Tibial tubercle transfer leads to clinically relevant improvement in patients with patellar maltracking without instability: a systematic review and meta-analysis.

PURPOSE: To assess the different surgical techniques and their outcomes following tibial tubercle transfer (TTT) in patients with patellar maltracking. METHODS: A systematic search of the literature was performed in PubMed, EMBASE and Cochrane Library. Studies reporting patient-reported outcome measures (PROMs) or clinical outcome following: TTT in patients with patellar maltracking were included. Collected PROMs were Lysholm, Kujala, IKDC score, and VAS pain. Clinical outcome included reported clinical success, patient satisfaction, complications and removal of hardware (ROH). Overall pre-, post-operative and change scores were estimated using random-effects meta-analysis models. Results were reported as overall mean and per transfer direction. RESULTS: A total of 26 studies and 761 patients (818 knees, mean age 35 years, mean follow-up 5.0 years) were included. In 73% of the studies, surgery was performed after failed conservative treatment. Transfer direction was anteromedial in 76% of all procedures. Overall Lysholm score improved from 61 to 91, Kujala from 52 to 85, IKDC from 53 to 81, and VAS from 6.2 to 2.5, respectively. Clinical success was reported in 79% of patients, and 80% of patients reported to have satisfactory results. Rates of complications and ROH were 13% and 29%, respectively. CONCLUSIONS: TTT for management of patellar maltracking can lead to good results with clinically meaningful improvement, an overall clinical success of 79% and overall patient satisfaction of 80% when appreciating the underlying anatomic condition and using appropriate technique. The level of evidence was low, and large-scale prospective, comparative cohort studies with uniform outcome scales are needed to confirm these findings. LEVEL OF EVIDENCE: IV.

Impingement following anterior cruciate ligament reconstruction: comparing the direct versus indirect femoral tunnel position.

PURPOSE: During anterior cruciate ligament (ACL) reconstruction, authors have suggested inserting the femoral tunnel at the biomechanically relevant direct fibres, but this higher position can cause more impingement. Therefore, we aimed to assess ACL graft impingement at the femoral notch for ACL reconstruction at both the direct and indirect tunnel positions. METHODS: A virtual model was created for twelve cadaveric knees with computed tomography scanning in which a virtual graft was placed at direct and indirect tunnel positions of the anteromedial bundle (AM), posterolateral bundle (PL) or centre of the both bundles (C). In these six tunnel positions, the volume (mm3) and mid-point location of impingement (°) were measured at different flexion angles. RESULTS: Generally, more impingement was seen with the indirect position compared with the direct position although this was only significant at 90° of flexion for the AM position (97 ± 28 vs. 76 ± 20 mm3, respectively; p = 0.046). The direct tunnel position impinged higher at the notch, whereas the indirect position impinged more towards the lateral wall, but this was only significant at 90° of flexion for the AM (24 ± 5° vs. 34 ± 4°, respectively; p < 0.001) and C position (34 ± 5° vs. 42 ± 5°, respectively; p = 0.003). CONCLUSION: In this cadaveric study, the direct tunnel position did not cause more impingement than the indirect tunnel position. Based on these results, graft impingement is not a limitation to reconstruct the femoral tunnel at the insertion of the biomechanically more relevant direct fibres.

Survivorship and functional outcomes of patellofemoral arthroplasty: a systematic review.

PURPOSE: Historically poor results of survivorship and functional outcomes of patellofemoral arthroplasty (PFA) have been reported in the setting of isolated patellofemoral osteoarthritis. More recently, however, fairly good results of PFA were reported, but the current status of PFA outcomes is unknown. Therefore, a systematic review was performed to assess overall PFA survivorship and functional outcomes. METHODS: A search was performed using PubMed, Embase and Cochrane systems, and the registries were searched. Twenty-three cohort studies and one registry reported survivorship using Kaplan-Meier curve, while 51 cohort studies reported functional outcomes of PFA. RESULTS: Twelve studies were level II studies, while 45 studies were level III or IV studies. Heterogeneity was mainly seen in type of prosthesis and year the cohort started. Nine hundred revisions in 9619 PFAs were reported yielding 5-, 10-, 15- and 20-year PFA survivorships of 91.7, 83.3, 74.9 and 66.6 %, respectively, and an annual revision rate of 2.18. Functional outcomes were reported in 2587 PFAs with an overall score of 82.2 % of the maximum score. KSS and Knee Function Score were 87.5 and 81.6 %, respectively. CONCLUSION: This systematic review showed that fairly good results of PFA survivorship and functional outcomes were reported at short- and midterm follow-up in the setting of isolated patellofemoral osteoarthritis. Heterogeneity existed mainly in prosthesis design and year the cohort started. CLINICAL RELEVANCE: These results provide a clear overview of the current status of PFA in the setting of isolated patellofemoral osteoarthritis. LEVEL OF EVIDENCE: IV.

