Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss.

The existing suite of therapies for bone diseases largely act to prevent further bone loss but fail to stimulate healthy bone formation and repair. We describe an endogenous osteopeptide (PEPITEM) with anabolic osteogenic activity, regulating bone remodeling in health and disease. PEPITEM acts directly on osteoblasts through NCAM-1 signaling to promote their maturation and formation of new bone, leading to enhanced trabecular bone growth and strength. Simultaneously, PEPITEM stimulates an inhibitory paracrine loop: promoting osteoblast release of the decoy receptor osteoprotegerin, which sequesters RANKL, thereby limiting osteoclast activity and bone resorption. In disease models, PEPITEM therapy halts osteoporosis-induced bone loss and arthritis-induced bone damage in mice and stimulates new bone formation in osteoblasts derived from patient samples. Thus, PEPITEM offers an alternative therapeutic option in the management of diseases with excessive bone loss, promoting an endogenous anabolic pathway to induce bone remodeling and redress the imbalance in bone turnover.

The role of orthobiologics in chronic wound healing.

Chronic wounds, characterized by prolonged healing processes, pose a significant medical challenge with multifaceted aetiologies, including local and systemic factors. Here, it explores the complex pathogenesis of chronic wounds, emphasizing the disruption in the normal phases of wound healing, particularly the inflammatory phase, leading to an imbalance in extracellular matrix (ECM) dynamics and persistent inflammation. Senescent cell populations further contribute to impaired wound healing in chronic lesions. Traditional medical management focuses on addressing underlying causes, but many chronic wounds resist to conventional treatments, necessitating innovative approaches. Recent attention has turned to autologous orthobiologics, such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF) and mesenchymal stem cells (MSCs), as potential regenerative interventions. These biologically derived materials, including bone marrow aspirate/concentrate (BMA/BMAC) and adipose tissue-derived stem cells (ADSCs), exhibit promising cytokine content and regenerative potential. MSCs, in particular, have emerged as key players in wound healing, influencing inflammation and promoting tissue regeneration. This paper reviews relevant scientific literature regarding basic science and brings real-world evidence regarding the use of orthobiologics in the treatment of chronic wounds, irrespective of aetiology. The discussion highlights the regenerative properties of PRP, PRF, BMA, BMAC and SVF, showcasing their potential to enhance wound healing. Despite advancements, further research is essential to elucidate the specific roles of each orthobiologic and determine optimal applications for different wound types. The conclusion underscores the evolving landscape in chronic wound management, with a call for more comprehensive studies to refine treatment strategies and maximize the benefits of regenerative medicine.

The characteristics and predictors of mortality in periprosthetic fractures around the knee.

Aims: Periprosthetic fractures (PPFs) around the knee are challenging injuries. This study aims to describe the characteristics of knee PPFs and the impact of patient demographics, fracture types, and management modalities on in-hospital mortality. Methods: Using a multicentre study design, independent of registry data, we included adult patients sustaining a PPF around a knee arthroplasty between 1 January 2010 and 31 December 2019. Univariate, then multivariable, logistic regression analyses were performed to study the impact of patient, fracture, and treatment on mortality. Results: Out of a total of 1,667 patients in the PPF study database, 420 patients were included. The in-hospital mortality rate was 6.4%. Multivariable analyses suggested that American Society of Anesthesiologists (ASA) grade, history of peripheral vascular disease (PVD), history of rheumatic disease, fracture around a loose implant, and cerebrovascular accident (CVA) during hospital stay were each independently associated with mortality. Each point increase in ASA grade independently correlated with a four-fold greater mortality risk (odds ratio (OR) 4.1 (95% confidence interval (CI) 1.19 to 14.06); p = 0.026). Patients with PVD have a nine-fold increase in mortality risk (OR 9.1 (95% CI 1.25 to 66.47); p = 0.030) and patients with rheumatic disease have a 6.8-fold increase in mortality risk (OR 6.8 (95% CI 1.32 to 34.68); p = 0.022). Patients with a fracture around a loose implant (Unified Classification System (UCS) B2) have a 20-fold increase in mortality, compared to UCS A1 (OR 20.9 (95% CI 1.61 to 271.38); p = 0.020). Mode of management was not a significant predictor of mortality. Patients managed with revision arthroplasty had a significantly longer length of stay (median 16 days; p = 0.029) and higher rates of return to theatre, compared to patients treated nonoperatively or with fixation. Conclusion: The mortality rate in PPFs around the knee is similar to that for native distal femur and neck of femur fragility fractures. Patients with certain modifiable risk factors should be optimized. A national PPF database and standardized management guidelines are currently required to understand these complex injuries and to improve patient outcomes.

