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Several genetic and immunological risk factors for severe COVID-19 have been identified, with monogenic conditions relating to 13 genes of type I interferon (IFN) immunity proposed to explain 4.8% of critical cases. However, previous cohorts have been clinically heterogeneous and were not subjected to thorough genetic and immunological analyses. We therefore aimed to systematically investigate the prevalence of rare genetic variants causing inborn errors of immunity (IEI) and functionally interrogate the type I IFN pathway in young adults that suffered from critical COVID-19 yet lacked comorbidities. We selected and clinically characterized a cohort of 38 previously healthy individuals under 50 years of age who were treated in intensive care units due to critical COVID-19. Blood samples were collected after convalescence. Two patients had IFN-α autoantibodies. Genome sequencing revealed very rare variants in the type I IFN pathway in 31.6% of the patients, which was similar to controls. Analyses of cryopreserved leukocytes did not indicate any defect in plasmacytoid dendritic cell sensing of TLR7 and TLR9 agonists in patients carrying variants in these pathways. However, lymphocyte STAT phosphorylation and protein upregulation upon IFN-α stimulation revealed three possible cases of impaired type I IFN signaling in carriers of rare variants. Together, our results suggest a strategy of functional screening followed by genome analyses and biochemical validation to uncover undiagnosed causes of critical COVID-19. [ABSTRACT FROM AUTHOR]

Aim: Cerebral small-vessel disease (SVD) is prevalent in type 1 diabetes and has been associated with the haptoglobin variant allele Hp1. Contrarily, the Hp2-allele has been linked to cardiovascular disease and the role of haptoglobin-genotype in asymptomatic SVD is unknown. We, therefore, aimed to evaluate the alleles' association with SVD. Methods: This cross-sectional study included 179 neurologically asymptomatic adults with type 1 diabetes (women 53%, mean age 39 ± 7 years, diabetes duration 23 ± 10 years, HbA1c 8.1 ± 3.2% [65 ± 12 mmol/mol]). Examinations included genotyping (genotypes Hp1-1, Hp2-1, Hp2-2) by polymerase chain reaction, clinical investigation, and magnetic resonance brain images assessed for SVD manifestations (white matter hyperintensities, cerebral microbleeds, and lacunar infarcts). Results: SVD prevalence was 34.6%. Haptoglobin genotype frequencies were 15.6% (Hp1-1), 43.6% (Hp1-2), and 40.8% (Hp2-2). Only diastolic blood pressure differed between the genotypes Hp1-1, Hp1-2, and Hp2-2 (81 [74–83], 75 [70–80], and 75 [72–81] mmHg, p = 0.019). Haptoglobin genotype frequencies by presence versus absence of SVD were 16.1%; 46.8%; 37.1% versus 15.4%; 41.9%; 42.7% (p = 0.758). Minor allele frequencies were 39.5% versus 36.3% (p = 0.553). Hp1 homozygotes and Hp2 carriers displayed equal proportions of SVD (35.7% vs 34.4%, p > 0.999) and SVD manifestations (white matter hyperintensities 14.3% vs 17.9%, p = 0.790; microbleeds 25.0% vs 21.9%, p = 0.904; lacunar infarcts 0% vs 3.6%, p > 0.999). Hp1-1 was not associated with SVD (OR 1.19, 95% CI 0.46–2.94, p = 0.712) when adjusting for age, blood pressure, and diabetic retinopathy. Conclusions: Although the SVD prevalence was high, we detected no significant association between SVD and haptoglobin-genotype. [ABSTRACT FROM AUTHOR]

The environment of a comet is a fascinating and unique laboratory to study plasma processes and the formation of structures such as shocks and discontinuities from electron scales to ion scales and above. The European Space Agency's Rosetta mission collected data for more than two years, from the rendezvous with comet 67P/Churyumov-Gerasimenko in August 2014 until the final touch-down of the spacecraft end of September 2016. This escort phase spanned a large arc of the comet's orbit around the Sun, including its perihelion and corresponding to heliocentric distances between 3.8 AU and 1.24 AU. The length of the active mission together with this span in heliocentric and cometocentric distances make the Rosetta data set unique and much richer than sets obtained with previous cometary probes. Here, we review the results from the Rosetta mission that pertain to the plasma environment. We detail all known sources and losses of the plasma and typical processes within it. The findings from in-situ plasma measurements are complemented by remote observations of emissions from the plasma. Overviews of the methods and instruments used in the study are given as well as a short review of the Rosetta mission. The long duration of the Rosetta mission provides the opportunity to better understand how the importance of these processes changes depending on parameters like the outgassing rate and the solar wind conditions. We discuss how the shape and existence of large scale structures depend on these parameters and how the plasma within different regions of the plasma environment can be characterised. We end with a non-exhaustive list of still open questions, as well as suggestions on how to answer them in the future. [ABSTRACT FROM AUTHOR]