Early functional outcome after lateral UKA is sensitive to postoperative lower limb alignment.

PURPOSE: The predictive role of patient-specific characteristics and radiographic parameters on medial unicompartmental knee arthroplasty (UKA) outcomes is well known, but knowledge of these predictors is lacking in lateral UKA. Therefore, purpose of this study was to assess the predictive role of these parameters on short-term functional outcomes of lateral UKA. METHODS: In this retrospective cohort study, Western Ontario and McMaster Universities Arthritis Index scores were collected at 2-year follow-up (median 2.2 years, range 2.0-4.0 years) in 39 patients who underwent lateral UKA. Patient-specific characteristics included age, BMI and gender, while radiographic parameters included osteoarthritis severity of all three compartments and both preoperative and postoperative hip-knee-ankle alignment. RESULTS: BMI, gender, age and preoperative valgus alignment were not correlated with functional outcomes, while postoperative valgus alignment was correlated with functional outcomes (0.561; p = 0.001). Postoperative valgus of 3°-7° was correlated with better outcomes than more neutral (-2° to 3° valgus) alignment (96.7 vs. 85.6; p = 0.011). Postoperative alignment was a predictor when corrected for patient-specific characteristics (regression coefficient 4.1; p < 0.001) and radiological parameters (regression coefficient 3.8; p = 0.002). CONCLUSIONS: Postoperative valgus alignment of 3°-7° was correlated with the best short-term functional outcomes in lateral UKA surgery, while patient-specific parameters and preoperative alignment were not correlated with functional outcomes. Based on these findings, a surgeon should aim for valgus alignment of 3°-7° when performing lateral UKA surgery for optimal functional outcomes. LEVEL OF EVIDENCE: Prognostic study, Level II.

Additive solutions differentially affect metabolic and functional parameters of platelet concentrates.

BACKGROUND: Pathogen inactivation (PI) of platelet concentrates with extension of shelf life to 7 days requires the use of platelet additive solutions (PAS). We examined the quality of platelets resuspended in three different PAS stored for up to 7 days. MATERIALS AND METHODS: Twelve triple adult dose platelet concentrates (PC) were collected using the TrimaAccel® collection system. Each highly concentrated product was divided into three equal parts, and the additive solutions (Composol® or SSP+® or Intersol™) were added to a final concentration of 56% PAS and 44% plasma. Samples were drawn on days 1, 5 and 7 to measure pH, glucose, lactate dehydrogenase (LDH), lactate, mean platelet volume (MPV) and the aggregation response to collagen and the thrombin receptor agonist peptide-6. Further, p-selectin expression on platelets was assessed. RESULTS: No statistically significant changes were observed for pH and MPV during 7 days of storage in all PAS containing PCs, whereas glucose decreased and LDH and lactate increased over time (P < 0·05). These changes were particularly evident in Intersol PCs on days 5 and 7 compared with Composol® PCs or SSP+® PCs (P < 0·05). Platelets from Intersol PCs exhibited the highest baseline activation of p-selectin and showed reduced collagen- and TRAP-6-induced aggregation. CONCLUSION: Resuspension of platelets in Intersol for 7 days results in increased platelet activation and platelet metabolism compared with SSP+® or Composol®. Further clinical studies are needed to evaluate whether the observed differences in PAS-PCs affect the recovery rate or the life span of transfused platelets.

Efficacy and safety of dapagliflozin monotherapy in people with Type 2 diabetes: a randomized double-blind placebo-controlled 102-week trial.