Predictors of mortality in periprosthetic fractures of the hip: Results from the national PPF study.

INTRODUCTION: Periprosthetic fractures (PPFs) around the hip joint are increasing in prevalence. In this collaborative study, we aimed to investigate the impact of patient demographics, fracture characteristics, and modes of management on in-hospital mortality of PPFs involving the hip. METHODS: Using a multi-centre cohort study design, we retrospectively identified adults presenting with a PPF around the hip over a 10-year period. Univariate and multivariable logistic regression analyses were performed to study the independent correlation between patient, fracture, and treatment factors on mortality. RESULTS: A total of 1,109 patients were included. The in-hospital mortality rate was 5.3%. Multivariable analyses suggested that age, male sex, abbreviated mental test score (AMTS), pneumonia, renal failure, history of peripheral vascular disease (PVD) and deep surgical site infection were each independently associated with mortality. Each yearly increase in age independently correlates with a 7% increase in mortality (OR 1.07, p=0.019). The odds of mortality was 2.99 times higher for patients diagnosed with pneumonia during their hospital stay [OR 2.99 (95% CI 1.07-8.37) p=0.037], and 7.25 times higher for patients that developed renal failure during their stay [OR 7.25 (95% CI 1.85-28.47) p=0.005]. Patients with history of PVD have a six-fold greater mortality risk (OR 6.06, p=0.003). Mode of treatment was not a significant predictor of mortality. CONCLUSION: The in-hospital mortality rate of PPFs around the hip exceeds 5%. The fracture subtype and mode of management are not independent predictors of mortality, while patient factors such as age, AMTS, history of PVD, pneumonia, and renal failure can independently predict mortality. Peri-operative optimisation of modifiable risk factors such as lung and kidney function in patients with PPFs around the hip during their hospital stay is of utmost importance.

Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta in Trauma Patients With Exsanguinating Hemorrhage: The UK-REBOA Randomized Clinical Trial.

Importance: Bleeding is the most common cause of preventable death after trauma. Objective: To determine the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) when used in the emergency department along with standard care vs standard care alone on mortality in trauma patients with exsanguinating hemorrhage. Design, Setting, and Participants: Pragmatic, bayesian, randomized clinical trial conducted at 16 major trauma centers in the UK. Patients aged 16 years or older with exsanguinating hemorrhage were enrolled between October 2017 and March 2022 and followed up for 90 days. Intervention: Patients were randomly assigned (1:1 allocation) to a strategy that included REBOA and standard care (n = 46) or standard care alone (n = 44). Main Outcomes and Measures: The primary outcome was all-cause mortality at 90 days. Ten secondary outcomes included mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours; the need for definitive hemorrhage control procedures; time to commencement of definitive hemorrhage control procedures; complications; length of stay; blood product use; and cause of death. Results: Of the 90 patients (median age, 41 years [IQR, 31-59 years]; 62 [69%] were male; and the median Injury Severity Score was 41 [IQR, 29-50]) randomized, 89 were included in the primary outcome analysis because 1 patient in the standard care alone group declined to provide consent for continued participation and data collection 4 days after enrollment. At 90 days, 25 of 46 patients (54%) had experienced all-cause mortality in the REBOA and standard care group vs 18 of 43 patients (42%) in the standard care alone group (odds ratio [OR], 1.58 [95% credible interval, 0.72-3.52]; posterior probability of an OR >1 [indicating increased odds of death with REBOA], 86.9%). Among the 10 secondary outcomes, the ORs for mortality and the posterior probabilities of an OR greater than 1 for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality were all increased in the REBOA and standard care group, and the ORs were increased with earlier mortality end points. There were more deaths due to bleeding in the REBOA and standard care group (8 of 25 patients [32%]) than in standard care alone group (3 of 18 patients [17%]), and most occurred within 24 hours. Conclusions and Relevance: In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone. Trial Registration: isrctn.org Identifier: ISRCTN16184981.

