David J. Deehan

Universal heteroplasmy of human mitochondrial DNA

Mammalian cells contain thousands of copies of mitochondrial DNA (mtDNA). At birth, these are thought to be identical in most humans. Here, we use long read length ultra-deep resequencing-by-synthesis to interrogate regions of the mtDNA genome from related and unrelated individuals at unprecedented resolution. We show that very low-level heteroplasmic variance is present in all tested healthy individuals, and is likely to be due to both inherited and somatic single base substitutions. Using this approach, we demonstrate an increase in mtDNA mutations in the skeletal muscle of patients with a proofreading-deficient mtDNA polymerase γ due to POLG mutations. In contrast, we show that OPA1 mutations, which indirectly affect mtDNA maintenance, do not increase point mutation load. The demonstration of universal mtDNA heteroplasmy has fundamental implications for our understanding of mtDNA inheritance and evolution. Ostensibly de novo somatic mtDNA mutations, seen in mtDNA maintenance disorders and neurodegenerative disease and aging, will partly be due to the clonal expansion of low-level inherited variants.

The Medial Patellofemoral Ligament Location of Femoral Attachment and Length Change Patterns Resulting From Anatomic and Nonanatomic Attachments

Background: Incompetence of the medial patellofemoral ligament (MPFL) is an integral factor in patellofemoral instability. Reconstruction of this structure is gaining increasing popularity. However, the natural behavior of the ligament is still not fully understood, and crucially, the correct landmark for femoral attachment of the MPFL at surgery is poorly defined. Purpose: To determine the length change pattern of the native MPFL, investigate the effect of nonanatomic femoral and differing patellar attachment sites on length changes, and recommend a reproducible femoral attachment site for undertaking anatomic MPFL reconstruction. Study Design: Descriptive laboratory study. Methods: Eight cadaveric knees were dissected of skin and subcutaneous fat and mounted in a kinematics rig with the quadriceps tensioned. The MPFL length change patterns were measured for combinations of patellar and femoral attachments using a suture and displacement transducer. Three attachments were along the superomedial border of the patella, and 5 femoral attachments were at the MPFL center and 5 mm proximal, distal, anterior, and posterior to this point. Reproducibility of attachment sites was validated radiographically. Results: The femoral attachment point, taking the anterior-posterior medial femoral condyle diameter to be 100%, was identified 40% from the posterior, 50% from the distal, and 60% from the anterior border of the medial femoral condyle. This point was most isometric, with a mean maximal length change to the central patellar attachment of 2.1 mm from 0° to 110° of knee flexion. The proximal femoral attachment resulted in up to 6.4 mm mean lengthening and the distal attachment up to 9.1 mm mean shortening through 0° to 110° of knee flexion, resulting in a significantly nonisometric graft (P < .05). Conclusion: We report the anatomic femoral and patellar MPFL graft attachments, with confirmation of the reproducibility of their location and resulting kinematic behavior. Nonanatomic attachments caused significant loss of isometry. Clinical Relevance: The importance of an anatomically positioned MPFL reconstruction is highlighted, and an identifiable radiographic point for femoral tunnel position is suggested for use intraoperatively.

The Association Between Body Mass Index and the Outcomes of Total Knee Arthroplasty