AIMS: To assess initial pharmacotherapy of Type 2 diabetes with the sodium-glucose cotransporter-2 inhibitor dapagliflozin. METHODS: This double-blind, placebo-controlled trial, randomly allocated people with Type 2 diabetes aged 18-77 years and inadequate glycaemic control on diet and exercise [HbA1c 53-86 mmol/mol (7.0-10.0%)] to receive placebo (n = 75) or dapagliflozin monotherapy 2.5 mg (n = 65), 5 mg (n = 64) or 10 mg (n = 70) once daily in the morning. After 24 weeks, low-dose double-blind metformin 500 mg/day was added to the placebo group regimen (placebo+low-dose metformin group). Changes in HbA1c level, fasting plasma glucose and body weight, as well as adverse events, were assessed over 102 weeks. RESULTS: Of the 274 participants randomized, 167 completed the study (60.9%). At 102 weeks, significant differences vs placebo+low-dose metformin with dapagliflozin 5 and 10 mg were observed for HbA1c (-5.8 mmol/mol [-0.53%], P = 0.018; and -4.8 mmol/mol [-0.44%], P = 0.048), respectively); and for FPG (-0.69 mmol/L, P = 0.044; and -1.12 mmol/l, P = 0.001, respectively). For body weight, the difference between the dapagliflozin 10-mg group and the placebo+low-dose metformin group was significant (-2.60 kg; P = 0.016). Hypoglycaemic events were uncommon, with rates of 5.3% for placebo+low-dose metformin group and 0-4.6% for the dapagliflozin groups. Genital infections and urinary tract infections were more common in the dapagliflozin groups than in the placebo+low-dose metformin group. CONCLUSIONS: Dapagliflozin as monotherapy in treatment-naïve people with early Type 2 diabetes improved glycaemic control and reduced weight without increasing hypoglycaemia over 102 weeks. Dapagliflozin may provide an alternative initial pharmacotherapy in such people.

Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes.

AIMS: Sodium-glucose co-transporter 2 (SGLT2) reabsorbs glucose and sodium in the renal proximal tubule. Dapagliflozin, an SGLT2 inhibitor, targets hyperglycaemia in type 2 diabetes by increasing renal glucose excretion. To investigate whether the parallel occurring sodium loss would have diuretic-like physiologic effects, we compared dapagliflozin and hydrochlorothiazide (HCTZ) effects on 24-h blood pressure (BP), body weight, plasma volume and glomerular filtration rate (GFR). METHODS: In this randomized, placebo-controlled, double-blind trial, 75 subjects with type 2 diabetes were assigned placebo, dapagliflozin 10 mg/day, or HCTZ 25 mg/day. Changes from baseline BP, body weight, plasma volume and GFR were assessed after 12 weeks of treatment. RESULTS: Subjects' mean age was 56 years, type 2 diabetes mellitus (T2DM) duration 6.3 years, and haemoglobin A1c (HbA1c) 7.5%. Treatment with placebo, dapagliflozin or HCTZ resulted in changes from baseline in 24-h ambulatory mean systolic blood pressure (SBP) of -0.9 (95%CI -4.2, +2.4), -3.3 (95%CI -6.8, +0.2), and -6.6 (95%CI -9.9, -3.2) mmHg, respectively at week 12, adjusted for baseline SBP. Body weight decreased with dapagliflozin and HCTZ. In a sub-study plasma volume appeared to decrease with dapagliflozin but did not change with placebo or HCTZ treatment. Dapagliflozin induced a greater reduction in GFR (-10.8%; 95%CI -14.6, -6.7) relative to placebo (-2.9%; 95% CI -6.9, +1.2) or HCTZ (-3.4%; 95%CI -7.3, +0.6). CONCLUSIONS: Dapagliflozin-induced SGLT2 inhibition for 12 weeks is associated with reductions in 24-h BP, body weight, GFR and possibly plasma volume. Cumulatively, these effects suggest that dapagliflozin may have a diuretic-like capacity to lower BP in addition to beneficial effects on glycaemic control.

Administration of prednisolone intravenously or dexamethason orally in random donors reveals equal results in granulocyte collection: a single centre experience.

Since cytokine--mobilization for granulocyte collections in random donors--is not licensed in Austria, we investigated in a prospective analysis the effects of prednisolone or dexamethasone (DXM) in 153 donors (35 women/118 men) and in the collected products. Either prednisolone (50 mg) intravenously 4 h before granulocyte collection or DXM (8 mg) orally 12 h before collection was given. Collections were performed with the Cobe Spectra (CardianBCT, Lakewood). We recorded a significantly higher percentage of granulocytes in the peripheral blood of the DXM. However, the collected number of granulocytes was equal in both groups.

