Does acute kidney injury alerting improve patient outcomes?

BACKGROUND: Electronic alerts (e-alerts) for Acute Kidney Injury (AKI) have been implemented into a variety of different Electronic Health Records (EHR) systems worldwide in order to improve recognition and encourage early appropriate management of AKI. We were interested in the impact on patient safety, specialist referral and clinical management. METHODS: All patients admitted to our institution with AKI were included in the study. We studied AKI progression, dialysis dependency, length of hospital stay, emergency readmission, ICU readmission, and death, before and after the introduction of electronic alerts. The impact on prescription of high risk drugs, fluid administration, and referral to renal services was also analysed. RESULTS: After the introduction of the e-alert, progression to higher AKI stage, emergency readmission to hospital and death during admission were significantly reduced. More prescriptions were stopped for drugs that adversely affect renal function in AKI and there was a significant increase in the ICU admissions and in the number of patients having dialysis, especially in earlier stages. Longer term mortality, renal referrals, and fluid alteration did not change significantly after the AKI e-alert introduction. CONCLUSIONS: AKI e-alerts can improve clinical outcomes in hospitalised patients.

Functional outcomes in patient specific instrumentation vs. conventional instrumentation for total knee arthroplasty; a systematic review and meta-analysis of prospective studies.

BACKGROUND: Total Knee Arthroplasty (TKA) is an established surgical option for knee osteoarthritis (OA). There are varying perceptions of the most suitable surgical technique for making bone cuts in TKA. Conventional Instrumentation (CI) uses generic cutting guides (extra- and intra-medullary) for TKA; however, patient specific instrumentation (PSI) has become a popular alternative amongst surgeons. METHODS: A literature search of electronic databases Embase, Medline and registry platform portals was conducted on the 16th May 2021. The search was performed using a predesigned search strategy. Eligible studies were critically appraised for methodological quality. The primary outcome measure was Knee Society Function Score. Functional scores were also collected for the secondary outcome measures: Oxford Knee Score (OKS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS) and Visual Analog Scale (VAS) for pain. Review Manager 5.3 was used for all data synthesis and analysis. RESULTS: There is no conclusive evidence in the literature to suggest that PSI or CI instrumentation is better for functional outcomes. 23 studies were identified for inclusion in this study. Twenty-two studies (18 randomised controlled trials and 4 prospective studies) were included in the meta analysis, with a total of 2277 total knee arthroplasties. There were 1154 PSI TKA and 1123 CI TKA. The majority of outcomes at 3-months, 6-months and 12 show no statistical difference. There was statistical significance at 24 months in favour of PSI group for KSS function (mean difference 4.36, 95% confidence interval 1.83-6.89). The mean difference did not exceed the MCID of 6.4. KSS knee scores demonstrated statistical significance at 24 months (mean difference 2.37, 95% confidence interval (CI) 0.42-4.31), with a MCID of 5.9. WOMAC scores were found to be statistically significant favouring PSI group at 12 months (mean difference -3.47, 95% confidence interval (CI) -6.57- -0.36) and 24 months (mean difference -0.65, 95% confidence interval (CI) -1.28--0.03), with high level of bias noted in the studies and a MCID of 10. CONCLUSIONS: This meta-analysis of level 1 and level 2 evidence shows there is no clinical difference when comparing PSI and CI KSS function scores for TKA at definitive post operative time points (3 months, 6 months, 12 months and 24 months). Within the secondary outcomes for this study, there was no clinical difference between PSI and CI for TKA. Although there was no clinical difference between PSI and CI for TKA, there was statistical significance noted at 24 months in favour of PSI compared to CI for TKA when considering KSS function, KSS knee scores and WOMAC scores. Studies included in this meta-analysis were of limited cohort size and prospective studies were prone to methodological bias. The current literature is limited and insufficiently robust to make explicit conclusions and therefore further high-powered robust RCTs are required at specific time points.

The impact of changes in coding on mortality reports using the example of sepsis.

