Ligament augmentation and reconstruction system (LARS) synthetic grafts are safe and effective for medial collateral ligament and posterolateral corner reconstructions in elite athletes.

PURPOSE: This study documents the efficacy and safety of using a Ligament Augmentation and Reconstruction System (LARS) ligament graft to augment extra-articular knee ligament reconstructions in elite athletes by reporting return-to-play (RTP) rates and levels, career longevity and complications. METHODS: A consecutive series of all extra-articular knee ligament reconstructions augmented by LARS ligaments in elite athletes undertaken by three specialist sports knee surgeons between 2013 and 2020 were reviewed. Seventy-six elite athletes, aged over 16 years old, and more than 2 years postsurgery were included. RTP was defined as competing at professional level or national/international level in amateur sport. RESULTS: There were 64 medial collateral ligament (MCL) and 12 posterolateral corner (PLC) reconstructions. Fifty-two (68.4%) underwent concomitant autograft cruciate ligament(s) reconstruction. The mean age was 25.1 years (SD ± 4.5). Most were football (35, 46.1%) or rugby players (35, 46.1%). Sixty-seven athletes (88.2%) RTP with 65 (97.0%) of these playing at the same or higher Tegner level. Fifty-six (83.6%) of the athletes that RTP were still playing at 2 years postsurgery. Twenty (57.1%) of those who had RTP and were more than 5 years postsurgery were still playing at 5 years. Six (7.9%) players required further surgery relating to the LARS/metalwork. One case had soft tissue inflammation adjacent to the proximal end of the synthetic graft, but it is unknown if this was mechanical irritation or a biological reaction. One MCL reruptured 4 years after RTP. CONCLUSION: Utilising LARS to augment extra-articular knee ligament reconstructions allows 88.2% of athletes with a variety of knee ligament injuries to return to elite sport. The low morbidity rates coupled with 57% of athletes still playing 5 years postsurgery demonstrates that the LARS is safe and effective in these cases. Although there are reports of LARS ligaments being used in MCL and PLC reconstructions, there is very little evidence investigating if they are safe and effective. This study demonstrates that LARS synthetic grafts can be safely used for MCL and PLC reconstructions in elite athletes and they permit a high RTP with a low risk of complications. LEVEL OF EVIDENCE: Level IV.

Research priorities of members of the British Association for Surgery of the Knee.

Aims: This study aims to identify the top unanswered research priorities in the field of knee surgery using consensus-based methodology. Methods: Initial research questions were generated using an online survey sent to all 680 members of the British Association for Surgery of the Knee (BASK). Duplicates were removed and a longlist was generated from this scoping exercise by a panel of 13 experts from across the UK who provided oversight of the process. A modified Delphi process was used to refine the questions and determine a final list. To rank the final list of questions, each question was scored between one (low importance) and ten (high importance) in order to produce the final list. Results: This consensus exercise took place between December 2020 and April 2022. A total of 286 clinicians from the BASK membership provided input for the initial scoping exercise, which generated a list of 105 distinct research questions. Following review and prioritization, a longlist of 51 questions was sent out for two rounds of the Delphi process. A total of 42 clinicians responded to the first round and 24 responded to the second round. A final list of 24 research questions was then ranked by 36 clinicians. The topics included arthroplasty, infection, meniscus, osteotomy, patellofemoral, cartilage, and ligament pathologies. The management of early osteoarthritis was the highest-ranking question. Conclusion: A Delphi exercise involving the BASK membership has identified the future research priorities in knee surgery. This list of questions will allow clinicians, researchers, and funders to collaborate in order to deliver high-quality research in knee surgery and further advance the care provided to patients with knee pathology.

A Comparative Biomechanical Study of Alternative Medial Collateral Ligament Reconstruction Techniques.