The effect of plasma removal from apheresis platelet concentrates on platelet function.

The effect of plasma removal on platelet function has scarcely been investigated. Plasma removal from apheresis platelet concentrates was achieved by centrifugation at 5000 g for 6 min or 2000 g for 10 min. After resting for 1 h, platelet concentrates were resuspended in 0·9% NaCl. Platelet function was tested before centrifugation and after resuspension by multiple electrode impedance aggregometry (MEA) and light transmission aggregometry (LTA). Plasma removal resulted in 10-14% lower response to TRAP-6 by MEA using both washing procedures, whereas TRAP-6-inducible aggregation by LTA increased slightly (2-5%). Neither plasma removal method affected collagen-induced aggregation. Thus, platelet function did not deteriorate significantly by either method.

Dapagliflozin monotherapy in drug-naïve patients with diabetes: a randomized-controlled trial of low-dose range.

AIMS: Many patients with type 2 diabetes are suboptimally managed with currently available therapies. Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, has shown efficacy in reducing diabetic hyperglycaemia. This study assessed efficacy of three lower doses in recently diagnosed patients. METHODS: This phase 3, randomized, double-blind, placebo-controlled study assigned treatment-naïve patients to placebo or dapagliflozin monotherapy (1, 2.5 or 5 mg) daily for 24 weeks. Patients were antidiabetic drug-naïve with inadequate glycaemic control [haemoglobin A1c (HbA1c) ≥7.0 and ≤10.0%]. The primary efficacy endpoint was change in HbA1c from baseline. Secondary endpoints included changes in body weight and fasting plasma glucose (FPG), and proportions achieving HbA1c <7%. RESULTS: A total of 282 patients with type 2 diabetes were randomly assigned to one of four treatment groups. Baseline characteristics were similar across groups. At week 24, mean HbA1c reduction was significantly greater with dapagliflozin: -0.68% for 1 mg, -0.72% for 2.5 mg, -0.82% for 5 mg, versus 0.02% for placebo (p < 0.0001); compared to mean baseline values of 7.8-8.1%. Mean FPG reduction was significantly greater for all dapagliflozin groups versus placebo (p < 0.02), as was mean weight reduction (p < 0.003). During the treatment period, 19.1% of placebo-treated patients received rescue medication or discontinued because of poor glycaemic control versus 6.9, 4.1 and 5.9% for dapagliflozin 1, 2.5 and 5 mg, respectively. Percentages of patients experiencing ≥1 adverse event were similar across groups. CONCLUSION: Dapagliflozin at doses of 1, 2.5 and 5 mg/day is effective in reducing glycaemic levels and body weight in treatment-naïve patients with type 2 diabetes. Dapagliflozin was generally well tolerated. This insulin-independent mechanism suggests a new treatment for type 2 diabetes.

Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial.

BACKGROUND: Combining metformin (XR) with dapagliflozin to initiate pharmacotherapy in patients with type 2 diabetes (T2D) and high baseline HbA1c may be advantageous. We conducted two randomised, double-blind, three-arm 24-week trials in treatment-naïve patients to compare dapagliflozin plus metformin, dapagliflozin alone and metformin alone. METHODS: Eligible patients had baseline HbA1c 7.5-12%. Each trial had three arms: dapagliflozin plus metformin, dapagliflozin monotherapy and metformin monotherapy. Dapagliflozin in combination and as monotherapy was dosed at 5 mg (Study 1) and 10 mg (Study 2). Metformin in combination and as monotherapy was titrated to 2000 mg. The primary endpoint was HbA1c change from baseline; secondary endpoints included change in fasting plasma glucose (FPG) and weight. RESULTS: In both trials, combination therapy led to significantly greater reductions in HbA1c compared with either monotherapy: -2.05 for dapagliflozin + metformin, -1.19 for dapagliflozin, and -1.35 for metformin (p < 0.0001) (Study 1); -1.98 for dapagliflozin + metformin, -1.45 for dapagliflozin and -1.44 for metformin (p < 0.0001) (Study 2). Combination therapy was statistically superior to monotherapy in reduction of FPG (p < 0.0001 for both studies); combination therapy was more effective than metformin for weight reduction (p < 0.0001). Dapagliflozin 10 mg was non-inferior to metformin in reducing HbA1c (Study 2). Events suggestive of genital infection were reported in 6.7%, 6.9% and 2.0% (Study 1) and 8.5%, 12.8% and 2.4% (Study 2) of patients in combination, dapagliflozin and metformin groups; events suggestive of urinary tract infection were reported in 7.7%, 7.9% and 7.5% (Study 1) and 7.6%, 11.0% and 4.3% (Study 2) of patients in the respective groups. No major hypoglycaemia was reported. CONCLUSION: In treatment-naïve patients with T2D, dapagliflozin plus metformin was generally well tolerated and effective in reducing HbA1c, FPG and weight. Dapagliflozin-induced glucosuria led to an increase in events suggestive of urinary tract and genital infections.