BACKGROUND In the United Kingdom, organizations involved in health-care commissioning have recently introduced legislation limiting access to total knee arthroplasty through the introduction of arbitrary thresholds unsupported by the literature and based on body mass index. This study aimed to establish the relationship between body mass index and patient-reported specific and general outcomes on total knee arthroplasty. METHODS Using national patient-reported outcome measures (PROMs) linked to the National Joint Registry, we identified 13,673 primary total knee arthroplasties performed for the treatment of osteoarthritis. The PROMs project involves the collection of condition-specific and general health outcomes before and at six months following total knee arthroplasty. The relationships between body mass index and the Oxford Knee Score, EuroQol 5D index, and EuroQol 5D Visual Analogue Scale were assessed with use of scatterplots and linear regression. The improvement in these measures was compared for three distinct groups based on body mass index (Group I [15 to 24.9 kg/m(2)], Group II [25 to 39.9 kg/m(2)], and Group III [40 to 60 kg/m(2)]) with use of multiple regression analysis to adjust for differences in age, sex, American Society of Anesthesiologists grade, general health rating, and number of comorbidities. RESULTS The preoperative and postoperative patient-reported outcome measures declined to a similar extent with increasing body mass index. The gradient of the linear regression equation relating to the change in scores was positive in all cases, indicating that there was a tendency for scores to improve to a greater extent as body mass index increased. After adjustment, the changes in patient-reported outcome measures in Group I and Group III were equivalent for the Oxford Knee Score (mean difference, 0.5 point [95% confidence interval, -0.5 to 1.5 points]; p = 0.78), the EuroQol 5D index (mean difference, 0.014 point [95% confidence interval, -0.021 to 0.048 point]; p = 1.00), and the EuroQol 5D Visual Analogue Scale (mean difference, 1.9 points [95% confidence interval, -0.4 to 4.1 points]; p = 0.13). Wound complications were significantly higher (p < 0.001) at a rate of 17% (168 of 1018 patients) in Group III compared with 9% (121 of 1292 patients) in Group I. CONCLUSIONS The improvements in patient-reported outcome measures experienced by patients were similar, irrespective of body mass index. Health policy should be based on the overall improvements in function and general health gained through surgery. Obese patients should not be excluded from the benefit of total knee arthroplasty, given that their overall improvements were equivalent to those of patients with a lower body mass index.

Endoscopic reconstruction of the anterior cruciate ligament with an ipsilateral patellar tendon autograft

A total of 90 patients with an isolated rupture of the anterior cruciate ligament (ACL) had a reconstruction using the ipsilateral patellar tendon secured with round-headed cannulated interference screws. Annual review for five years showed three failures of the graft (two traumatic and one atraumatic); none occurred after two years. Ten patients sustained a rupture of the contralateral ACL. At five years, 69% of those with surviving grafts continued to participate in moderate to strenuous activity. Using the International Knee Documentation Committee assessment, 90% reported their knee as being normal or nearly normal and had a median Lysholm knee score of 96 (64 to 100). Most patients (98%) had a pivot shift of grade 0 with the remaining 2% being grade 1; 90% of the group had a Lachman test of grade 0. The incidence of subsequent meniscectomy was similar in the reconstructed joint to that in the contralateral knee. Radiological examination was normal in 63 of 65 patients. Our study supports the view that reconstruction of the ACL is a reliable technique allowing full rehabilitation of the previously injured knee. In the presence of normal menisci there is a low incidence of osteoarthritic change despite continued participation in sporting activity.

The Effect of Femoral Tunnel Position and Graft Tension on Patellar Contact Mechanics and Kinematics After Medial Patellofemoral Ligament Reconstruction