Background: Individuals with type 1 diabetes have a markedly increased risk of stroke. In the general population, genetic predisposition has been linked to increased risk of stroke, but this has not been assessed in type 1 diabetes. Our aim was, therefore, to study how parental risk factors affect the risk of stroke in individuals with type 1 diabetes. Methods: This study represents an observational follow-up of 4011 individuals from the Finnish Diabetic Nephropathy Study, mean age at baseline 37.6 ± 11.9 years. All strokes during follow-up were verified from medical records or death certificates. The strokes were classified as either ischemic or hemorrhagic. All individuals filled out questionnaires concerning their parents' medical history of hypertension, diabetes, stroke, and/or myocardial infarction. Results: During a median follow-up of 12.4 (10.9–14.2) years, 188 individuals (4.6%) were diagnosed with their first ever stroke; 134 were ischemic and 54 hemorrhagic. In Cox regression analysis, a history of maternal stroke increased the risk of hemorrhagic stroke, hazard ratio 2.86 (95% confidence interval 1.27–6.44, p = 0.011) after adjustment for sex, age, BMI, retinal photocoagulation, and diabetic kidney disease. There was, however, no association between maternal stroke and ischemic stroke. No other associations between parental risk factors and ischemic or hemorrhagic stroke were observed. Conclusion: A history of maternal stroke increases the risk of hemorrhagic stroke in individuals with type 1 diabetes. Other parental risk factors seem to have limited impact on the risk of stroke. [ABSTRACT FROM AUTHOR]

Purpose: To examine healing adaptations over 17 weeks post Achilles tendon (AT) rupture in the injured region (IR) compared to an uninjured region (UIR) of the AT. Methods: Twenty-four rats were subjected to a complete right-sided AT rupture, while the left side served as a control. ATs were harvested at 1, 2, 8 and 17 weeks post-rupture and stained with antibodies specific to Collagen type I (Col I) and II (Col II) as well as Alcian Blue and Picrosirius Red staining techniques. Histopathological changes, proteoglycan content, collagen alignment and immunoexpression were assessed. Results: Both regions examined, IR and UIR, exhibited over weeks 1–17 similar healing adaptations of increasing collagen alignment, decreasing Col I immunoexpression, as well as increasing proteoglycan content and Col II occurrence. Increased proteoglycan content was found already at week 2 in the UIR, while it first increased at week 8 in the IR. The area positive to Col II was increased compared to controls at week 8 in the UIR, whereas it first raised at week 17 in the IR. Collagen disorganization successively declined to reach control levels at week 17 in the UIR, but was still higher in the IR. Conclusion: This study demonstrated that uninjured areas of the AT remote from the rupture site also undergo pronounced remodeling, although with time-span differences relative to injured AT portions. These changes including the pathologic heterotopic mineralization and chondrogenic differentiation observed in both regions may have implications in the choice of rehabilitation regimes in order to prevent secondary rupture. [ABSTRACT FROM AUTHOR]

The objective of this study was to compare the function and activity level in patients with anterior cruciate ligament injuries, who participated in competitive sports (Tegner activity level > or = 7) and underwent a reconstruction of the anterior cruciate ligament, either subacute (2-12 weeks, group I) or late (12-24 months, group II) after the injury. The patients in group I (n = 97) were comparable with those in group II (n = 103) in terms of gender, age, preinjury activity level, and the reconstruction technique. At the final follow-up (2-5.5 years after the operation), the Lysholm score, the IKDC evaluation system and the one-leg-hop test revealed no differences between the groups. There were also no differences between the groups in terms of the patients' subjective evaluation or expectations. The Tegner activity level at follow-up was 8 (range 2-10) in group I and 6 (range 2-9) in group II (P = 0.0001). The same thing was found in terms of the desired Tegner activity level, which was 9 (range 4-9) in group I and 7 (range 3-10) in group II (P = 0.0002). The KT-1000 laxity meter revealed a total side-to-side difference of 1.5 mm (-3.5-8.5) in group I and 1.5 mm (-3.5-7) in group II (NS). Associated meniscal surgery between the index injury and the reconstruction, or during the reconstruction, was performed in 37/97 (38%) of the patients in group I and 59/103 (57%) of the patients in group II (P < 0.01). This study revealed that competitive athletes who underwent reconstruction at a subacute stage after the anterior cruciate ligament injury had a higher activity level 2-5.5 years after the index operation, as well as a higher desired level of activity compared to athletes who had the reconstruction delayed by 12-24 months. Furthermore, meniscal injuries were significantly more frequent if the reconstruction was delayed. [ABSTRACT FROM AUTHOR]

The aim of the study was to assess knee function after arthroscopic anterior cruciate ligament reconstruction and to analyse complications impeding rehabilitation, additional surgery until the final follow-up, as well as residual patellofemoral pain and donor-site problems. Between 1991 and 1994, 635 patients were operated on using patellar tendon autografts and interference screw fixation. Of these, 604 (95.1%) patients (403 male and 201 female) were re-examined by independent observers at the final follow-up 38 (range 21–68) months post-operatively. The Lysholm score was 85 (range 14–100) points and the Tegner activity level was 6 (range 1–10). Using the IKDC score, 206 patients (34.1%) were classified as normal, 244 (40.4%) as nearly normal, 122 (20.2%) as abnormal and 32 (5.3%) as severely abnormal. In patients with an uninjured contralateral knee ( n = 527), the KT-1000 revealed a total side-to-side difference of 1.5 (range –7–11) mm, and 384/527 (72.9%) had a side-to-side difference of ≤ 3 mm. The one-leg-hop test was 95% (range 0%–167%). One or more complications impeding rehabilitation were recorded in 184/604 patients (30.5%). The most common was an extension deficit (> 5°), in 81 patients (13.4%). During the period until the final follow-up, 196 re-operations were performed in 161/604 (26.7%) patients. More than one re-operation was required in 27 patients. Shaving and anterior scar resection due to extension deficit were the most common procedures performed (on 65 occasions). Moderate to severe subjective anterior knee pain related to activity, walking up and down stairs, and sitting with the knee flexed was found in 203/604 patients (33.6%). The median loss of anterior knee sensitivity was 16 (range 0–288) cm2. Patients with a full range of motion had less anterior knee pain than patients with isolated flexion or extension deficits, or combined flexion and extension deficits ( P < 0.05, P = 0.08 and P < 0.001, respectively). Patients with a full range of motion had less anterior knee pain than patients with extension deficits (with and without flexion deficits) ( P < 0.001). Patients with a full range of motion and a minimal loss (≤ 4 cm2) of anterior knee sensitivity had significantly ( P < 0.01) less subjective anterior knee pain than patients who did not fulfil these criteria. A considerable number of complications hindering the rehabilitation and conditions requiring additional surgery until the final follow-up were recorded. Anterior knee pain and problems with knee-walking were correlated with the loss of range of motion and anterior knee sensitivity. [ABSTRACT FROM AUTHOR]