BACKGROUND: There is little evidence of the biomechanical performance of medial collateral ligament (MCL) reconstructions for restoring stability to the MCL-deficient knee regarding valgus, external rotation (ER), and anteromedial rotatory instability (AMRI). HYPOTHESIS: A short isometric reconstruction will better restore stability than a longer superficial MCL (sMCL) reconstruction, and an additional deep MCL (dMCL) graft will better control ER and AMRI than single-strand reconstructions. STUDY DESIGN: Controlled laboratory study. METHODS: Nine cadaveric human knees were tested in a kinematics rig that allowed tibial loading while the knee was flexed-extended 0° to 100°. Optical markers were placed on the femur and tibia and displacements were measured using a stereo camera system. The knee was tested intact, and then after MCL (sMCL + dMCL) transection, and loaded in anterior tibial translation (ATT), ER, varus-valgus, and combined ATT + ER (AMRI loading). Five different isometric MCL reconstructions were tested: isolated long sMCL, a short construct, each with and without dMCL addition, and isolated dMCL reconstruction, using an 8 mm-wide synthetic graft. RESULTS: MCL deficiency caused an increase in ER of 4° at 0° of flexion (P = .271) up to 14° at 100° of flexion (P = .002), and valgus laxity increased by 5° to 8° between 0° and 100° of flexion (P < .024 at 0°-90°). ATT did not increase significantly in isolated MCL deficiency (P > .999). All 5 reconstructions restored native stability across the arc of flexion apart from the isolated long sMCL, which demonstrated residual ER instability (P≤ .047 vs other reconstructions). CONCLUSION: All tested techniques apart from the isolated long sMCL graft are satisfactory in the context of restoring the valgus, ER, and AMRI stability to the MCL-deficient knee in a cadaveric model. CLINICAL RELEVANCE: Contemporary MCL reconstruction techniques fail to control ER and therefore AMRI as they use a long sMCL graft and do not address the dMCL. This study compares 5 MCL reconstruction techniques. Both long and short isometric constructs other than the long sMCL achieved native stability in valgus and ER/AMRI. Double-strand reconstructions (sMCL + dMCL) tended to provide more stability. This study shows which reconstructions demonstrate the best biomechanical performance, informs surgical reconstruction techniques for AMRI, and questions the efficacy of current popular techniques.

Effectiveness of clinical decision support in controlling inappropriate red blood cell and platelet transfusions, speciality specific responses and behavioural change.

BACKGROUND: Electronic clinical decision support (CDS) within Electronic Health Records has been used to improve patient safety, including reducing unnecessary blood product transfusions. We assessed the effectiveness of CDS in controlling inappropriate red blood cell (RBC) and platelet transfusion in a large acute hospital and how speciality specific behaviours changed in response. METHODS: We used segmented linear regression of interrupted time series models to analyse the instantaneous and long term effect of introducing blood product electronic warnings to prescribers. We studied the impact on transfusions for patients in critical care (CC), haematology/oncology (HO) and elsewhere. RESULTS: In non-CC or HO, there was significant and sustained decrease in the numbers of RBC transfusions after introduction of alerts. In CC the alerts reduced transfusions but this was not sustained, and in HO there was no impact on RBC transfusion. For platelet transfusions outside of CC and HO, the introduction of alerts stopped a rising trend of administration of platelets above recommended targets. In CC, alerts reduced platelet transfusions, but in HO alerts had little impact on clinician prescribing. CONCLUSION: The findings suggest that CDS can result in immediate change in user behaviour which is more obvious outside specialist settings of CC and HO. It is important that this is then sustained. In CC and HO, blood transfusion practices differ. CDS thus needs to take specific circumstances into account. In this case there are acceptable reasons to transfuse outside of these crude targets and CDS should take these into account.

Rates and Levels of Elite Sport Participation at 5 Years After Revision ACL Reconstruction.