OBJECTIVES: NHS Digital issued new guidance on sepsis coding in April 2017 which was further modified in April 2018. During these timeframes some centres reported increased sepsis associated mortality, whilst others reported reduced mortality, in some cases coincident with specific quality improvement programmes. We hypothesised that changes in reported mortality could not be separated from changes in coding practice. METHODS: Hospital Episode Statistics from the Admitted Patient Care dataset for NHS hospitals in England, from April 2016 to March 2020 were analysed. Admissions of adults with sepsis: an International Classification of Diseases 10 (ICD-10) code associated with the Agency for Healthcare Research and Quality Clinical Classifications Software class 'Septicaemia (except in labour)', were assessed. Patient comorbidities were defined by other ICD-10 codes recorded within the admission episode. RESULTS: 1,081,565 hospital episodes with a coded diagnosis of sepsis were studied. After April 2017 there was a significant increase in admission episodes with sepsis coded as the primary reason for admission. There were significant changes in the case-mix of patients with a primary diagnosis of sepsis after April 2017. An analysis of case-mix, hospital and year treated as random effects, defined a small reduction in sepsis associated mortality across England following the first change in coding guidance. No centre specific improvement in outcome could be separated from these random-effects. CONCLUSION: Changes in sepsis coding practice altered case-mix and case selection, in ways that varied between centres. This was associated with changes in centre-specific sepsis associated mortality, over time. According to the direction of change these may be interpreted either as requiring local investigation for cause or as supporting coincident changes in clinical practice. A whole system analysis showed that centre specific changes in mortality cannot be separated from system-wide changes. Caution is therefore required when interpreting sepsis outcomes in England, particularly when using single centre studies to inform or support guidance or policy.

Evaluating semantic similarity methods for comparison of text-derived phenotype profiles.

BACKGROUND: Semantic similarity is a valuable tool for analysis in biomedicine. When applied to phenotype profiles derived from clinical text, they have the capacity to enable and enhance 'patient-like me' analyses, automated coding, differential diagnosis, and outcome prediction. While a large body of work exists exploring the use of semantic similarity for multiple tasks, including protein interaction prediction, and rare disease differential diagnosis, there is less work exploring comparison of patient phenotype profiles for clinical tasks. Moreover, there are no experimental explorations of optimal parameters or better methods in the area. METHODS: We develop a platform for reproducible benchmarking and comparison of experimental conditions for patient phentoype similarity. Using the platform, we evaluate the task of ranking shared primary diagnosis from uncurated phenotype profiles derived from all text narrative associated with admissions in the medical information mart for intensive care (MIMIC-III). RESULTS: 300 semantic similarity configurations were evaluated, as well as one embedding-based approach. On average, measures that did not make use of an external information content measure performed slightly better, however the best-performing configurations when measured by area under receiver operating characteristic curve and Top Ten Accuracy used term-specificity and annotation-frequency measures. CONCLUSION: We identified and interpreted the performance of a large number of semantic similarity configurations for the task of classifying diagnosis from text-derived phenotype profiles in one setting. We also provided a basis for further research on other settings and related tasks in the area.

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.

Characterization of ABH-subtype donor-specific antibodies in ABO-A-incompatible kidney transplantation.

ABO-incompatible (ABOi) transplantation requires preemptive antibody reduction; however, the relationship between antibody-mediated rejection (AMR) and ABO-antibodies, quantified by hemagglutination (HA), is inconsistent, possibly reflecting variable graft resistance to AMR or HA assay limitations. Using an ABH-glycan microarray, we quantified ABO-A antigen-subtype (A-subtype)-specific IgM and IgG in 53 ABO-O recipients of ABO-A kidneys, before and after antibody removal (therapeutic plasma exchange [TPE] or ABO-A-trisaccharide immunoadsorption [IA]) and 1-year posttransplant. IgM binding to all A-subtypes correlated highly (R2  ≥ .90) and A-subtype antibody specificities was reduced equally by IA versus TPE. IgG binding to the A-subtypes (II-IV) expressed in kidney correlated poorly (.27 ≤ R2  ≤ .69). Reduction of IgG specific to A-subtype-II was equivalent for IA and TPE, whereas IgG specific to A-subtypes-III/IV was not as greatly reduced by IA (p < .005). One-year posttransplant, IgG specific to A-II remained the most reduced antibody. Immunostaining revealed only A-II on vascular endothelium but A-subtypes II-III/IV on tubular epithelium. These results show that ABO-A-trisaccharide is sufficient for IgM binding to all A-subtypes; this is true for IgG binding to A-II, but not subtypes-III/IV, which exhibits varying degrees of specificity. We identify A-II as the major, but importantly not the sole, antigen relevant to treatment and immune modulation in adult ABO-A-incompatible kidney transplantation.

