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Background: Psychosocial factors, such as social support, can reduce pain. Virtual reality (VR) is a powerful tool to decrease pain, but social factors in VR-based pain analgesia have rarely been studied. Specifically, it is unclear whether social support by virtual characters can reduce pain and whether the perceived control behind virtual characters (agency) and varying degrees of social cues impact pain perception., Methods: Healthy participants (N = 97) received heat pain stimulation while undergoing four within-subject conditions in immersive VR: (1) virtual character with a low number of social cues (virtual figure) provided verbal support, (2) virtual character with a high number of social cues (virtual human) provided verbal support, (3) no social support (hearing neutral words), (4) no social support. Perceived agency of the virtual characters served as between-subjects factor. Participants in the avatar group were led to believe that another participant controlled the virtual characters. Participants in the agent group were told they interacted with a computer. However, in both conditions, virtual characters were computer-controlled. Pain ratings, psychophysiological measurements and presence ratings were recorded., Results: Virtual social support decreased pain intensity and pain unpleasantness ratings but had no impact on electrodermal activity nor heart rate. A virtual character with a high number of social cues led to lower pain unpleasantness and higher feelings of presence. Agency had no significant impact., Conclusions: Virtual characters providing social support can reduce pain independent of perceived agency. A more human visual appearance can have beneficial effects on social pain modulation by virtual characters., Significance: Social influences are important factors in pain modulation. The current study demonstrated analgesic effects through verbal support provided by virtual characters and investigated modulating factors. A more human appearance of a virtual character resulted in a higher reduction of pain unpleasantness. Importantly, agency of the virtual characters had no impact. Given the increasing use of digital health interventions, the findings suggest a positive impact of virtual characters for digital pain treatments., (© 2023 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Background: Cancer increases the risk of thromboembolic events in patients including those receiving anticoagulation treatments., Objectives: To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants for the long-term treatment of venous thromboembolism (VTE) in patients with cancer., Search Methods: We conducted a comprehensive search for studies of anticoagulation in cancer patients including 1. a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL Issue 12, 2012), MEDLINE, and EMBASE; 2. a handsearch of conference proceedings; 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. a search of clinicaltrials.gov for ongoing studies., Selection Criteria: We included randomized controlled trials (RCTs) comparing long-term treatment with LMWH versus oral anticoagulants (vitamin K antagonist (VKA) or ximelagatran) in patients with cancer and symptomatic objectively confirmed VTE., Data Collection and Analysis: Using a standardized data form, we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and postphlebitic syndrome. We assessed the quality of evidence at the outcome level following the GRADE approach., Main Results: Of 9559 identified citations, 10 RCTs (11 reports) were eligible and reported data for 1981 patients with cancer. We excluded 14 studies in which patients with cancer constituted study subgroups, but did not report outcome data for them. Meta-analysis of seven RCTs comparing LMWH with VKA found no statistically significant survival benefit (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.81 to 1.14) but a statistically significant reduction in VTE (HR 0.47; 95% CI 0.32 to 0.71). The remaining findings did not exclude a beneficial or harmful effect of LMWH compared with VKA for the outcomes of major bleeding (RR 1.07; 95% CI 0.52 to 2.19), minor bleeding (RR 0.89; 95% CI 0.51 to 1.55), or thrombocytopenia (RR 0.98; 95% CI 0.57 to 1.66). We judged the quality of evidence as low for mortality, major bleeding, and minor bleeding, and as moderate for recurrent VTE.One RCT comparing dabigatran with VKA did not exclude beneficial or harmful effects of one agent over the other. One RCT comparing six months' extension of anticoagulation with 18 months of ximelagatran 24 mg twice daily versus no extended ximelagatran did not exclude beneficial or harmful effects for the outcomes of reduction in VTE, mortality, and minor bleeding. One RCT comparing once-weekly subcutaneous injection of idraparinux for three or six months versus standard treatment (parenteral anticoagulation followed by warfarin or acenocoumarol) suggested a reduction in recurrent VTE (HR 0.39; 95% CI 0.14 to 1.11) at six months, but did not exclude beneficial or harmful effects for the outcomes of mortality (HR 0.99; 95% CI 0.66 to 1.48) and major bleeding (RR 1.04; 95% CI 0.39 to 2.83)., Authors' Conclusions: For the long-term treatment of VTE in patients with cancer, LMWH compared with VKA reduces venous thromboembolic events but not mortality. The decision for a patient with cancer and VTE to start long-term LMWH versus oral anticoagulation should balance the benefits and harms and integrate the patient's values and preferences for the important outcomes and alternative management strategies.