BACKGROUND: There is a paucity of data regarding return to play (RTP), level of competition, and longevity of play after revision of anterior cruciate ligament (ACL) reconstruction (ACLR) in elite athletes. PURPOSE: To report RTP rates and competition levels in elite athletes at the point of RTP, as well as at 2 and 5 years after revision ACLR, and the effect of meniscal and chondral pathology at revision surgery on these outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A retrospective review of a consecutive series of all revision ACLRs undertaken by the senior author between 2009 and 2019, with a minimum 2-year follow-up, was carried out. Outcome measures were RTP rates and competition level. RESULTS: A total of 49 knees in 48 elite athletes met the inclusion criteria. After revision ACLR, 43 (87.8%) elite athletes achieved RTP, of whom 75.5% were at the same level. At 2 years after surgery, 39 (79.6%) were still playing, 25 (51%) at the same level; at 5 years after surgery, 20 (44.4%) were still playing, 9 (20%) at the same level. Elite athletes with <50% thickness or no articular cartilage lesions were more likely to RTP (94.6% vs 66.7%; P = .026), as well as return to the same competition level (83.8% vs 50%; P = .047), compared with those with ≥50% thickness chondral lesions. Those without medial meniscal pathology were more likely to RTP at the same level after revision surgery (94.4% vs 64.5%; P = .036). The median time elite athletes continued to play after revision ACLR was 73 months (95% CI, 43.4-102.6); 23 months at the same level (95% CI, 13.6-32.4). The probability of still playing at 5 years after surgery was 55.9%, with a 22.5% chance of maintaining preinjury competition level. CONCLUSION: In elite athletes, RTP rates and competition level decreased over time after revision ACLR. The presence of >50% thickness chondral pathology was associated with lower RTP rates and competition level at RTP time, while medial meniscal pathology was associated with lower competition level at RTP.

Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial.

INTRODUCTION: We report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC. METHODS: Chemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS). RESULTS: The intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49-0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64-1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71-1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively. CONCLUSIONS: IMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified.

Elite and Professional sports facial injuries management - a consensus report.

Whilst there have been great improvements in the management of elite and professional athletes with the formalisation of the clinical specialty of Sports and Exercise medicine, the management of facial injuries has perhaps lagged in this group. Professional athletic careers can be put in jeopardy due to unnecessarily long absences from training and competition after facial injuries. Professional and elite sports athletes can benefit from different approaches to the management of their facial injuries to reduce time away from competing but maximise their safety. On 6th December 2018, a consensus meeting of interested clinicians involved in the management of facial injuries of elite and professional athletes was held at the Royal Society of Medicine, London, UK to provide a contemporary review of the approaches to conservative, operative and recovery management of facial injuries. National experts with specialist experience of facial injuries presentation and athlete needs from a range of elite and professional sports led the day's programme and the discussions so that guidelines could be formulated. These are presented in this review paper.

Length-change patterns of the medial collateral ligament and posterior oblique ligament in relation to their function and surgery.

PURPOSE: To define the length-change patterns of the superficial medial collateral ligament (sMCL), deep MCL (dMCL), and posterior oblique ligament (POL) across knee flexion and with applied anterior and rotational loads, and to relate these findings to their functions in knee stability and to surgical repair or reconstruction. METHODS: Ten cadaveric knees were mounted in a kinematics rig with loaded quadriceps, ITB, and hamstrings. Length changes of the anterior and posterior fibres of the sMCL, dMCL, and POL were recorded from 0° to 100° flexion by use of a linear displacement transducer and normalised to lengths at 0° flexion. Measurements were repeated with no external load, 90 N anterior draw force, and 5 Nm internal and 5 Nm external rotation torque applied. RESULTS: The anterior sMCL lengthened with flexion (p < 0.01) and further lengthened by external rotation (p < 0.001). The posterior sMCL slackened with flexion (p < 0.001), but was lengthened by internal rotation (p < 0.05). External rotation lengthened the anterior dMCL fibres by 10% throughout flexion (p < 0.001). sMCL release allowed the dMCL to become taut with valgus rotation (p < 0.001). The anterior and posterior POL fibres slackened with flexion (p < 0.001), but were elongated by internal rotation (p < 0.001). CONCLUSION: The structures of the medial ligament complex react differently to knee flexion and applied loads. Structures attaching posterior to the medial epicondyle are taut in extension, whereas the anterior sMCL, attaching anterior to the epicondyle, is tensioned during flexion. The anterior dMCL is elongated by external rotation. These data offer the basis for MCL repair and reconstruction techniques regarding graft positioning and tensioning.

