative score of 3.0 ± 1.6. There was limited data regarding improvements in range of motion. The complication rate was 15.7% and the failure rate was 9%.
Conclusion:
This systematic review demonstrated improvement in subjective clinical outcomes following PVA hydrogel implant for the management of hallux rigidus. A moderate complication rate and failure rate was noted at short term follow-up. Further studies with longer follow-up periods are warranted to elucidate the precise outcomes following PVA hydrogel implant for the management of hallux rigidus.
Category:
Midfoot/Forefoot; Other
Introduction/Purpose:
The purpose of this systematic review was to examine the clinical and radiological outcomes of various surgical treatments for symptomatic ...accessory naviculars.
Methods:
During February 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies examining outcomes following surgical treatment for symptomatic accessory navicular. Data regarding surgical characteristics, subjective clinical outcomes, radiological outcomes, complications and failure rates were extracted and analyzed. 26 studies were included for review.
Results:
In total, 520 patients (614 feet) underwent surgical treatment for the management of symptomatic accessory navicular. The weighted mean age was 28.18 ± 8.18 and the weighted mean follow-up time was 46.23 ± 34.76 months. The mean AOFAS score was 49.9 ± 7.39 preoperatively and 88.9 ± 5.61 postoperatively. The mean complication rate at final follow-up was 9.02% and the failure rate was 4.23%, with only 2.7% of patient ultimately requiring a further procedure. We also compared outcomes in patient who underwent a Kidner or Modified Kidner procedure (n=245) with those treated with a different surgical technique such as fusion or simple excision (n=275). There was no significant difference in outcome scores, complication rates, failure rates, or secondary surgical procedure rates between these cohorts.
Conclusion:
This systematic review demonstrated improvement in clinical outcomes following surgical treatment for symptomatic accessory naviculars. The markedly low complication and failure rates further indicate that surgical intervention is beneficial in the management of symptomatic accessory naviculars. Kidner and Modified Kidner procedures resulted in equivocally good outcomes compared with other surgical approaches such as fusion and simple excision. However, the marked heterogeneity between the included studies and few high level comparative studies limits the generation of any robust conclusions for optimal surgical technique. Further research is warranted to determine whether the Kidner procedure confers any particular advantages over other approaches.
Category:
Midfoot/Forefoot; Other
Introduction/Purpose:
The purpose of this systematic review and meta-analysis is to compare outcomes between patients who underwent open chevron osteotomy (OCO) and ...minimally invasive Chevron osteotomy (MICA) for the management of hallux valgus deformity.
Methods:
During January 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies comparing outcomes between patients who underwent open chevron osteotomy (OCO) and minimally invasive Chevron osteotomy (MICO) for the management of hallux valgus deformity. Data regarding surgical characteristics, subjective clinical outcomes, radiographic outcomes, failure rates and complications were extracted and analysed. In total, 6 comparative studies were included in this review.
Results:
In total, 183 patients (208 feet) underwent OCO and 209 patients (244 feet) MICA for the management of hallux valgus deformity. Meta-analysis demonstrated no difference in post-operative MOFXQ scores (SMD: 0.0849, -0.2584, 0.4282, p = 0.6277), hallux valgus angle (SMD: -0.1245, -0.4204, 0.1715, p = 0.4099), intermetatarsal angle (SMD:-0.2565, -0.5539, 0.0408, p = 0.909) and failures (RR: 1.0765, 0.0993, 11.6760, p = 0.9278) between the OCO cohort and the MICO cohort. There was a lower complication rate in the OCO cohort compared to the MICO cohort (RR: 0.2614, 0.1453, 0.4704, p < 0.0001).
Conclusion:
This systematic review found comparable improvements in subjective clinical outcomes, functional outcomes and radiographic outcomes following both OCO and MICO at short-term follow-up. However, a lower RR with respect to complications was found in the OCO cohort compared to the MICO cohort. Despite the significant heterogeneity across the included studies, the similar outcomes between the 2 cohorts reinforces that further research is warranted to determine the optimal role of OCO and MICO in the management of hallux valgus deformity.