Evaluation and improvement of the National Early Warning Score (NEWS2) for COVID-19: a multi-hospital study.

BACKGROUND: The National Early Warning Score (NEWS2) is currently recommended in the UK for the risk stratification of COVID-19 patients, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for the prediction of severe COVID-19 outcome and identify and validate a set of blood and physiological parameters routinely collected at hospital admission to improve upon the use of NEWS2 alone for medium-term risk stratification. METHODS: Training cohorts comprised 1276 patients admitted to King's College Hospital National Health Service (NHS) Foundation Trust with COVID-19 disease from 1 March to 30 April 2020. External validation cohorts included 6237 patients from five UK NHS Trusts (Guy's and St Thomas' Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals, University Hospitals Birmingham), one hospital in Norway (Oslo University Hospital), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID-19 disease (transfer to intensive care unit (ICU) or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity, and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models. RESULTS: A baseline model of 'NEWS2 + age' had poor-to-moderate discrimination for severe COVID-19 infection at 14 days (area under receiver operating characteristic curve (AUC) in training cohort = 0.700, 95% confidence interval (CI) 0.680, 0.722; Brier score = 0.192, 95% CI 0.186, 0.197). A supplemented model adding eight routinely collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, C-reactive protein, estimated glomerular filtration rate, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI 0.715, 0.757), and these improvements were replicated across seven UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites. CONCLUSIONS: NEWS2 score had poor-to-moderate discrimination for medium-term COVID-19 outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID.

An informatics consult approach for generating clinical evidence for treatment decisions.

BACKGROUND: An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis. METHODS: We examined four sources of evidence for the effect of warfarin on stroke risk or all-cause mortality from: (1) randomised controlled trials (RCTs), (2) meta-analysis of prior observational studies, (3) trial emulation (using population electronic health records (N = 3,854,710) and (4) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems. RESULTS: We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71, CI 0.39-1.29). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61, CI 0.49-0.76) and ischaemic stroke (HR = 0.27, CI 0.08-0.91). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results. CONCLUSION: We performed a proof-of-concept Informatics Consult for evidence generation, which may inform treatment decisions in situations where there is dearth of randomised trials. Patients are surprised to know that their clinicians are currently not able to learn in clinic from data on 'patients like me'. We identify the key challenges in offering such an Informatics Consult as a service.

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.

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.

Cardiovascular, thromboembolic and renal outcomes in IgA vasculitis (Henoch-Schönlein purpura): a retrospective cohort study using routinely collected primary care data.

BACKGROUND: IgA vasculitis (IgAV, Henoch-Schönlein purpura) is a small-vessel vasculitis most common in children but also occurring in adults. Case series have suggested that IgAV may be associated with cardiovascular disease and venous thromboembolism, but this has not been evaluated in population-based studies. Renal disease and hypertension are possible complications of the disease with unknown incidence. METHODS: Using a large UK primary care database, we conducted an open retrospective matched cohort study of cardiovascular, venous thrombotic and renal outcomes in adult-onset and childhood-onset IgAV. Control participants were selected at a 2:1 ratio, matched for age and sex. Adjusted HRs (aHRs) were calculated using Cox proportional hazards models. RESULTS: 2828 patients with adult-onset IgAV and 10 405 patients with childhood-onset IgAV were compared with age-matched and sex-matched controls. There was significantly increased risk of hypertension (adult-onset aHR 1.42, 95% CI 1.19 to 1.70, p < 0.001; childhood-onset aHR 1.52, 95% CI 1.22 to 1.89, p < 0.001) and stage G3-G5 chronic kidney disease (adult-onset aHR 1.54, 95% CI 1.23 to 1.93, p < 0.001; childhood-onset aHR 1.89, 95% CI 1.16 to 3.07, p=0.010). There was no evidence of association with ischaemic heart disease, cerebrovascular disease or venous thromboembolism. All-cause mortality was increased in the adult-onset IgAV cohort compared with controls (aHR 1.27, 95% CI 1.07 to 1.50, p=0.006). CONCLUSIONS: Patients with IgAV are at increased risk of hypertension and chronic kidney disease (CKD) compared with individuals without IgAV; analysis restricted to adult-onset IgAV patients showed increased mortality. Appropriate surveillance and risk factor modification could improve long-term outcomes in these patients.