Diagnostic accuracy of whole-body MRI versus standard imaging pathways for metastatic disease in newly diagnosed non-small-cell lung cancer: the prospective Streamline L trial.

BACKGROUND: Whole-body magnetic resonance imaging (WB-MRI) could be an alternative to multi-modality staging of non-small-cell lung cancer (NSCLC), but its diagnostic accuracy, effect on staging times, number of tests needed, cost, and effect on treatment decisions are unknown. We aimed to prospectively compare the diagnostic accuracy and efficiency of WB-MRI-based staging pathways with standard pathways in NSCLC. METHODS: The Streamline L trial was a prospective, multicentre trial done in 16 hospitals in England. Eligible patients were 18 years or older, with newly diagnosed NSCLC that was potentially radically treatable on diagnostic chest CT (defined as stage IIIb or less). Exclusion criteria were severe systemic disease, pregnancy, contraindications to MRI, or histologies other than NSCLC. Patients underwent WB-MRI, the result of which was withheld until standard staging investigations were complete and the first treatment decision made. The multidisciplinary team recorded its treatment decision based on standard investigations, then on the WB-MRI staging pathway (WB-MRI plus additional tests generated), and finally on all tests. The primary outcome was difference in per-patient sensitivity for metastases between standard and WB-MRI staging pathways against a consensus reference standard at 12 months, in the per-protocol population. Secondary outcomes were difference in per-patient specificity for metastatic disease detection between standard and WB-MRI staging pathways, differences in treatment decisions, staging efficiency (time taken, test number, and costs) and per-organ sensitivity and specificity for metastases and per-patient agreement for local T and N stage. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN50436483, and is complete. FINDINGS: Between Feb 26, 2013, and Sept 5, 2016, 976 patients were screened for eligibility. 353 patients were recruited, 187 of whom completed the trial; 52 (28%) had metastasis at baseline. Pathway sensitivity was 50% (95% CI 37-63) for WB-MRI and 54% (41-67) for standard pathways, a difference of 4% (-7 to 15, p=0·73). No adverse events related to imaging were reported. Specificity did not differ between WB-MRI (93% [88-96]) and standard pathways (95% [91-98], p=0·45). Agreement with the multidisciplinary team's final treatment decision was 98% for WB-MRI and 99% for the standard pathway. Time to complete staging was shorter for WB-MRI (13 days [12-14]) than for the standard pathway (19 days [17-21]); a 6-day (4-8) difference. The number of tests required was similar WB-MRI (one [1-1]) and standard pathways (one [1-2]). Mean per-patient costs were £317 (273-361) for WBI-MRI and £620 (574-666) for standard pathways. INTERPRETATION: WB-MRI staging pathways have similar accuracy to standard pathways, and reduce the staging time and costs. FUNDING: UK National Institute for Health Research.

Combined liver-kidney transplantation versus liver transplant alone based on KDIGO stratification of estimated glomerular filtration rate: data from the United Kingdom Transplant registry - a retrospective cohort study.

Patient selection for combined liver-kidney transplantation (CLKT) is a current issue on the background of organ shortage. This study aimed to compare outcomes and post-transplant renal function for patients receiving CLKT and liver transplantation alone (LTA) based on native renal function using estimated glomerular filtration rate (eGFR) stratification. Using the UK National transplant database (NHSBT) 6035 patients receiving a LTA (N = 5912; 98%) or CLKT (N = 123; 2%) [2001-2013] were analysed, and stratified by KDIGO stages of eGFR at transplant (eGFR group-strata). There was no difference in patient/graft survival between LTA and CLKT in eGFR group-strata (P > 0.05). Of 377 patients undergoing renal replacement therapy (RRT) at time of transplantation, 305 (81%) and 72 (19%) patients received LTA and CLKT respectively. A significantly greater proportion of CLKT patients had severe end-stage renal disease (eGFR < 30 ml/min/1.73 m2 ) at 1 year post-transplant compared to LTA (9.5% vs. 5.7%, P = 0.001). Patient and graft survival benefit for patients on RRT at transplantation was favouring CLKT versus LTA (P = 0.038 and P = 0.018, respectively) but the renal function of the long-term survivors was not superior following CLKT. The data does not support CLKT approach based on eGFR alone, and the advantage of CLKT appear to benefit only those who are on established RRT at the time of transplant.