Continuous wave interdigital H-mode cavities for alternating phase focusing heavy ion acceleration.

In the future, a new superconducting (SC) continuous wave (CW) high intensity heavy ion HElmholtz LInear ACcelerator (HELIAC) should provide ion beams with maximum beam energy above the Coulomb barrier for the Super Heavy Element program at GSI (Gesellschaft für Schwerionenforschung, in Engl.: Association for Heavy Ion Research). The HELIAC consists of a SC main accelerator supplied by a normal conducting injector, which comprises an electron cyclotron resonance ion source, a radio-frequency quadrupole, and two separate interdigital H-mode drift-tube linear accelerator cavities, based on an Alternating Phase Focusing (APF) scheme. Together, both cavities will accelerate ions from 300 to 1400 keV/u with only one external quadrupole triplet for transverse focusing in between. Due to the demanding requirements of the APF concept on the voltage distribution along the beam axis on the one hand and the CW operation on the other hand, the optimization of each cavity concerning RF, mechanical, and thermal properties is crucial for the successful operation of the HELIAC injector.

Effects of saxagliptin on ß-cell stimulation and insulin secretion in patients with type 2 diabetes.

AIM: To study the effect of dipeptidyl peptidase-4 (DPP-4) inhibition with saxagliptin on ß-cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. METHODS: Patients in this randomized, parallel-group, double-blind, placebo-controlled study were drug-naïve, aged 43-69 years, with baseline haemoglobin A1c (HbA1c) 5.9-8.1%. Twenty patients received saxagliptin 5 mg once daily; 16 received placebo. Patients were assessed at baseline and week 12 by intravenous hyperglycaemic clamp (0-180 min, fasting state), and intravenous-oral hyperglycaemic clamp (180-480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C-peptide deconvolution. RESULTS: After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. In the fasting state, saxagliptin significantly increased insulin secretion by a 27.9% adjusted difference versus placebo (p = 0.02). Saxagliptin also improved glucagon area under the curve in the postprandial state (adjusted difference -21.8% vs. placebo, p = 0.03). CONCLUSIONS: DPP-4 inhibition with saxagliptin improves pancreatic ß-cell function in postprandial and fasting states, and decreases postprandial glucagon concentration. Given the magnitude of enhancement of the insulin response in the fasting state, further study into the effect of DPP-4 inhibition on the ß-cell is warranted.

A dynamic collimation and alignment system for the Helmholtz linear accelerator.

The upcoming commissioning of the superconducting (SC) continuous wave Helmholtz linear accelerators first of series cryomodule is going to demand precise alignment of the four internal SC cavities and two SC solenoids. For optimal results, a beam-based alignment method is used to reduce the misalignment of the whole cryomodule, as well as its individual components. A symmetric beam of low transverse emittance is required for this method, which is to be formed by a collimation system. It consists of two separate plates with milled slits, aligned in the horizontal and vertical direction. The collimation system and alignment measurements are proposed, investigated, and realized. The complete setup of this system and its integration into the existing environment at the GSI High Charge State Injector are presented, as well as the results of the recent reference measurements.

Red blood units collected from bone marrow harvests after mononuclear cell selection qualify for autologous use.