Background: Several basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect., Objectives: To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation., Search Methods: We performed a comprehensive search for studies of anticoagulation in patients with cancer including 1. a February 2013 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE; 2. a handsearch of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with the 2003 issue); 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. searching clinical trials.gov for ongoing studies., Selection Criteria: Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants with no intervention or placebo in patients with cancer without clinical evidence of venous thromboembolism., Data Collection and Analysis: Using a standardized data form, we extracted data on risk of bias, participants, interventions and outcomes of interest that included all-cause mortality, venous thromboembolism, major bleeding, and minor bleeding., Main Results: Of 9559 identified citations, seven RCTs (eight reports) fulfilled the inclusion criteria. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The use of warfarin had no effect on mortality at six months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.82 to 1.22), one year (RR 0.97; 95% CI 0.89 to 1.04), two years (RR 0.98; 95% CI 0.81 to 1.18), or five years (RR 0.92; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and did not show or exclude a beneficial or detrimental of effect (RR 0.15; 95% CI 0.02 to 1.20). Warfarin increased both major bleeding (RR 4.24; 95% CI 1.86 to 9.65) and minor bleeding (RR 3.19; 95% CI 1.83 to 5.55). We judged the quality of evidence as moderate for all outcomes.The study assessing the effect of apixaban did not show or exclude a beneficial effect or detrimental of apixaban on mortality at six months (RR 0.16; 95% CI 0.01 to 1.66); major bleeding (RR 0.62; 95% CI 0.06 to 6.63); and minor bleeding (RR 2.87; 95% CI 0.16 to 51.82). We judged the quality of evidence as low for all outcomes., Authors' Conclusions: Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while the risk for bleeding is increased.

Background: The choice of the appropriate perioperative thromboprophylaxis in patients with cancer depends on the relative benefits and harms of low molecular weight heparin (LMWH) and unfractionated heparin (UFH)., Objectives: To update a systematic review of the evidence for the relative efficacy and safety of LMWH and UFH for perioperative thromboprophylaxis in patients with cancer., Search Methods: We performed a comprehensive search for trials of anticoagulation in patients with cancer including a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE. We also handsearched conference proceedings, reviewed reference list of included studies, used the 'related citations' feature in PubMed, and searched clinicaltrials.gov for ongoing studies., Selection Criteria: Randomized controlled trials (RCTs) that enrolled patients with cancer undergoing a surgical intervention and compared the effects of LMWH to UFH on mortality, deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding outcomes, or thrombocytopenia., Data Collection and Analysis: Two review authors independently used a standardized form to extract in duplicate data on participants, interventions, outcomes of interest, and risk of bias. Where possible, we conducted meta-analyses using the random-effects model., Main Results: Of 9559 identified unique citations, we included 16 RCTs with 12,890 patients with cancer, all using preoperative prophylactic anticoagulation. We identified no new study with this update. The overall quality of evidence was moderate. The meta-analyses did not conclusively rule out either a beneficial or harmful effect of LMWH compared with UFH for the following outcomes: mortality (risk ratio (RR) 0.89; 95% confidence interval (CI) 0.74 to 1.08), PE (RR 0.73; 95% CI 0.34 to 1.54), symptomatic DVT (RR 0.50; 95% CI 0.20 to 1.28), asymptomatic DVT (RR 0.81; 95% CI 0.66 to 1.01),major bleeding (RR 0.85; 95% CI 0.52 to 1.37), and minor bleeding (RR 0.92; 95% CI 0.47 to 1.79). LMWH was associated with lower incidence of wound hematoma (RR 0.68; 95% CI 0.52 to 0.88) but higher volume of intraoperative transfusion (mean difference (MD) 74 mL; 95% CI 47 to 102). The meta-analyses found no statistically significant differences for any of the following outcomes: reoperation for bleeding (RR 0.72; 95% CI 0.06 to 8.48) , intraoperative blood loss (MD= -6mL; 95% CI -87 to 74), postoperative transfusion (MD= 79mL; 95% CI -54 to 211), postoperative drain volume (MD= 27mL; 95% CI -44 to 98), and thrombocytopenia (RR 1.33; 95% CI 0.59 to 3.00)., Authors' Conclusions: We found no difference between perioperative thromboprophylaxis with LMWH versus UFH in their effects on mortality, thromboembolic outcomes, major bleeding, or minor bleeding in patients with cancer. Further trials are needed to evaluate the benefits and harms of different heparin thromboprophylaxis strategies in this population more thoroughly.