Characteristics and risk factors of UCS fracture subtypes in periprosthetic fractures around the hip.

Aims: Periprosthetic fractures (PPFs) following hip arthroplasty are complex injuries. This study evaluates patient demographic characteristics, management, outcomes, and risk factors associated with PPF subtypes over a decade. Methods: Using a multicentre collaborative study design, independent of registry data, we identified adults from 29 centres with PPFs around the hip between January 2010 and December 2019. Radiographs were assessed for the Unified Classification System (UCS) grade. Patient and injury characteristics, management, and outcomes were compared between UCS grades. A multinomial logistic regression was performed to estimate relative risk ratios (RRR) of variables on UCS grade. Results: A total of 1,104 patients were included. The majority were female (57.9%; n = 639), ethnically white (88.5%; n = 977), used mobility aids (67%; n = 743), and had a median age of 82 years (interquartile range (IQR) 74 to 87). A total of 77 (7%) had pain prior to the PPF. The most common UCS grade was B2 (33%; n = 368). UCS type D fractures had the longest length of stay (median 19 days (IQR 11 to 26)), highest readmission to hospital (21%; n = 9), and highest rate of discharge to step-down care (52%; n = 23). Multinomial regression suggests that uncemented femoral stems are associated with a reduced risk of UCS C (RRR 0.36 (95% confidence interval (CI) 0.2 to 0.7); p = 0.002) and increased risk of UCS A (RRR 3.3 (95% CI 1.9 to 5.7); p < 0.001), compared to UCS B fracture. Conclusion: The most common PPF type in elderly frail patients is UCS B2. Uncemented stems have a lower risk of UCS C fractures compared to cemented stems. A national PPF database is needed to further identify correlation between implants and fracture subtypes.

Angiogenesis and Tissue Repair Depend on Platelet Dosing and Bioformulation Strategies Following Orthobiological Platelet-Rich Plasma Procedures: A Narrative Review.

Angiogenesis is the formation of new blood vessel from existing vessels and is a critical first step in tissue repair following chronic disturbances in healing and degenerative tissues. Chronic pathoanatomic tissues are characterized by a high number of inflammatory cells; an overexpression of inflammatory mediators; such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1); the presence of mast cells, T cells, reactive oxygen species, and matrix metalloproteinases; and a decreased angiogenic capacity. Multiple studies have demonstrated that autologous orthobiological cellular preparations (e.g., platelet-rich plasma (PRP)) improve tissue repair and regenerate tissues. There are many PRP devices on the market. Unfortunately, they differ greatly in platelet numbers, cellular composition, and bioformulation. PRP is a platelet concentrate consisting of a high concentration of platelets, with or without certain leukocytes, platelet-derived growth factors (PGFs), cytokines, molecules, and signaling cells. Several PRP products have immunomodulatory capacities that can influence resident cells in a diseased microenvironment, inducing tissue repair or regeneration. Generally, PRP is a blood-derived product, regardless of its platelet number and bioformulation, and the literature indicates both positive and negative patient treatment outcomes. Strangely, the literature does not designate specific PRP preparation qualifications that can potentially contribute to tissue repair. Moreover, the literature scarcely addresses the impact of platelets and leukocytes in PRP on (neo)angiogenesis, other than a general one-size-fits-all statement that "PRP has angiogenic capabilities". Here, we review the cellular composition of all PRP constituents, including leukocytes, and describe the importance of platelet dosing and bioformulation strategies in orthobiological applications to initiate angiogenic pathways that re-establish microvasculature networks, facilitating the supply of oxygen and nutrients to impaired tissues.

Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma.