Category:
Ankle Arthritis
Introduction/Purpose:
End-stage ankle osteoarthritis is a debilitating pathology and is most commonly preceded by trauma. Surgical intervention via ankle arthrodesis or ...ankle arthroplasty is the mainstay management option. Heterotopic ossification (HO) is a common finding following joint arthroplasty. However, no consensus regarding the impact of heterotopic ossification on clinical outcomes following total ankle arthroplasty has been reached to date. The purpose of this systematic review and meta- analysis was to evaluate the prevalence and clinical outcomes of heterotopic ossification following total ankle arthroplasty.
Methods:
During January 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies reporting heterotopic ossification following TAA. Data regarding surgical characteristics, subjective clinical outcomes, radiographic outcomes, failure rates and complications were extracted and analysed.
Results:
Twenty-seven studies with 2639 patients (2695 ankles) at a weighed mean follow-up time of 52.8 ± 26.9 months were included. The pooled prevalence rate was 45% (0.25; 0.66). The implant with the highest rate of HO was the INBONE I (100%) and BOX (100%) implants. The most common modified Brooker staging was grade 1 (120 patients, 33.9%). Random effects models of standardized mean differences found no difference in AOFAS, VAS and ROM between patients with HO and patients without HO. Random effects models of correlation coefficients found no correlation between AOFAS, VAS and ROM and the presence of HO. The surgical intervention rate for symptomatic HO was 10.5%.
Conclusion:
This systematic review and meta-analysis found that HO is a common finding following TAA that is not associated with inferior clinical outcomes. Surgical intervention was required only for moderate-severe, symptomatic HO following TAA. This study is limited by the significant heterogeneity and low level and quality of evidence of the included studies. Further higher quality studies are warranted to determine the precise prevalence and impact of HO on outcomes following TAA.
Category:
Ankle Arthritis; Other
Introduction/Purpose:
End stage ankle osteoarthritis is a significantly debilitating pathology that is most commonly preceded by trauma. The emergence of 3rd and 4th ...generation total ankle arthroplasty (TAA) implant designs have led to more favorable outcomes compared to its predecessors. TAA implants can be broadly divided into fixed bearing and mobile bearing implant designs, however, no consensus has been reached regarding the optimal TAA implant design for the management of end stage ankle arthritis. The purpose of this systematic review and meta-analysis was to compare outcomes between patients who received fixed bearing TAA implants and mobile bearing TAA implants.
Methods:
During January 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies comparing outcomes between patients who underwent fixed bearing TAA implant and patients who underwent mobile bearing TAA implant for the management of end stage ankle arthritis. Data regarding surgical characteristics, subjective clinical outcomes, radiographic outcomes, failure rates and complications were extracted and analysed.
Results:
Overall, 13 studies were included in this review. In total, 2793 patients underwent mobile bearing TAA implant and 2241 patients underwent fixed bearing TAA implant for the management of end stage ankle arthritis. No difference existed between the 2 cohorts with regards to post-operative subjective clinical outcome scores nor radiological outcomes. The mobile bearing TAA implant cohort was associated with higher complications (RR = 1.4710; 1.0375-2.0857; p = 0.0373) and failures (RR = 1.3916; 1.2038 - 1.6086; p = 0.0032) compared to the fixed bearing TAA implant cohort.
Conclusion:
This systematic review and meta-analysis found no difference in subjective clinical outcomes and radiological outcomes between patients who underwent mobile bearing TAA implant and fixed bearing TAA implant for the management of ankle arthritis. Interestingly, the mobile bearing TAA implant cohort was associated with higher complications and failures compared to the fixed bearing TAA implant cohort. Due to the marked under-reporting of data and significant heterogeneity between the included studies, further high quality research is warranted to determine the optimal TAA implant type for the management of end stage ankle arthritis.