A prospective multicenter observational study of cell-mediated immunity as a predictor for cytomegalovirus infection in kidney transplant recipients.

T cell immunity is essential for the control of cytomegalovirus (CMV) infection after transplantation. We evaluated a CMV-specific peptide-based enzyme-linked immunosorbent spot (ELISPOT) assay to determine whether assay results could predict subsequent CMV events. Adult kidney transplant recipients at 43 centers underwent ELISPOT testing to enumerate interferon gamma (IFN-γ) binding spot-forming units (sfu) after stimulation of cells with an overlapping peptide pool of CMV phosphoprotein 65 (pp65) and immediate early-1 (IE-1) protein at the end of antiviral prophylaxis (EOP) and various time points thereafter. The primary outcome was a CMV event in the first posttransplant year. In 583 kidney transplant recipients (260 seropositive donor [D+]/seronegative recipient [R-] and 277 R+), CMV events occurred in 44 of 368 eligible patients (11.8%) at a median of 227 days (range 92-360) posttransplant. A cutoff value of >40 sfu/2.5 × 105  cells for either IE-1 or pp65 was derived as a threshold for positivity, with a negative predictive value of >97% for CMV events. CMV events were significantly lower in assay positive vs assay negative patients (3.0% vs 19.5%, P < .0001 for pp65). Time to CMV event post-EOP was significantly greater in those with sfu >40 at EOP (P < .0001). In this large, multicenter trial of kidney transplant recipients, we show that an assessment of CMV-specific immunity using a novel ELISPOT assay is able to predict protection from CMV infection.

It is safe and effective to use all inside meniscal repair devices for posteromedial meniscal 'ramp' lesions.

PURPOSE: Recently, it has been recognized that meniscocapsular ('ramp') lesions of the posterior one-third of the medial meniscus frequently occur during injuries causing ACL rupture, and that these lesions are easily missed at arthroscopy. Furthermore, it is clear that these lesions are biomechanically significant, adding to the deficits caused by ACL rupture, and that their repair can reverse this. The efficacy of an all inside repair technique has been questioned by some authors and by those who advocate a suture shuttle technique via an accessory posteromedial portal. The use of Ultra FastFix and FastFix 360 meniscal repair devices to repair posteromedial meniscocapsular separations was investigated in terms of safe deployment and the effectiveness. METHODS: Twenty cadaveric fresh frozen knees were used-ten in each of two groups. A ramp lesion was created using a Beaver knife. The lesion was then repaired with either 4 Ultra FastFix (Smith and Nephew) or 4 FastFix 360 (Smith and Nephew) meniscal repair devices. The knees were put through a standardized loading cycle consisting of 10 Lachman's tests and ten maximum loading manual anterior drawer tests at 90° of flexion. Each knee was then flexed and extended fully ten times. The specimens were sectioned just proximal to the menisci and each suture anchor identified and its position recorded and photographed. RESULTS: In the Ultra FastFix group, a single anchor was found to be in an intra-articular position-a failure rate of 2.5%. In the FastFix 360 group, 5 anchors failed-a 12.5% failure rate. In all cases, the anchors were attached to their suture and so not truly loose within the joint. CONCLUSIONS: This study confirms the safe and effective deployment of an all inside repair device for repair of medial meniscal 'ramp' lesions, and therefore its use is advocated in treating these difficult lesions. Ultra FastFix had the lower failure rate of 2.5%, which the authors believe is acceptable, and makes this device preferable to the FastFix360.

The infrapatellar fat pad is a dynamic and mobile structure, which deforms during knee motion, and has proximal extensions which wrap around the patella.