T cells demonstrate impaired function in multiple myeloma (MM) but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8+ T-cell function is decreased in MM compared with controls, and is also consistently lower within bone marrow samples than in matched peripheral blood samples. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modeling confirmed that uptake of bone marrow lipids suppresses CD8+ T function, which is impaired in autologous bone marrow plasma but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8+ T cells in MM, and FATP1 blockade also rescued CD8+ T-cell function, thereby identifying this as a novel target to augment T-cell activity in MM. Finally, analysis of samples from cohorts of patients who had received treatment identified that CD8+ T-cell metabolic dysfunction resolves in patients with MM who are responsive to treatment but not in patients with relapsed MM, and is associated with substantial T-cell functional restoration.

Cannabidiol for musculoskeletal regenerative medicine.

Chronic musculoskeletal (MSK) pain is one of the most prevalent causes, which lead patients to a physician's office. The most common disorders affecting MSK structures are osteoarthritis, rheumatoid arthritis, back pain, and myofascial pain syndrome, which are all responsible for major pain and physical disability. Although there are many known management strategies currently in practice, phytotherapeutic compounds have recently begun to rise in the medical community, especially cannabidiol (CBD). This natural, non-intoxicating molecule derived from the cannabis plant has shown interesting results in many preclinical studies and some clinical settings. CBD plays vital roles in human health that go well beyond the classic immunomodulatory, anti-inflammatory, and antinociceptive properties. Recent studies demonstrated that CBD also improves cell proliferation and migration, especially in mesenchymal stem cells (MSCs). The foremost objective of this review article is to discuss the therapeutic potential of CBD in the context of MSK regenerative medicine. Numerous studies listed in the literature indicate that CBD possesses a significant capacity to modulate mammalian tissue to attenuate and reverse the notorious hallmarks of chronic musculoskeletal disorders (MSDs). The most of the research included in this review report common findings like immunomodulation and stimulation of cell activity associated with tissue regeneration, especially in human MSCs. CBD is considered safe and well tolerated as no serious adverse effects were reported. CBD promotes many positive effects which can manage detrimental alterations brought on by chronic MSDs. Since the application of CBD for MSK health is still undergoing expansion, additional randomized clinical trials are warranted to further clarify its efficacy and to understand its cellular mechanisms.

Instructional review of key factors to achieve successful outcomes when using low-intensity pulsed ultrasound in fracture repair.

Low-intensity pulsed ultrasound (LIPUS) treatment of fractures has been available to the orthopaedic community for nearly three decades; however, it is still considered an experimental treatment by some clinicians, even though there is a wealth of clinical data. Based on the evaluation of clinical trial data, we have established key criteria which can lead to LIPUS success and avoid failure. These are fracture gap size and stability, accurate transducer placement and minimum treatment number. However, from a clinician's view, the correct attitude to treatment must be observed, and this has also been discussed. It is hoped, armed with this new evaluation of the clinical data, that clinicians can treat patients with LIPUS more effectively, resulting in fewer failures of treatment.

The perceptions of clinicians using low-intensity pulsed ultrasound (LIPUS) for orthopaedic pathology: A national qualitative study.

INTRODUCTION: Low-intensity pulsed ultrasound (LIPUS) is a non-invasive treatment modality for delayed union or non-union of acute fractures. We aimed to assess the current use of LIPUS at a national level in the United Kingdom, why and how clinicians use it, what treatment protocols are followed, and what the current perceptions are on this technology. METHODOLOGY: Using a detailed online survey compromised of 20 questions delivered to known LIPUS users, we were able to collect qualitative data on indication of use, type of machine used, personal views on the technology, frequency of usage, and treatment protocols. Each question was peer-reviewed to exclude bias. RESULTS: A total of 70 respondents completed the survey. LIPUS was used by most clinicians for cases of non-union (N = 55, 78.5%) and delayed union (N = 51, 72.8%). The majority of respondents personally used a LIPUS device between 1 and 5 times in 12 months (N = 38, 54.3%). Most considered LIPUS a failure after three to six months of treatment without clinical improvement (N = 39, 55.7%). A total of 32 respondents (45.7%) mentioned the need for funding approval before accessing LIPUS technology. Poor revision surgery candidates (N = 48, 68.6%) and atrophic non-union (N = 46, 65.7%) were the most frequently cited reasons for using LIPUS technology as treatment. Most participants (N = 48, 68.6%) considered LIPUS to be cost-effective. Despite most clinicians being comfortable with the use of LIPUS, some respondents did not understand the basic science underpinning the technology nor could explain the need for LIPUS to patients comfortably. CONCLUSION: LIPUS technology may have a significant role to play in the treatment of orthopaedic fracture related pathology. Regular users perceived the technology to be cost-effective and efficacious. Further research should standardize treatment protocols and aim to establish a national LIPUS registry.