BACKGROUND: After large volume bone marrow (BM) harvest, donors and patients can develop severe anaemia, because collected BM can contain up to 20% of their red cell mass. In a prospective analysis, we investigated the feasibility to recover red blood cells (RBCs) from the harvested BM and investigated whether these RBC units meet the quality requirements of the European Council. PATIENTS AND METHODS: From 19 patients (median age 51 yrs, range 31-77) with acute myocardial infarction, who participated in the MYSTAR study, a median volume of 1299 ml (range, 700-1870 ml) BM was collected. During BM processing, mononuclear cells (MNC) were separated using the Cobe Spectra apheresis system and the residual RBCs were collected in a separate bag. The quality of the collected RBCs was assessed by measuring LDH, free haemoglobin, potassium and lactate. Haemolysis was calculated and the intracellular concentration of ATP, ADP, AMP was determined by HPLC. RESULTS: RBC units recovered from BM after MNC separation had a mean volume of 312 +/- 95 ml with a haematocrit of 47 +/- 8.9%, a haemoglobin content of 51 +/- 15 g per unit, a haemolysis of 0.15 +/- 0.005%, a pH of 6.8 +/- 0.007 and an intracellular ATP concentration of 135 pmol/10(6) RBC +/- 41, which is comparable with freshly collected packed red blood cells (PRBCs). CONCLUSION: RBCs, collected from bone marrow harvests, can be used for autologous blood support to minimize allogeneic blood transfusions in donors and patients after large volume BM donation.

Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight.

AIM: Dapagliflozin is a stable, competitive, reversible, and highly selective inhibitor of sodium-glucose co-transporter 2, the major transporter responsible for renal glucose reabsorption. With an insulin-independent mechanism of action, dapagliflozin is currently being developed for the treatment of type 2 diabetes mellitus (T2DM). This work aims to compare the efficacy of dapagliflozin, as measured by the change in hemoglobin A1c concentration (A1c) and body weight, and to determine the pharmacodynamic effects of dapagliflozin, as measured by urinary glucose excretion in early-stage and late-stage T2DM patient populations. METHODS: A total of 151 early-stage patients and 58 late-stage patients with T2DM randomly assigned 10 or 20 mg once daily (QD) dapagliflozin treatment or placebo for 12 weeks from two phase 2 studies were included in the analysis. A1c, body weight, and urinary glucose were compared between the two patient populations. RESULTS: Compared with the early-stage population, patients in the late-stage population had a longer duration of T2DM and higher baseline levels of A1c, body weight, fasting plasma glucose, and urinary glucose excretion. After 12 weeks of dapagliflozin treatment, A1c reduction, weight loss, and increased urinary glucose excretion from baseline were observed in both populations. Baseline A1c level impacted the A1c reduction after dapagliflozin treatment with a comparable effect in patients with early and late stage disease. Late-stage patients had greater reduction in body weight. There was no statistically significant difference in the amount of urinary glucose excretion between the early-stage and late-stage patients. CONCLUSIONS: Dapagliflozin treatment at 10 and 20 mg QD for 12 weeks resulted in significant improvement in glycaemic control and body weight reduction in both early-stage and late-stage patients with T2DM. The findings suggest that dapagliflozin could be a promising treatment option for a wide range of patients with T2DM.

Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial.

AIMS: Assess the efficacy and safety of saxagliptin added to a submaximal sulphonylurea dose vs. uptitration of sulphonylurea monotherapy in patients with type 2 diabetes and inadequate glycaemic control with sulphonylurea monotherapy. METHODS AND PATIENTS: A total of 768 patients (18-77 years; HbA(1c) screening >or= 7.5 to

Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes.