PURPOSE: The infrapatellar fat pad (IFP) is a common cause of knee pain and loss of knee flexion and extension. However, its anatomy and behavior are not consistently defined. METHODS: Thirty-six unpaired fresh frozen knees (median age 34 years, range 21-68) were dissected, and IFP attachments and volume measured. The rectus femoris was elevated, suprapatellar pouch opened and videos recorded looking inferiorly along the femoral shaft at the IFP as the knee was flexed. The patellar retinacula were incised and the patella reflected distally. The attachment of the ligamentum mucosum (LMuc) to the intercondylar notch was released from the anterior cruciate ligament (ACL), both menisci and to the tibia via meniscotibial ligaments. IFP strands projecting along both sides of the patella were elevated and the IFP dissected from the inferior patellar pole. Magnetic resonance imaging (MRI) of one knee at ten flexion angles was performed and the IFP, patella, tibia and femur segmented. RESULTS: In all specimens the IFP attached to the inferior patellar pole, femoral intercondylar notch (via the LMuc), proximal patellar tendon, intermeniscal ligament, both menisci and the anterior tibia via the meniscotibial ligaments. In 30 specimens the IFP attached to the anterior ACL fibers via the LMuc, and in 29 specimens it attached directly to the central anterior tibia. Proximal IFP extensions were identified alongside the patella in all specimens and visible on MRI [medially (100% of specimens), mean length 56.2 ± 8.9 mm, laterally (83%), mean length 23.9 ± 6.2 mm]. Mean IFP volume was 29.2 ± 6.1 ml. The LMuc, attached near the base of the middle IFP lobe, acting as a 'tether' drawing it superiorly during knee extension. The medial lobe consistently had a pedicle superomedially, positioned between the patella and medial trochlea. MRI scans demonstrated how the space between the anterior tibia and patellar tendon ('the anterior interval') narrowed during knee flexion, displacing the IFP superiorly and posteriorly as it conformed to the trochlear and intercondylar notch surfaces. CONCLUSION: Proximal IFP extensions are a novel description. The IFP is a dynamic structure, displacing significantly during knee motion, which is, therefore, vulnerable to interference from trauma or repetitive overload. Given that this trauma is often surgical, it may be appropriate that surgeons learn to minimize injury to the fat pad at surgery.

Leg length discrepancy: the importance of a complete history and examination.

A 26-year-old woman with a 1-year history of right knee pain had failed to respond to analgesia and activity modification in the community. Her general practitioner referred her to the orthopaedic department for specialist review. A thorough history revealed that she had multiple orthopaedic interventions as a child. The patient had significant postoperative infection of the left knee following knee surgery at 7 years of age. Examination demonstrated the presence of a limp, scoliosis and suspected leg length discrepancy. Plain film radiography confirmed the presence of leg length discrepancy, with the right limb measuring 30 mm longer than the left. The leg length discrepancy was likely secondary to a growth arrest of the left knee following the postoperative infection in childhood. The patient was managed with physiotherapy and heel raises and received regular orthopaedic follow-up.

Hospital acquired Acute Kidney Injury is associated with increased mortality but not increased readmission rates in a UK acute hospital.

BACKGROUND: Acute Kidney Injury (AKI) has evoked much interest over the past decade and is reported to be associated with high inpatient mortality. Preventable death and increased readmission rates related to AKI have been the focus of considerable interest. METHODS: We studied hospital acquired AKI in all emergency hospital admissions, except transfers from ICU to ICU or patients known to renal services, to ascertain mortality and readmission rates, and trackable modifiable factors for death, using cox regression and Kaplan Meier survival curves. Data was extracted from the electronic patient records and a series of case notes reviewed. Admissions were included between April 2006 and March 2010 (and patients followed up until September 2011). RESULTS: Overall incidence of AKI was 2.2%, (AKI stage 1, 61%, stage 2,27% and stage 3, 12%). In patients who sustain in-hospital AKI, 34% die in hospital, 42% are dead at 90 days and 48% at 1 year post discharge, compared to 12% 1 year mortality in patients without AKI. In multivariable analyses, AKI is an independent risk factor for in-hospital mortality (Hazard Ratio 1.6: 95% confidence intervals 1.43-1.75: P < 0.001), death within 90 days of discharge (Hazard Ratio 1.5: 95% confidence intervals 1.3-1.9: P < 0.001) and subsequent mortality beyond 90 days (Hazard Ratio 2.9: 95% confidence intervals 2.7-3.1: P < 0.001) after adjustment for co-morbidities and peak C-reactive protein. Thirty percent of the patients who died in the first 90 days post discharge and had AKI, also had malignancy. Readmission rates at 30 and 90 days were not increased by AKI after adjustment for co-morbidities and peak C-reactive protein. CONCLUSIONS: A significant proportion of deaths in the first 90 days post-discharge may not be avoidable, due to malignancy and other end-stage disease. Readmission rates were not higher in patients who had had AKI.