Ethnomedicinal appraisal of plants used for the treatment of gastrointestinal complaints by tribal communities living in Diamir district, Western Himalayas, Pakistan.

Majority of the mountain dwelling communities living in the Himalayas rely on traditional herbal medicines for primary healthcare needs. Present study was conducted in fairy meadows and allied valleys in District Diamir, Gilgit Baltistan autonomous territory in northern Pakistan. Documentation of traditional medicinal knowledge (TMK) of local communities for the treatment of gastrointestinal disorders was carried out as a component of a wider medico-botanical expedition conducted in the entire base camp of the great Nanga Parbat peak during 2016-19. Various ethnobotanical parameters i.e. use value (UV), informant consensus factor (ICF), Fidelity level (FL), direct matrix ranking test (DMRT) and preference ranking (PR) were applied to evaluate the data collected during field surveys. The plants were also subjected to a comparative review for novelty assessment. A total of 61 medicinal plant species belonging to 55 genera and 35 families are reported here for the treatment of GIDs. Compositae was the leading family with 8 (13%) species. Fourteen gastrointestinal disorders were cured with 32% taxon were reported for stomachic followed by diarrhea (15%) and constipation (14%). Highest use reports (5) and use citations (207) were reported for Mentha longifolia L. while highest UV (1.79) was obtained for Artemisia maritima L. Hylotelephium telephioides (Ledeb.), A. maritima, M. longifolia, M. piperita L., Allium cepa L., and A. annua L. exhibited 100% FL. Highest ICF was calculated against dysentery and flatulence. DMRT ranked Prunus persica L. first for its multipurpose uses. Taking constipation as a reference gastrointestinal disease, PR for ten plant species was calculated where H. telephioides was ranked first followed by A. maritima. Present study concluded that 19 out of 61 plant species were documented for the first time with novel medicinal uses to cure GIDs. These plant species could act as potential reservoirs of novel lead compounds for the treatments of gastrointestinal disorders.

Mortality risk of surgically managing orthopaedic trauma during the COVID-19 pandemic.

AIMS: It is imperative to understand the risks of operating on urgent cases during the COVID-19 (SARS-Cov-2 virus) pandemic for clinical decision-making and medical resource planning. The primary aim was to determine the mortality risk and associated variables when operating on urgent cases during the COVID-19 pandemic. The secondary objective was to assess differences in the outcome of patients treated between sites treating COVID-19 and a separate surgical site. METHODS: The primary outcome measure was 30-day mortality. Secondary measures included complications of surgery, COVID-19 infection, and length of stay. Multiple variables were assessed for their contribution to the 30-day mortality. In total, 433 patients were included with a mean age of 65 years; 45% were male, and 90% were Caucasian. RESULTS: Overall mortality was 7.6% for all patients and 15.9% for femoral neck fractures. The mortality rate increased from 7.5% to 44.2% in patients with fracture neck of femur and a COVID-19 infection. The COVID-19 rate in the 30-day postoperative period was 11%. COVID-19 infection, age, and Charlson Comorbidity Index were independent risk factor for mortality. CONCLUSION: There was a significant risk of contracting COVID-19 due to being admitted to hospital. Using a site which was not treating COVID-19 respiratory patients for surgery did not identify a difference with respect to mortality, nosocomial COVID-19 infection, or length of stay. The COVID-19 pandemic significantly increases perioperative mortality risk in patients with fractured neck of femora but patients with other injuries were not at increased risk. Cite this article: Bone Jt Open 2021;2(5):330-336.

A Comparison of Improvised and Commercially Available Point-of-Wounding Tourniquets in Simulated Traumatic Amputation with Catastrophic Hemorrhage.