Background: An incorrect femoral tunnel position or inappropriate graft tensioning during medial patellofemoral ligament (MPFL) reconstruction may cause altered patellofemoral joint kinematics and contact mechanics, potentially resulting in pain and joint degeneration. Hypothesis: Nonanatomic positioning of the tunnel or graft overtensioning during MPFL reconstruction will have an adverse effect on patellar tracking and patellofemoral joint contact mechanics. Study Design: Controlled laboratory study. Methods: Eight fresh-frozen cadaveric knees were placed on a customized testing rig, with the femur fixed and the tibia mobile through 90° of flexion. Individual heads of the quadriceps muscle and the iliotibial band were separated and loaded with 205 N in anatomic directions using a system of cables and weights. Patellofemoral contact pressures and patellar tracking were measured through the flexion range at 10° intervals using Tekscan pressure-sensitive film inserted between the patella and trochlea and an optical tracking system. The MPFL was transected and then reconstructed using a double-strand gracilis tendon graft. Pressures and kinematics were recorded for reconstructions with the graft positioned in anatomic, proximal, and distal tunnel positions. Measurements were then repeated with an anatomic tunnel and graft tension of 2 N, 10 N, and 30 N, fixed at 3 different flexion angles of 0°, 30°, and 60°. Statistical analysis was undertaken using repeated-measures analysis of variance, Bonferroni post hoc analysis, and paired t tests. Results: For a graft tensioned to 2 N, anatomically positioned MPFL reconstruction restored intact medial and lateral joint contact pressures and patellar tracking (P > .05), but femoral tunnels positioned proximal or distal to the anatomic origin resulted in significant increases in peak and mean medial pressures and medial patellar tilt during knee flexion or extension, respectively (P < .05). Grafts tensioned with 10 N or 30 N also caused significant increases in medial pressure and tilt. Graft fixation at 30° or 60° restored all measures to intact values (P > .05), but fixation at 0° caused significant increases (P < .05) in medial joint contact pressures compared with intact knees. Conclusion: Anatomically positioned reconstruction with 2-N tension fixed at 30° or 60° of knee flexion restored joint contact pressures and tracking. However, graft overtensioning or femoral tunnels positioned too proximal or distal caused significantly elevated medial joint contact pressures and increased medial patellar tilting. The importance of a correct femoral tunnel position and graft tensioning in restoring normal patellofemoral joint kinematics and articular cartilage contact stresses is therefore evident. Clinical Relevance: A malpositioned femoral tunnel or overtensioned graft during MPFL reconstruction resulted in increased medial contact pressures and patellar tilting. This may lead to adverse outcomes such as early degenerative joint changes or pain if occurring in a clinical population.

The biology of integration of the anterior cruciate ligament

The anterior cruciate ligament (ACL) is a short, stout, intra-articular, extrasynovial structure which acts to control rotational movements and anterior translation of the femur upon the fixed tibia.[1][1] Rupture is a traumatic event, often as a consequence of twisting upon the weight-bearing limb

Complications following anterior cruciate ligament reconstruction in the English NHS

Unlike the English National Joint Registry (NJR) for arthroplasty, no surgeon driven national database currently exists for ligament surgery in England. Therefore information on outcome and adverse events following anterior cruciate ligament (ACL) surgery is limited to case series. This restricts the ability to make formal recommendations upon surgical care. Prospectively collected data, which is routinely collected on every NHS patient admitted to hospital in England, was analysed to determine national rates of 90-day symptomatic deep venous thrombosis (DVT), pulmonary thromboembolism (PTE) rate, 30-day wound infection and readmission rates following primary ACL reconstruction between March 2008 and February 2010 (13,941 operations, annual incidence 13.5 per 100,000 English population). 90-day DVT and PTE rates were 0.30% (42) and 0.18% (25) respectively. There were no in-hospital deaths. 0.75% (104) of the consecutive patient cohort had a wound complication recorded. 0.25% (35) underwent a further procedure to wash out the infected knee joint and 1.36% (190) were readmitted to an orthopaedic ward within 30days. This is the first national comprehensive study of the incidence of significant complications following ACL surgery in England. This should allow meaningful interpretation of future baseline data supporting the development of a national ligament registry.

Randomised, prospective study comparing cemented and cementless total knee replacement - Results of press-fit condylar total knee replacement at five years

Early implants for total knee replacement were fixed to bone with cement. No firm scientific reason has been given for the introduction of cementless knee replacement and the long-term survivorship of such implants has not shown any advantage over cemented forms. In a randomised, prospective study we have compared cemented and uncemented total knee replacement and report the results of 139 prostheses at five years. Outcome was assessed both clinically by independent examination using the Nottingham knee score and radiologically using the Knee Society scoring system. Independent statistical analysis of the data showed no significant difference between cemented and cementless fixation for pain, mobility or movement. There was no difference in the radiological alignment at five years, but there was a notable disparity in the radiolucent line score. With cemented fixation there was a significantly greater number of radiolucent lines on anteroposterior radiographs of the tibia and lateral radiographs of the femur. At five years, our clinical results would not support the use of the more expensive cementless fixation whereas the radiological results are of unknown significance. Longer follow-up will determine any changes in the results and conclusions.