The aim of this prospective study was to follow the development of repair tissue in the donor-site area using serial magnetic resonance imaging (MRI) evaluation and to assess whether the MRI findings were correlated with donor-site morbidity. Thirty-seven consecutive patients with unilateral anterior cruciate ligament injuries undergoing elective reconstruction of the ligament were included in the study. They were aged 27 (range 14-50) years. The graft was harvested through two 25-mm vertical incisions with the aim of protecting the infrapatellar nerve and sparing the paratenon. The tendon defect was left open. The patients underwent MRI evaluation at 6 weeks, 6 months and 27 months postoperatively. A final clinical follow-up was made 25 (range 23-29) months postoperatively. MRI demonstrated that the donor-site gap, i.e. the area corresponding to a pathological non-tendinous-like tissue signal, was 9 (range 4-18) mm at 6 weeks, 5 (range 2-14) mm at 6 months and 2 (range 0-5) mm at 27 months. The size of the donor-site gap had significantly decreased at 6 months compared with 6 weeks (P = 0.0001), as well as at 27 months compared with 6 months (P = 0.0001). We conclude that the patellar tendon at the donor site healed gradually, as expressed by a decrease in the area of non-tendinous-like tissue signal on the serial MRI evaluations. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess knee function after anterior cruciate ligament reconstruction focusing on residual donor-site problems. Ninety consecutive patients with chronic unilateral anterior cruciate ligament rupture were operated on by the same surgeon using patellar tendon autografts, the all-inside arthroscopic technique, and interference screw fixation. At the follow-up examination 24 (range 22– 32) months after the index operation, the median total anterior-posterior KT-1000 side-to-side difference was 2.5 (–7 to 11) mm. The median Lysholm score was 86 (range 37–100) points and the median Tegner activity level was 6 (range 1–9). Using the IKDC evaluation system, 62 of 90 (69%) were classified as normal or nearly normal. The median one-leg-hop quotient was 93 (range 0– 167)% of the uninjured leg. Of 90 patients, 44 (49%) had minor or no discomfort when asked to walk on their knees (kneewalkers) and 46 of 90 (51%) patients had severe problems or found it impossible to perform the test (non-kneewalkers). The ‘kneewalkers’ had a median loss of anterior knee sensitivity of 10 (range 0–120) cm2. The corresponding value for the ‘non-kneewalkers’ was 25 (range 0–200) cm2 ( P = 0.0001). Palpatory donor-site tenderness was registered in 19 of 44 (43%) of the ‘kneewalkers’ and 37 of 46 (80%) of the ‘non-kneewalkers’ ( P < 0.001). Full hyperextension was not regained by 9 of 44 (20%) of the ‘kneewalkers’ and 19 of 46 (41%) of the ‘non-kneewalkers’ ( P < 0.05). Additional surgery during the follow-up period was required by 6 of 44 (14%) of the ‘kneewalkers’ and 19 of 46 (41%) of the ‘non-kneewalkers’ ( P < 0.01). Magnetic resonance imaging focusing on the donor site was performed on 31 randomly selected patients and revealed no difference between the ‘kneewalkers’ and the ‘non-kneewalkers’ in terms of patellar tendon width, thickness, length, and residual donor-site gap size. The kneewalking test was found to be a functional and reliable test for detecting donor-site morbidity. It appears that donor-site morbidity was related to problems requiring additional surgery during the follow-up period, such as extension deficit and pain near the metal implant on the tibial side, as well as the loss of anterior knee sensitivity. It appears to be important to attempt to preserve the sensitivity in the operated area during surgery and to regain full hyperextension in the post-operative period to minimize donor-site morbidity. [ABSTRACT FROM AUTHOR]

Purpose: Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor dabigatran etexilate (hereafter referred to as dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation.Methods: We extracted and analysed data from the elderly or from moderately renally impaired patients (n 632 of = 5,539) from the orthopaedic clinical development programme of dabigatran.Results: Dabigatran 150 mg once daily was as effective as the standard European enoxaparin regimen, with numerically fewer major bleeding events. Rates of major VTE were 4.3% vs 6.4% of patients, respectively. Major bleeding events occurred in four (1.3%) vs 11 (3.3%), which shows a trend towards lower bleeding with dabigatran 150 mg [odds ratio (OR) 0.40; 95% confidence interval (CI) 0.13-1.25; p = 0.110]. Mean volume of blood loss was 395 vs 417 ml, and transfused units were 2.4 vs 2.5, respectively. Other safety parameters, including the incidence of wound infections and complications, were similar for 150 mg once daily dabigatran and enoxaparin.Conclusion: For patients at higher risk of bleeding, dabigatran 150 mg once daily is as effective as enoxaparin following major orthopaedic surgery and is associated with a favourable bleeding rate. [ABSTRACT FROM AUTHOR]