INTRODUCTION: Catastrophic hemorrhage is the leading cause of preventable trauma deaths in the military and civilian populations. The use of tourniquets by first responders (medical and nonmedically trained) is supported and has the potential to save lives if applied correctly. AIMS: We sought to examine the use of 5 tourniquets: 1 improvised and 4 commercially available tourniquets to investigate the time taken to stop simulated bleeding and to secure the device; evidence of rebleeding when the "blood pressure" was restored and to gain qualitative feedback on their application. MATERIALS AND METHODS: Four commercially available tourniquets (Combat Application Tourniquet [C-A-T], Special Operations Forces Tactical Tourniquet - Wide (SOFTT-W), stretch, wrap, and tuck tourniquet [SWAT-T], and the Tourni-key) and an improvised tourniquet (tie & wooden spoon) were tested on a complex silicone simulation model used to replicate catastrophic hemorrhage from a blast injury with above traumatic knee amputation (SAM 4.1 Trauma Simulation Ltd, UK). To limit the user variability, the same investigator applied each tourniquet and each was tested 3 times. No ethical approval was required to conduct this study. RESULTS: None of the devices took longer than 1 minute to secure. The C-A-T and SOFTT-W were quickest to occlude and secure. Although the Tourni-key took longer statistically, this was unlikely to be a clinically important difference. Compared to the others, the SOFTT-W rebled on 2 out of 3 applications. The improvised tourniquet had an obvious ligature effect because of its narrowness, followed by the Tourni-key. This effect was least evident with the SWAT-T; however, particular care was needed to ensure it was safely secured as it was slippery when wet. CONCLUSIONS: All tourniquets tested were effective and swift to apply. The Tourni-key's antipinch card seems helpful in reducing local pain under the windlass. Reinspection for rebleeding is important and should be routinely performed irrespective of the device. The width of the SWAT-T may be beneficial, thereby, reducing the risk of crush injury.

Basic science and clinical aspects of achilles tendinopathy.

Achilles tendinopathy is one of the common disorders seen in athletes. It is a degenerative rather than an inflammatory, condition. There is a lifetime risk of 52% in former elite male distance runners. This condition is difficult to manage and up to 29% of Achilles tendinopathy patients may require surgery. It often results in chronic pain and discomfort along with failure to regain full function. It can be complicated by partial tears or complete rupture causing long-term burden on healthcare system and making treatment quite difficult.

Minimally invasive hip arthroplasty: a quantitative review of the literature.

PURPOSE: To perform a comprehensive quantitative review of the published literature and to assess the methodology of studies comparing the surgical outcomes in minimally invasive hip arthroplasty (MIHA). METHODS: We conducted a comprehensive literature search using Medline, Embase, Cochrane, CINAHL and Google Scholar. The bibliographies of papers were also examined. All relevant articles in peer-reviewed journals were retrieved except those not mentioning outcomes, case reports, review of literature and letters to editors. Two authors independently scored the quality of the studies using a modified Coleman Methodology Score with 10 criteria which allow critical analysis of the design and implementation of a particular study. The results are recorded as a final score between 0 and 100. We collected data for year of publication, type of study, patient numbers, surgical method, follow-up, complications and patient satisfaction. RESULTS: Thirty-six studies met our inclusion criteria giving details of 6434 HAs, 78.5% (4031) of which were implanted using MIHA techniques. The only statistically significant outcome was a reduction in length of hospital stay (P = 0.02). With no significant difference noted between the two groups with respect to operating time, blood loss, dislocation and revision rates, neurological injury and incidence of peri-operative fracture, patient selection and surgeons' experience may have had a significant effect on outcome. For instance, studies reporting outcomes on an average patient age of 48 years had significantly different results to one reporting on patients with a mean age of over 70 years. Scores were predominantly low for quality of the studies, with patient number, follow-up time and validated outcome measures being the weakest areas. CONCLUSION: At present, there is still a lack of quality evidence to advocate the expansion of MIHA. The better designed studies suggest that it should even be limited further to recognized expert centres. The complication rates and learning curve may be altered by changes in training and adapting surgical techniques. We emphasize the need for meticulous design in future studies comparing the outcomes of these two procedures.