Center and surgeon volume influence the revision rate following unicondylar knee replacement: an analysis of 23,400 medial cemented unicondylar knee replacements.

BACKGROUND Revision rates following unicondylar knee replacement vary among reporting institutions. Revision rates from institutions involved in the design of these implants and independent single-center series are comparable with those following total knee replacement, suggesting that higher operative volumes and surgical enthusiasm improve revision outcomes. METHODS This registry-based cohort study involved the analysis of 23,400 medial cemented Oxford unicondylar knee replacements for the treatment of osteoarthritis. Total center and surgeon operative volumes were calculated over an eight-year time span since the inception of the registry (April 2003 to December 2010). The revision rate was calculated according to center volume and surgeon volume, each of which was grouped into five categories. The groups were compared with use of life tables, Kaplan-Meier plots, and Cox regression models that adjusted for variations in age, sex, and American Society of Anesthesiologists (ASA) grade among the groups. RESULTS A total of 919 surgeons and a total of 366 centers performed at least one replacement, with the majority performing a small number of procedures. The revision rate for the centers with the lowest volume (fifty or fewer procedures over the eight-year study period) was 1.62 (95% confidence interval [CI], 1.42 to 1.82) revisions per 100 component years; this was significantly higher than the rate for the centers with the highest volume (more than 400 procedures), which was 1.16 (95% CI, 0.97 to 1.36) revisions per 100 component years. The five-year implant survival rate of 92.3% (95% CI, 91.2% to 93.3%) for the lowest-volume centers was significantly lower than the rate of 94.1% (95% CI, 93.0% to 95.2%) for the highest-volume centers. Similarly, the revision rate for the surgeons with the lowest volume (twenty-five or fewer procedures), 2.16 (95% CI, 1.91 to 2.41) revisions per 100 component years, was significantly higher than that for the surgeons with the highest volume (more than 200 procedures), 0.80 (95% CI, 0.62 to 0.98) revisions per 100 component years. The five-year survival rate of 90.1% (95% CI, 88.8% to 91.3%) for the lowest-volume surgeons was also significantly lower than the rate of 96.0% (95% CI, 95.0% to 97.0%) for the highest-volume surgeons. When center and surgeon volume were considered simultaneously, the hazard of revision was greater for lower-volume surgeons at lower-volume centers compared with higher-volume surgeons at higher-volume centers (hazard ratio = 1.87 [95% CI, 1.58 to 2.22], p < 0.001). CONCLUSIONS High-volume centers and surgeons specializing in such procedures had superior results following unicondylar knee replacement compared with their low-volume counterparts. These results suggest that centers and surgeons should undertake a minimum of thirteen such procedures per year to achieve results comparable with the high-volume operators.

The effect of surgical factors on early patient-reported outcome measures (PROMS) following total knee replacement

Patient-reported outcome measures (PROMs) are increasingly being used to assess functional outcome and patient satisfaction. They provide a framework for comparisons between surgical units, and individual surgeons for benchmarking and financial remuneration. Better performance may bring the reward of more customers as patients and commissioners seek out high performers for their elective procedures. Using National Joint Registry (NJR) data linked to PROMs we identified 22,691 primary total knee replacements (TKRs) undertaken for osteoarthritis in England and Wales between August 2008 and February 2011, and identified the surgical factors that influenced the improvements in the Oxford knee score (OKS) and EuroQol-5D (EQ-5D) assessment using multiple regression analysis. After correction for patient factors the only surgical factors that influenced PROMs were implant brand and hospital type (both p < 0.001). However, the effects of surgical factors upon the PROMs were modest compared with patient factors. For both the OKS and the EQ-5D the most important factors influencing the improvement in PROMs were the corresponding pre-operative score and the patients general health status. Despite having only a small effect on PROMs, this study has shown that both implant brand and hospital type do influence reported subjective functional scores following TKR. In the current climate of financial austerity, proposed performance-based remuneration and wider patient choice, it would seem unwise to ignore these effects and the influence of a range of additional patient factors.