In critically ill patients, ventilator-induced diaphragm muscle fibre dysfunction (VIDD) contributes to weaning problems, increasing hospitalisation time and related costs. VIDD pathophysiology remains partially unknown, especially the characterisation of the contractile dysfunction. In the present study, it was hypothesised that Ca2+ activation is affected during VIDD. Ca2+ sensitivity of contraction was therefore evaluated at the single skinned diaphragm muscle fibre level in piglets randomised into sham operation or 5-day mechanical ventilation. Ca2+ sensitivities of force and stiffness in fibres were significantly impaired in all mechanically ventilated piglets compared with sham-operated controls, suggesting a less efficient Ca2+ activation of cells, i.e. a lower relative number of strongly attached cross-bridges for each sub-maximal concentration of Ca2+. In an attempt to test whether this negative effect of VIDD is reversible, single muscle fibres were exposed to the EMD 57033 Ca2+ sensitiser. EMD 57033 (30 µM) improved the Ca2+ sensitivity of force and stiffness in fibres from animals that were mechanically ventilated for 5 days as well as in sham-operated piglets. Thus, EMD 57033 partly restored the Ca2+ activation of cells, reducing VIDD. This finding offers a strong basis for evaluating the effect of Ca2+ sensitisers on diaphragm function in vivo. [ABSTRACT FROM AUTHOR]

Studies evaluating treatment effects on muscle function after an Achilles tendon rupture often use various tests for evaluating calf muscle strength. However, these tests rarely demonstrate the difference between treatment groups; therefore, new tests with a higher ability to detect possible differences in outcome are needed. The purpose of this study was to evaluate the validity and ability to detect differences in outcome of a heel-rise work test that would measure both the height of each heel-rise and the number of repetitions. Seventy-eight patients (65 men and 13 women) at a mean (standard deviation) age of 42 (9) years with Achilles tendon ruptures were included. The patients were evaluated with the new heel-rise test at 6 and 12 months after injury. The limb symmetry index (LSI = involved/uninvolved × 100) was calculated to determine the size of the difference in function between the injured and the uninjured side. The heel-rise height differed significantly between the injured and uninjured sides at the 6- and 12-month evaluations ( P < 0.001). At the 6-month evaluation, the patients had achieved a mean LSI of 84% on the number of repetitions parameter but only a mean LSI of 61% on the work parameter. At the 12-month evaluation the mean, LSI of the heel-rise repetition parameter was 95%, indicating that the patients had fully recovered function, but on the work parameter the mean LSI was only 76%. The heel-rise work test in the present study has good validity and greater ability to detect differences between the injured and the uninjured sides than a test that measures only the number of heel-rise repetitions in patients with Achilles tendon rupture. [ABSTRACT FROM AUTHOR]

Deep venous thrombosis (DVT) is common after lower limb injury, but the effect of prophylactic treatment has not been documented in large randomised trials or meta-analyses. As a result, evidence-based recommendations have not been established. The purpose of this study was to evaluate the incidence of venous thromboembolism in patients with Achilles tendon rupture. A total of 100 consecutive patients with an acute Achilles tendon rupture were included in a prospective study and randomised to either surgical or non-surgical treatment. At 8 weeks after the initiation of treatment, 95/100 patients were screened for DVT using colour duplex sonography (CDS) with blinded interpretation by two experienced examiners and adjudication in cases of disagreement by a third person. A total of 95 patients (79 male and 16 female) with a median (range) age of 41 (24–63) years were screened for CDS at 8 weeks. Of the 95 patients, 32 had a CDS-verified thrombosis, 5 proximal and 27 distal, whereas 3 had non-fatal pulmonary embolism. Surgical treatment was performed in 49 patients, non-surgical in 46. There were no significant differences in DVT frequency between the two treatment groups. The incidence of asymptomatic and symptomatic deep venous thrombosis is high after Achilles tendon rupture and there is a need to define the possible benefit of thromboprophylaxis. [ABSTRACT FROM AUTHOR]

For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban [PD 0348292] and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery. METHODS: Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban. RESULTS: An oral one-compartment model described the population pharmacokinetics of rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of rivaroxaban were generally small, and predictions of ‘extreme’ case scenarios suggested that fixed dosing of rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 µg/L) in the hip study and 4.2 seconds/(100 µg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%. CONCLUSION: This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery. [ABSTRACT FROM AUTHOR]

Background: There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery.Methods: Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban.Results: An oral one-compartment model described the population pharmacokinetics of rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of rivaroxaban were generally small, and predictions of 'extreme' case scenarios suggested that fixed dosing of rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 microg/L) in the hip study and 4.2 seconds/(100 microg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%.Conclusion: This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery. [ABSTRACT FROM AUTHOR]