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.

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.

Bioequivalence of twice-daily oral tacrolimus in transplant recipients: More evidence for consensus?

In this Perspective on the clinical trial by Rita Alloway and colleagues, Simon Ball explains the benefits to healthcare systems and individual patients of the bioequivalence established between generic and brand-name formulations of an immunosuppressive drug in transplant recipients.

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.

Clinical outcomes with ABO antibody titer variability in a multicenter study of ABO-incompatible kidney transplantation in the United Kingdom.

BACKGROUND: ABO blood group-incompatible kidney transplantation (ABOiKTx) outcomes are good, but complications are more common than in conventional transplantation. Regimens that use extracorporeal antibody removal therapy (EART) and enhanced immunosuppression are guided by titration of ABO blood group antibodies (using hemagglutination [HA] dilution assays), and these assays vary significantly in performance between centers. This study aims to describe the differences in titer measurement and the effect on clinical practice and outcomes. STUDY DESIGN AND METHODS: This multicentre, prospective cohort study of 100 ABOiKTx recipients assessed treatment and outcome data, including HA assay results measured retrospectively in a single central laboratory. RESULTS: Patient and allograft survival at 1 year was 99% and 94%, respectively. There were significant differences in the number of pretransplantation EART sessions in centers undertaking plasma exchange (PEx), compared with immunoadsorption (IA) (median, 6 vs. 4 sessions; p = 0.007). The pre-EART HA titer in both groups was the same when centrally assayed. The local HA assay used to guide treatment yielded significantly higher titers in centers undertaking PEx compared with IA (median, 128 vs. 32; p < 0.005). Patients undergoing PEx rather than IA were significantly more likely to suffer postoperative hematoma (12.9% vs. 1.8%; p = 0.05) or any perioperative collection requiring drainage (19.4% vs. 3.6%; p = 0.02). CONCLUSION: The colinearity of HA assay sensitivity with the receipt of PEx and EART limits some conclusions regarding the likely direction of causation. However, the association of differences in clinical practice with recognized perioperative complications of ABOiKTx identifies targets for further investigation and quality improvement.

Loss of Gnas imprinting differentially affects REM/NREM sleep and cognition in mice.

It has been suggested that imprinted genes are important in the regulation of sleep. However, the fundamental question of whether genomic imprinting has a role in sleep has remained elusive up to now. In this work we show that REM and NREM sleep states are differentially modulated by the maternally expressed imprinted gene Gnas. In particular, in mice with loss of imprinting of Gnas, NREM and complex cognitive processes are enhanced while REM and REM-linked behaviors are inhibited. This is the first demonstration that a specific overexpression of an imprinted gene affects sleep states and related complex behavioral traits. Furthermore, in parallel to the Gnas overexpression, we have observed an overexpression of Ucp1 in interscapular brown adipose tissue (BAT) and a significant increase in thermoregulation that may account for the REM/NREM sleep phenotypes. We conclude that there must be significant evolutionary advantages in the monoallelic expression of Gnas for REM sleep and for the consolidation of REM-dependent memories. Conversely, biallelic expression of Gnas reinforces slow wave activity in NREM sleep, and this results in a reduction of uncertainty in temporal decision-making processes.

Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster.

Genomic imprinting results in allele-specific silencing according to parental origin. Silencing is brought about by imprinting control regions (ICRs) that are differentially marked in gametogenesis. The group of imprinted transcripts in the mouse Gnas cluster (Nesp, Nespas, Gnasxl, Exon 1A and Gnas) provides a model for analyzing the mechanisms of imprint regulation. We previously identified an ICR that specifically regulates the tissue-specific imprinted expression of the Gnas gene. Here we identify a second ICR at the Gnas cluster. We show that a paternally derived targeted deletion of the germline differentially methylated region (DMR) associated with the antisense Nespas transcript unexpectedly affects both the expression of all transcripts in the cluster and methylation of two DMRs. Our results establish that the Nespas DMR is the principal ICR at the Gnas cluster and functions bidirectionally as a switch for modulating expression of the antagonistically acting genes Gnasxl and Gnas. Uniquely, the Nespas DMR acts on the downstream ICR at exon 1A to regulate tissue-specific imprinting of the Gnas gene.