AIM: Enhancing the physiologic actions of the endogenous incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, by inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for their degradation, is an emerging treatment for type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate the safety and efficacy of dose ranges of the DPP-4 inhibitor saxagliptin (BMS-477118) in patients with T2DM. METHODS: In a 12-week, multicentre, randomized, parallel-group, double-blind, placebo-controlled trial conducted at 152 out-patient US study centres, 338 (low-dose cohort) and 85 (high-dose cohort) drug-naive patients with T2DM and inadequate glycaemic control (baseline HbA1c > or =6.8 and < or =9.7%) were randomized. Following a 2-week washout, patients received saxagliptin 2.5, 5, 10, 20 or 40 mg once daily, or placebo, for 12 weeks (low-dose cohort). In a second cohort, patients received saxagliptin 100 mg once daily, or placebo, for 6 weeks (high-dose cohort). The main outcome measure was saxagliptin dose response assessed as change from baseline in HbA1c following double-blind treatment. RESULTS: In all treatment arms, saxagliptin significantly reduced HbA1c by 0.7-0.9% from an average baseline of 7.9% vs. placebo (0.3% reduction) in the low-dose cohort. Placebo-subtracted HbA1c reductions were 0.45-0.63% (low-dose cohort). Saxagliptin had significant placebo-subtracted reductions in fasting serum glucose (14-25 mg/dl). Postprandial glucose levels at 60 min following a standard liquid meal test were reduced by 24-41 mg/dl vs. placebo. Saxagliptin was weight neutral. Adverse events were similar across treatment groups, including placebo, with a very low incidence of confirmed hypoglycaemia in saxagliptin treatment arms. CONCLUSIONS: Saxagliptin effectively improved glycaemic control in drug-naive patients with T2DM and was generally safe, with a tolerability profile similar to placebo.

Why do patellofemoral arthroplasties fail today? A systematic review.

BACKGROUND: Historically poor results of patellofemoral arthroplasty (PFA) were reported in the setting of isolated patellofemoral osteoarthritis (OA). In order to lower PFA failure rates, it is important to identify failure modes using a standardized method. In this systematic review, PFA failure modes were assessed and compared in early vs. late failures and older vs. recent studies. METHODS: Databases of PubMed, Embase and Cochrane and annual registries were searched for studies reporting PFA failures. Failure modes in studies with mean follow-up <5years were classified as early failures while >5years were classified late failures. Cohorts started before 2000 were classified as older studies and started after 2000 as recent studies. RESULTS: Thirty-nine cohort studies (10 level II and 29 level III or IV studies) and three registries were included with overall low quality of studies (GRADE criteria). A total of 938 PFA failures were included and were caused by OA progression (38%), pain (16%), aseptic loosening (14%) and patellar maltracking (10%). Pain was responsible for most early failures (31%), while OA progression was most common in late failures (46%). In older studies, OA progression was more commonly reported as failure mode than in more recent studies (53% vs. 39%, p=0.005). CONCLUSION: This level IV systematic review with low quality of studies identified OA progression and pain as major failure modes. Reviewing these studies, appropriate patient selection could prevent PFA failures in select cases. Future studies assessing the role of PFA in isolated patellofemoral OA are necessary.

Cost effectiveness of patellofemoral versus total knee arthroplasty in younger patients.

AIMS: Patellofemoral arthroplasty (PFA) has experienced significant improvements in implant survivorship with second generation designs. This has renewed interest in PFA as an alternative to total knee arthroplasty (TKA) for younger active patients with isolated patellofemoral osteoarthritis (PF OA). We analysed the cost-effectiveness of PFA versus TKA for the management of isolated PF OA in the United States-based population. PATIENTS AND METHODS: We used a Markov transition state model to compare cost-effectiveness between PFA and TKA. Simulated patients were aged 60 (base case) and 50 years. Lifetime costs (2015 United States dollars), quality-adjusted life year (QALY) gains and incremental cost-effectiveness ratio (ICER) were calculated from a healthcare payer perspective. Annual rates of revision were derived from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man. Deterministic and probabilistic sensitivity analysis was performed for all parameters against a $50 000/QALY willingness to pay. RESULTS: PFA was more expensive ($49 811 versus $46 632) but more effective (14.3 QALYs versus 13.3 QALYs) over a lifetime horizon. The ICER associated with the additional effectiveness of PFA was $3097. The model was mainly sensitive to utility values, with PFA remaining cost-effective when its utility exceeded that of TKA by at least 1.0%. PFA provided incremental benefits at no increased cost when annual rates of revision decreased by 24.5%. CONCLUSIONS: Recent improvements in rates of implant of survival have made PFA an economically beneficial joint-preserving procedure in younger patients, delaying TKA until implant failure or tibiofemoral OA progression. The present study quantified the minimum required marginal benefit for PFA to be cost-effective compared with TKA and identified survivorship targets for PFA to become both less expensive and more effective. These benchmarks might be used to assess clinical outcomes of PFA from an economic standpoint within the United States healthcare system. Cite this article: Bone Joint J 2017;99-B:1028-36.