If permission of full active and passive extension immediately after an anterior cruciate ligament (ACL) reconstruction will increase the post-operative laxity of the knee has been a subject of discussion. We investigated whether a post-operative rehabilitation protocol including active and passive extension without any restrictions in extension immediately after an ACL reconstruction would increase the post-operative anterior–posterior knee laxity (A–P laxity). Our hypothesis was that full active and passive extension immediately after an ACL reconstruction would have no effect on the A–P laxity and clinical results up to 2 years after the operation. Twenty-two consecutive patients (14 men, 8 women, median age 21 years, range 17–41) were included. All the patients had a unilateral ACL rupture and no other ligament injuries or any other history of previous knee injuries. The surgical procedure was identical in all patients and one experienced surgeon operated on all the patients, using the bone-patellar tendon-bone autograft. The post-operative rehabilitation programme was identical in both groups, except for extension training during the first 4 weeks post-operatively. The patients were randomly allocated to post-operative rehabilitation programmes either allowing (Group A, n=11) or not allowing [Group B (30 to −10°), n=11] full active and passive extension immediately after the operation. They were evaluated pre-operatively and at 6 months and 2 years after the reconstruction. To evaluate the A–P knee laxity, radiostereometric analysis (RSA) and KT-1000 arthrometer (KT-1000) measurements were used, range of motion, Lysholm score, Tegner activity level, the International Knee Documentation Committee (IKDC) evaluation system and one-leg-hop test quotient were used. Pre-operatively, the RSA measurements revealed side-to-side differences in Group A of 8.6 mm (2.3–15.4), median (range) and in Group B of 7.2 mm (2.2–17.4) (n.s.). The corresponding KT-1000 values were for Group A, 2.0 mm (0–8.0) and Group B, 4.0 mm (0–10.0) (n.s.). At 2 years, the differences between the two groups were minimal, regardless of the method that had been used. The RSA measurements in Group A were 2.7 mm (0–10.7) and in Group B 2.8 (−1.8 to 9.5). The KT-1000 values were for Group A, 1.0 mm (−1.5 to 3.5), and for Group B, 0.5 mm (−1.0 to 4.0), without any significant differences between the groups. Nor did the Lysholm score, Tegner activity level, IKDC or one-leg-hop test differ. Early active and passive extension training, without any restrictions in extension, immediately after an ACL reconstruction using bone-patellar tendon-bone graft did not increase post-operative knee laxity up to 2 years after the ACL reconstruction. [ABSTRACT FROM AUTHOR]

The Rosetta dual Langmuir probe instrument, LAP, utilizes the multiple powers of a pair of spherical Langmuir probes for measurements of basic plasma parameters with the aim of providing detailed knowledge of the outgassing, ionization, and subsequent plasma processes around the Rosetta target comet. The fundamental plasma properties to be studied are the plasma density, the electron temperature, and the plasma flow velocity. However, study of electric fields up to 8 kHz, plasma density fluctuations, spacecraft potential, integrated UV flux, and dust impacts is also possible. LAP is fully integrated in the Rosetta Plasma Consortium (RPC), the instruments of which together provide a comprehensive characterization of the cometary plasma. [ABSTRACT FROM AUTHOR]

The Rosetta Plasma Consortium (RPC) will make in-situ measurements of the plasma environment of comet 67P/Churyumov-Gerasimenko. The consortium will provide the complementary data sets necessary for an understanding of the plasma processes in the inner coma, and the structure and evolution of the coma with the increasing cometary activity. Five sensors have been selected to achieve this: the Ion and Electron Sensor (IES), the Ion Composition Analyser (ICA), the Langmuir Probe (LAP), the Mutual Impedance Probe (MIP) and the Magnetometer (MAG). The sensors interface to the spacecraft through the Plasma Interface Unit (PIU). The consortium approach allows for scientific, technical and operational coordination, and makes optimum use of the available mass and power resources. [ABSTRACT FROM AUTHOR]

Current anticoagulant provision is dominated by parenteral heparin and oral warfarin, which act by inhibiting several steps of the coagulation pathway indirectly. Recent research efforts have focused on the identification of small molecule inhibitors of the coagulation enzymes as novel therapies for thrombotic disorders. There has been particular success in developing nonpeptidic, orally available, small molecules to directly inhibit the key proteases, factor IIa and factor Xa. Of the new oral anticoagulants in development, the two agents in the most advanced stage are dabigatran etexilate (BIBR 1048) and rivaroxaban (BAY 59-7939), which inhibit factor IIa and factor Xa, respectively. Other agents in the early stages of development include several Xa inhibitors (LY-517717, YM150, DU-176b and apixaban [BMS-562247]), a factor IXa inhibitor (TTP889), and an orally active glycosaminoglycan enhancer (odiparcil [SB-424323]), which indirectly enhances thrombin inhibition via heparin cofactor II. Results have been reported from important, phase II dose-finding studies, and a number of registration-track phase III studies have been initiated, reflecting the drive towards potentially more effective, but primarily safer and more convenient therapies for the prevention and treatment of venous and arterial thrombosis. Indeed, two unmet needs for anticoagulation that can be easily identified are safety and ease of use. Safety relates primarily to the incidence of major bleeding and this remains the key concern of orthopaedic surgeons, over and above any efficacy advantage, and convenience of use, which centres on oral administration replacing the need for injections. The clinical development of these new anticoagulants is following the well tested strategy of dose-ranging and registration studies in major orthopaedic surgery, prior to development in arterial indications. There are a number of subtle issues, including the timing of the first perioperative dose, duration of prophylactic treatment and definition/assessment of study endpoints that can influence study outcome and require careful consideration when evaluating study results with new agents and in the comparison with established agents, and which are considered in this review. It is anticipated that over the next 3 years, at least one of these agents will be successfully licensed for the prevention of venous thromboembolism after major orthopaedic surgery, which will act as a springboard for the gradual replacement of current anticoagulants. [ABSTRACT FROM AUTHOR]