The scientific rationale for lateral tenodesis augmentation of intra-articular ACL reconstruction using a modified 'Lemaire' procedure.

PURPOSE: The purpose of this work was to develop the rationale for adding a lateral extra-articular tenodesis to an ACL reconstruction in a knee with an injury that included both the ACL and anterolateral structures, and to show the early clinical picture. METHODS: The paper includes a review of recent anatomical and biomechanical studies of the anterolateral aspect of the knee. It then provides a detailed description of a modified Lemaire tenodesis technique. A short-term clinical follow-up of a case and control group was performed, with two sequential groups of patients treated by isolated ACL reconstruction, and by combined ACL plus lateral tenodesis. RESULTS: The anatomical and biomechanical literature guide the surgeon towards a procedure based on the ilio-tibial band. The clinical study found a reduction in pivot-shift instability in the group of patients with the combined procedure. CONCLUSION: The evidence suggests that it should be appropriate to add a lateral extra-articular procedure to an ACL reconstruction in selected cases, but it was concluded that further data are required before definitive guidelines on the use of a lateral tenodesis can be established. LEVEL OF EVIDENCE: III.

Sulforaphane promotes ER stress, autophagy, and cell death: implications for cataract surgery.

Posterior capsule opacification (PCO) commonly develops following cataract surgery and is a wound-healing response that can ultimately lead to secondary visual loss. Improved management of this problem is required. The isothiocyanate, sulforaphane (SFN), is reported to exert cytoprotective and cytotoxic actions, and the latter may be exploited to treat/prevent PCO. SFN concentrations of 10 µM and above significantly impaired wound-healing in a human lens capsular bag model. A similar pattern of response was also seen with a human lens cell line, FHL124. SFN treatment promoted increased expression of endoplasmic reticulum (ER) stress genes, which also corresponded with protein expression. Evidence of autophagy was observed in response to SFN as determined by increased microtubule-associated protein 1A/1B-light chain 3 (LC3)-II levels and detection of autophagic vesicles. This response was disrupted by established autophagy inhibitors chloroquine and 3-MA. SFN was found to promote MAPK signaling, and inhibition of ERK activation using U0126 prevented SFN-induced LC3-II elevation and vesicle formation. SFN also significantly increased levels of reactive oxygen species. Taken together, our findings suggest that SFN is capable of reducing lens cell growth and viability and thus could serve as a putative therapeutic agent for PCO. KEY MESSAGE: SFN reduces lens epithelial cell growth, migration, and viability. SFN can promote ER stress and autophagy in lens cells. SFN promotes MAPK signaling, and inhibition of MEK can suppress SFN-induced autophagy. ER stress and autophagy in lens cells are likely promoted by ROS production. SFN may help prevent posterior capsule opacification after cataract surgery.

The Spectrum of Renal Allograft Failure.