The KT-1000 and similar non-invasive arthrometers are used as a complement to clinical examination in the diagnosis of anterior cruciate ligament (ACL) rupture and during the follow-up after surgery. We compared the two methods, KT-1000 and Radiostereometric analysis (RSA), when used to measure anterior-posterior knee laxity (A-P laxity) in patients with ACL rupture, before and after the reconstruction of this ligament, in a prospective, comparative study. Twenty-two consecutive patients (14 men, 8 women) with a median age of 24 years (range 16–41) were studied. All the patients had a unilateral ACL rupture and an intact contralateral knee. The patients were operated on by one experienced surgeon using the bone-patellar tendon-bone (BTB) autograft. Preoperatively and 2 years after the reconstruction, all the patients were evaluated using KT-1000 and RSA measurements of A-P laxity. The side-to-side differences between the injured and the intact knees, that is, total A-P laxity for both knees, are presented. Preoperatively, the median side-to-side differences using the two methods (KT-1000/RSA) were 4.0 (0–10)/7.4 mm (2.2–17.4) ( P<0.0001). The total A-P laxity on the injured side was 11.0 (6.0–18.0)/10.9 mm (6.2–19.6) (n.s), while it was 8.0 (6.0–10.0)/3.1 mm (0.2–8.6) on the intact side ( P<0.0001). A side-to-side difference of more than 3.0 mm was defined as the cut-off value for indicating ACL rupture. Using the KT-1000, 11 of 22 (50%) patients had a cut-off value above 3.0 mm, while the corresponding figure for RSA was 21/22 (95%) patients. At the 2-year follow-up, the median side-to-side differences using the two methods (KT-1000/RSA) were 0.5 (−1.5 to 4.0)/2.8 mm (−1.8 to 10.7) ( P<0.0001). The total A-P laxity on the operated side was 9.5 (7.5–14.0)/6.5 mm (2.4–14.1) ( P<0.0001). We conclude that the KT-1000 recorded significantly smaller side-to-side differences than did the RSA, both before and after the reconstruction of the ACL using a BTB autograft. Before it was mainly an effect of larger A-P laxity recordings with KT-1000 on the intact side, and after the reconstruction, the KT-1000 still recorded larger A-P laxity on the intact side and also larger A-P laxity on the reconstructed side than RSA. [ABSTRACT FROM AUTHOR]

Objectives: To examine the influence of timing of postoperative initiation of subcutaneous melagatran followed by oral ximelagatran, and of risk factors for venous thromboembolism (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and bleeding complications, on the efficacy and safety of this regimen, compared with preoperative enoxaparin sodium, following total hip replacement (THR) or total knee replacement (TKR) surgery. Design: Statistical analyses of efficacy and safety in subgroups of the METHRO III intention-to-treat population. Main outcome measures: Main efficacy outcome measures were major VTE (proximal DVT, PE or VTE-related death) and total VTE (distal or proximal DVT, fatal or non-fatal PE). The main safety outcome measures were blood transfusion, severe bleeding events, blood loss, bleeding-related adverse events and need for reoperation. Results: In the combined THR and TKR population, melagatran initiated 4 – <8 hours postoperatively was non-inferior to enoxaparin sodium with respect to the risks of total VTE (absolute risk reduction [ARR] 0; 95% confidence interval [CI] –4.4, 4.4) and major VTE (ARR –0.63; 95% CI –2.94, 1.67). The rate of major VTE was unaffected by the different risk factors. In the combined THR and TKR population, blood transfusion requirements were lower with melagatran/ximelagatran than enoxaparin sodium (odds ratio 0.83; 95% CI 0.71, 0.96; p = 0.016). Conclusions: Melagatran/ximelagatran initiated 4 – <8 hours postoperatively provided a comparable level of protection against total and major VTE to preoperative enoxaparin sodium. Major VTE rates and safety were consistent across different patient subgroups. Subcutaneous melagatran followed by fixed-dose oral ximelagatran offers an alternative to the standard European low molecular-weight heparin regimen in a wide range of patients. [ABSTRACT FROM AUTHOR]

Patients undergoing total hip or total knee replacement are at high risk of venous thromboembolism (VTE), and are therefore considered to be populations well suited for the evaluation and dose optimisation of new anticoagulants. Deep vein thrombosis may lead to life-threatening pulmonary embolism, disabling morbidity in the form of the post-thrombotic syndrome, and risk of recurrent thrombotic events. There is increasing evidence that anticoagulant treatment for the prevention of VTE should be extended from 1 to at least 4 weeks after surgery. Anticoagulation with vitamin K antagonists (such as warfarin), low molecular weight heparin or unfractionated heparin effectively lowers the risk of VTE, but these anticoagulants have limitations such as the need for coagulation monitoring and subsequent dose adjustment (vitamin K antagonists), difficulty of continuing prophylaxis out of hospital because of the requirement for parenteral administration, and risk of heparin-induced thrombocytopenia. The development of new anticoagulants has been pursued with the aim of finding more effective, safer and/or more convenient therapies.___TAGSTART___BR___TAGEND___Thrombin is a central regulator in the coagulation and inflammation process and several direct thrombin inhibitors (DTIs) with distinct pharmacological profiles, as well as pharmacological differences from the conventional anticoagulants, are currently in clinical use for certain indications or are under development. Clinical experience with parenterally administered DTIs has accumulated since the mid 1990s, although only desirudin (a recombinant hirudin) is currently approved for use in patients undergoing orthopaedic surgery. Two oral DTIs, ximelagatran and dabigatran etexilate, are in clinical development. Dabigatran etexilate has recently been evaluated in phase II clinical trials in patients undergoing total hip replacement. Several large phase III trials have now demonstrated the efficacy and safety of ximelagatran in the prevention of VTE following total hip or knee replacement. Ximelagatran can be used with an oral fixed dose without the need for coagulation monitoring or dose adjustment. Hence, it offers significant potential to facilitate the management of anticoagulation in or out of hospital. [ABSTRACT FROM AUTHOR]