BACKGROUND: Causes of "true" late kidney allograft failure remain unclear as study selection bias and limited follow-up risk incomplete representation of the spectrum. METHODS: We evaluated all unselected graft failures from 2008-2014 (n = 171; 0-36 years post-transplantation) by contemporary classification of indication biopsies "proximate" to failure, DSA assessment, clinical and biochemical data. RESULTS: The spectrum of graft failure changed markedly depending on the timing of allograft failure. Failures within the first year were most commonly attributed to technical failure, acute rejection (with T-cell mediated rejection [TCMR] dominating antibody-mediated rejection [ABMR]). Failures beyond a year were increasingly dominated by ABMR and 'interstitial fibrosis with tubular atrophy' without rejection, infection or recurrent disease ("IFTA"). Cases of IFTA associated with inflammation in non-scarred areas (compared with no inflammation or inflammation solely within scarred regions) were more commonly associated with episodes of prior rejection, late rejection and nonadherence, pointing to an alloimmune aetiology. Nonadherence and late rejection were common in ABMR and TCMR, particularly Acute Active ABMR. Acute Active ABMR and nonadherence were associated with younger age, faster functional decline, and less hyalinosis on biopsy. Chronic and Chronic Active ABMR were more commonly associated with Class II DSA. C1q-binding DSA, detected in 33% of ABMR episodes, were associated with shorter time to graft failure. Most non-biopsied patients were DSA-negative (16/21; 76.1%). Finally, twelve losses to recurrent disease were seen (16%). CONCLUSION: This data from an unselected population identifies IFTA alongside ABMR as a very important cause of true late graft failure, with nonadherence-associated TCMR as a phenomenon in some patients. It highlights clinical and immunological characteristics of ABMR subgroups, and should inform clinical practice and individualised patient care.

PARP-1 inhibition influences the oxidative stress response of the human lens.

Poly(ADP-ribose) polymerase-1 (PARP-1) is best characterised for its involvement in DNA repair. PARP-1 activity is also linked to cell fate, confounding its roles in maintaining genome integrity. The current study assessed the functional roles of PARP-1 within human lens cells in response to oxidative stress. The human lens epithelial cell line FHL124 and whole human lens cultures were used as experimental systems. Hydrogen peroxide (H2O2) was employed to induce oxidative stress and cell death was assessed by LDH release. The functional influence of PARP-1 was assessed using targeted siRNA and chemical inhibition (by AG14361). Immunocytochemistry and western blotting were used to assess PARP-1 expression and the alkaline comet assay determined the levels of DNA strand breaks. PARP-1 was generally observed in the cell nucleus in both the FHL124 cell line and whole human lenses. PARP-1 inhibition rendered FHL124 cells more susceptible to H2O2-induced DNA strand breaks. Interestingly, reduction of PARP-1 activity significantly inhibited H2O2-induced cell death relative to control cells. Inhibition of PARP-1 in whole human lenses resulted in a reduced level of lens opacity and cell death following exposure to H2O2 relative to matched pair controls. Thus, we show that PARP-1 could play a role in the fate of human lens cells, and these first observations in human lenses suggest that it could impact on lens opacity. Further studies are required to elucidate the regulatory processes that give rise to these effects.

Ku80 Counters Oxidative Stress-Induced DNA Damage and Cataract Formation in the Human Lens.

PURPOSE: Oxidative stress in the human lens leads to a wide range of damage including DNA strand breaks, which are likely to contribute to cataract formation. The protein Ku80 is a fundamental component of the nonhomologous end-joining pathway that repairs DNA double strand breaks. This study investigates the putative impact of Ku80 in cataract prevention in the human lens. METHODS: The present study used the human lens epithelial cell line FHL124 and whole human lens organ culture. Targeted siRNA was used to deplete Ku80, with Western blot and immunocytochemistry employed to assess Ku80 expression levels. Oxidative stress was induced with hydrogen peroxide and DNA strand breaks measured by alkaline comet assay and γH2AX foci counts. Visual quality of whole human lenses was measured with image analysis software. RESULTS: Expression of Ku80 was predominately found in the cell nucleus of both FHL124 cells and native human lens epithelium. Treatment of FHL124 cells and whole lens cultures with siRNA targeted against Ku80 resulted in a significant knockdown at the protein level. Application of oxidative stress (30 µM H2O2) created more DNA strand breaks when added to Ku80 knockdown cells than in scrambled siRNA control cells as determined by the alkaline comet assay and the number of γH2AX foci. In whole lens cultures, exposure to 1 mM H2O2 resulted in more lens opacity in Ku80 knockdown lenses than match-paired controls. CONCLUSIONS: Depletion of Ku80 in the lens through acute change or a consequence of aging is likely to increase levels of DNA strand breaks, which could negatively influence physiological function and promote lens opacity. It is therefore feasible that Ku80 plays a role in retarding cataract formation.