Objective: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined.Design and Methods: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model.Results: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT.Conclusions: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment. [ABSTRACT FROM AUTHOR]

Objectives: Muscle weakness is associated with immobilization, prolonged mechanical ventilation, critical illness and various critical care therapies. This study used an animal model simulating the critical care environment to investigate the effects of 5 days' mechanical ventilation and inactivity on diaphragm contractility and neurophysiologic function. Design: Prospective laboratory study. Setting: Animal research laboratory. Subjects: Seven 2–3 month old piglets weighing 20–25 kg. Interventions: The animals received constant-flow, volume-controlled mechanical ventilation (Tv 12–15 ml/kg, PEEP 3–5 cmH2O, I:E 1:2) and sedation without paralysis, and spontaneous breathing efforts were prevented. Evoked diaphragm contractions were achieved by transvenous phrenic nerve pacing. Measurements and main findings: Transdiaphragmatic pressure (Pdi) measurements were used to assess force frequency relationships. Evoked electrophysiologic measures included lowest stimulus threshold and latency, compound muscle action potential (CMAP) amplitude and duration, and amplitude during repetitive nerve stimulation at 3 Hz. Lung function measures included airway pressures, tidal and minute volumes, and dynamic compliance and resistance. There were no clinically significant changes in hemodynamics, oxygenation or ventilation. Indirect measures of lung volume remained stable. Pdi decreased by 20% at all frequencies tested and was accompanied by a 30% decrease in evoked CMAP amplitude, (6.7±4.7 mV to 4.5±3.9 mV, p=0.01) while CMAP threshold, latency and duration were unchanged and no significant decrement in amplitude was seen during repetitive stimulation at 3 Hz. Conclusion: In this in-vivo model of prolonged mechanical ventilation in an intensive caring setting, 5 days of mechanical ventilation with sedation and complete diaphragm inactivity resulted in disturbed diaphragm contractility and activation, while nerve conduction and neuromuscular transmission were not affected. Based on these findings, it is likely that the changes seen occur at the level of peripheral muscle. [ABSTRACT FROM AUTHOR]

This study included 527 patients (178 female and 349 male) with unilateral anterior cruciate ligament (ACL) rupture who underwent arthroscopic ACL reconstruction using bone-patellar tendon-bone autograft and interference screw fixation. The follow-up examination was performed by independent observers at a median of 38 (21–68) months after the index operation. At the follow-up, the Lysholm score was 86 (14–100) points, the Lysholm instability subscore was 22 (0–25) points and the Lysholm pain subscore was 19 (0–25) points. The Tegner activity level was 6 (1–10). The one-leg-hop test was 91 (0–167)% of the non-injured knee. The difference in the anterior side-to-side laxity as measured with the KT-1000 arthrometer at 89 Newton (N) was 1.5 (–5–13) mm and the total KT-1000 side-to-side difference at 89 N was 2 (–7–11) mm. Using the International Knee Documentation Committee (IKDC) evaluation system, 177 (33.6%) patients were classified as normal (group A), 211 (40%) as nearly normal (group B), 109 (20.7%) as abnormal (group C) and 30 (5.7%) as severely abnormal (group D). The highest correlation coefficients were recorded between the IKDC evaluation system and the Lysholm score (ρ = 0.66), the patients’ subjective evaluation (ρ = 0.53), the Tegner activity level (ρ = 0.34), all the laxity tests (ρ≥ 0.34) and the one-leg-hop test (ρ = 0.28). The resumption of sporting activities and work as evaluated by the Tegner activity level correlated with the patients’ subjective evaluation (ρ = 0.34) but did not correlate with the laxity tests, i.e., the manual Lachman test (ρ = –0.06) and the total and anterior KT-1000 tests (ρ = –0.06). Furthermore, none of the laxity tests correlated with the functional tests or the patients’ subjective evaluation. We conclude that the IKDC evaluation system is a reliable and useful tool for evaluating the post-operative outcome after an ACL reconstruction. [ABSTRACT FROM AUTHOR]

The most common graft in anterior cruciate ligament (ACL) surgery involves using the central one-third of the patellar tendon. Knowledge concerning the postoperative disability after harvesting the patellar tendon is, however, limited. The aim of this study was to evaluate the impact patellar tendon suture and bone grafting of the patellar bone defect might have in terms of functional outcome and patellofemoral pain after harvesting the bone-tendon-bone graft, compared with leaving the harvested site non-sutured and non-grafted. Sixty patients, scheduled for arthroscopically assisted ACL reconstruction, were randomly allocated to two groups. In group I, suture of the patellar tendon and bone grafting of the patellar defect were performed. In group II, the tendon gap and the patellar defect were left open. Preoperatively, there was no significant difference between the groups when comparing objective knee stability, as measured with a KT-1000 laxity meter, Lysholm score, Tegner activity level, IKDC score, or patellofemoral pain score. Both groups had a significantly improved Lysholm score at the 2-year follow-up, without any difference between them. Tegner's activity level was significantly lower at follow-up, compared with the pre-injury level in both groups. The patellofemoral pain score improved significantly after the reconstruction, without any difference between the groups. Ultrasonography did not reveal any difference between the groups in terms of healing of the tendon gap. This study revealed no differences in donor site morbidity, functional outcome, patellofemoral pain score or knee joint stability between the two treatment groups. The conclusion is that suture of the patellar tendon and bone grafting of the patellar defect do not improve the functional results or reduce donor site morbidity after arthroscopically assisted ACL. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effect of a standard postoperative rehabilitation knee brace on function, stability and postoperative complications at the 2-year follow-up after anterior cruciate ligament (ACL) reconstructive surgery. Seventy-eight consecutive patients with a unilateral chronic ACL rupture reconstructed by the same surgeon using the endoscopic “all-inside” technique, patellar tendon autograft and interference screw fixation were included in the study. The rehabilitation followed a standard protocol. Group A included 39 patients who were supplied postoperatively with a knee brace for 4 (range 3–6) weeks. Group B included 39 patients for whom a brace was not used. The median age was 27 (range 16–48) years in group A and 26 (range 14–51) years in group B. The median time period between the injury and the index operation was 24 (range 3–150) months in group A and 18 (range 3–360) months in group B. All 78 patients were re-examined by two independent observers after a median follow-up period of 25 (range 23–28) months in group A and 24 (range 22– 27) months in group B. The median KT-1000 total side-to-side difference between the reconstructed and the uninjured knees at 89 N was 3 (range –5.5–11) mm in group A and 3 (range –7–10) mm in group B (NS). When the anterior translation was tested separately at 89 N, the corresponding values were 3 (range –4–13) mm in group A and 3 (range –5–10) mm in group B (NS). The median one-leg hop quotient was 95% (range 50%–167%) of the uninjured leg in group A and 92% (range 64%–119%) in group B (NS). The median Lysholm score was 89 (range 39–100) points in group A and 85 (range 37–100) points in group B (NS). In group A, 27/39 (69%) patients and in group B 21/39 (54%) patients were classified as excellent or good (NS). The median Tegner activity level was 7 (range 3–9) in group A and 6 (range 3–9) in group B (NS). Using the IKDC scale, 27/39 (69%) in group A and 24/39 (62%) in group B were classified as normal or nearly normal (NS). The median sick leave in group A was 62 (range 0–357) days and 59 (range 0–243) days in group B (NS). No serious complications occurred during the first 6 postoperative weeks. Two serious complications were, however, registered after the 6th postoperative week. One patient in group A sustained a rupture of the reconstructed ACL 8 weeks postoperatively (3 weeks after removing the brace), and one patient in group B sustained an undislocated patellar fracture during the 7th postoperative week after a fall. This study indicates that the use of a postoperative rehabilitation brace after an arthroscopic ACL reconstruction did not appear to influence either objective stability or subjective function by the 2-year follow-up. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the analgesic effect of an external cooling system with or without the combined effect of intra-articularly administered bupivacaine/morphine after arthroscopic anterior cruciate ligament (ACL) reconstruction. Fifty patients with isolated ACL insufficiency operated on under general anaesthesia were randomized to three different postoperative treatment groups. Group I was treated with the cooling system during the first 24 h after surgery and an intra-articular injection of 20 ml of physiological saline given at the completion of surgery; in group II, the cooling system was combined with an intra-articular injection of 20 ml bupivacaine 3.75 mg/ml and 1 mg of morphine at the end of the operation; while group III (placebo group) received an intra-articular injection of 20 ml of physiological saline at the completion of surgery. Pain was assessed using a visual analogue scale (VAS) at 1, 2, 4, 6, 24 and 48 h postoperatively. Supplementary analgesic requirements were registered. In group I 80% (16/20) and in group II 90% (18/20) of the patients were satisfied with the postoperative pain control regimen (NS). This was significantly better than in group III, where 30% (3/10) were satisfied. The pain scores were significantly lower in the two treatment groups compared with the placebo group during the entire postoperative period. The pain score was significantly lower in group II than in group I at 24 and 48 h after surgery. The supplementary analgesic requirements were also lower in the two treatment groups compared with the placebo group. No complications due to the use of the cooling system or the intra-articular injections of bupivacaine/morphine were observed. The external cooling system used in this study provides an effective method of obtaining pain relief after arthroscopic surgery. The combination with an intra-articular injection of morphine and bupivacaine results in a slightly greater analgesic effect than the cooling system alone. [ABSTRACT FROM AUTHOR]

Residual neuromuscular block is a major risk factor behind critical events in the immediate postoperative period. Residual weakness due to muscle relaxants is seen in more than thirds of postoperative patients with ventilatory failure and hypoxia. Residual neuromuscular block should therefore be regarded as a serious adverse event in the same way as we regard ventilatory depression due to opioids and anaesthetic agents. This presentation aim to clarify our present knowledge and shortcomings in the field of residual neuromuscular blockade. [ABSTRACT FROM AUTHOR]

In March 2008, the European Commission granted marketing authorization for dabigatran etexilate (Pradaxa; Boehringer Ingelheim), a direct thrombin inhibitor, for the prevention of venous thromboembolic events in patients who have undergone total hip- or knee-replacement surgery. [ABSTRACT FROM AUTHOR]