Background: Compared with patients without cancer, patients with cancer who receive anticoagulant treatment for venous thromboembolism (VTE) are more likely to develop recurrent VTE., Objectives: To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose low molecular weight heparin (LMWH), adjusted-dose unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in patients with cancer., Search Methods: A comprehensive search for studies of anticoagulation in patients with cancer including a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and ISI Web of Science., Selection Criteria: Randomized clinical trials (RCTs) comparing LMWH, UFH, and fondaparinux in patients with cancer and objectively confirmed VTE., Data Collection and Analysis: Using a standardized data form, review authors extracted data in duplicate on methodologic quality, participants, interventions, and outcomes of interest that included mortality, recurrent VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia., Main Results: Of 9559 identified citations, 16 RCTs were eligible: 13 compared LMWH with UFH, two compared fondaparinux with heparin, and one compared dalteparin with tinzaparin. Meta-analysis of 11 studies showed a statistically significant reduction in mortality at three months of follow-up with LMWH compared with UFH (risk ratio (RR) 0.71; 95% confidence interval (CI) 0.52 to 0.98). There was little change in the effect estimate after excluding studies of lower methodologic quality (RR 0.72; 95% CI 0.52 to 1.00). A meta-analysis of three studies comparing LMWH with UFH showed no statistically significant reduction in VTE recurrence (RR 0.78; 95% CI 0.29 to 2.08). The overall quality of evidence was low for LMWH versus UFH due to imprecision and likely publication bias. There were no statistically significant differences between heparin and fondaparinux for the outcomes of mortality (RR 1.27; 95% CI 0.88 to 1.84), recurrent VTE (RR 0.95; 95% CI 0.57 to 1.60), major bleeding (RR 0.79; 95% CI 0.39 to1.63), or minor bleeding (RR 1.50; 95% CI 0.87 to 2.59). The one study comparing dalteparin with tinzaparin found no statistically significant difference in mortality (RR 0.86; 95% CI 0.43 to 1.73)., Authors' Conclusions: LMWH is possibly superior to UFH in the initial treatment of VTE in patients with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review.

Vitamin K antagonists (VKAs) prevent stroke in atrial fibrillation (AF) at the cost of bleeding risk. To determine major bleeding rates in AF patients, we conducted a systematic review that identified 51 eligible studies including more than 342,699 patients. The pooled estimate of the rate of major bleeding was 2.51 (99% confidence interval: 2.03-3.11) bleeds per 100 patient-years. The results represent the best estimates of bleeding risk that most patients contemplating VKA use may expect.

Background: Treatment with proton pump inhibitors (PPIs) improves clinical outcomes in patients with peptic ulcer bleeding. However, the optimal dose and route of administration of PPIs remains controversial., Objectives: To evaluate the efficacy of different regimens of PPIs in the management of acute peptic ulcer bleeding using evidence from direct comparison randomized controlled trials (RCTs).We specifically intended to assess the differential effect of the dose and route of administration of PPI on mortality, rebleeding, surgical intervention, further endoscopic haemostatic treatment (EHT), length of hospital stay, transfusion requirements and adverse events., Search Methods: We searched CENTRAL (in The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE (from inception to September 2010) and proceedings of major gastroenterology meetings (January 2000 to September 2010), without language restrictions. Original investigators were contacted to request missing data., Selection Criteria: RCTs that compared at least two different regimens of the same or a different PPI in patients with acute peptic ulcer bleeding, diagnosed endoscopically., Data Collection and Analysis: Two reviewers independently selected studies, extracted data and assessed risk of bias. We synthesized data using the Mantel-Haenszel random-effects method and performed multivariate meta-regression with random permutations based on Monte Carlo simulation. We measured heterogeneity with the I² statistic and Cochrane Q test and assessed publication bias with funnel plots and Egger's test. We graded the overall quality of evidence using the GRADE approach., Main Results: Twenty two RCTs were included; risk of bias was high in 17 and unclear in 5. The main analysis included 13 studies (1716 patients) comparing "high" dose regimens (72-hour cumulative dose > 600 mg of intravenous PPI) to other doses; there was no significant heterogeneity for any clinical outcome. We found low quality evidence that did not exclude a potential reduction or increase in mortality, rebleeding, surgical interventions or endoscopic haemostatic treatment (EHT) with "high" dose regimens. For mortality, pooled risk ratio (RR) was 0.85 (95% confidence interval (CI) 0.47 to 1.54); pooled risk difference (RD) was 0 more deaths per 100 patients treated with "high" dose (95% CI from 1 fewer to 2 more deaths per 100 treated). For rebleeding, pooled RR was 1.27 (95% CI 0.96 to 1.67); pooled RD was 2 more rebleeding events per 100 patients treated with "high" dose (95% CI from 0 fewer to 5 more rebleeding events per 100 treated). For surgical interventions, pooled RR was 1.33 (95% CI 0.63 to 2.77); pooled RD was 1 more surgical intervention per 100 patients treated with "high" dose (95% CI from 1 fewer to 2 more surgical interventions per 100 treated). For further EHT, pooled RR was 1.39 (95% CI 0.88 to 2.18), pooled RD was 2 more events per 100 patients treated with "high" dose PPI (95% CI from 1 fewer to 5 more events per 100 treated). We found moderate quality evidence suggesting no important difference between the two regimens with regards to length of hospital stay (mean difference (MD) 0.26 days; 95% CI -0.08 to 0.6 days) or blood transfusion requirements (MD 0.05 units; 95% CI -0.21 to 0.3 units). There was visual and statistical evidence of "inverse" publication bias for mortality (missing small studies with favourable outcomes for "high" dose), but not for any other outcome. The results were similar for all subgroup analyses (according to risk of bias, geographical location, route of administration for non-"high" dose regimens, continuous infusion vs. bolus administration for intravenous non-"high" regimens group), sensitivity analyses (restriction to patients who had EHT for high risk stigmata, use of different dose thresholds for comparative regimens) and post hoc analyses (inclusion of all studies (N = 22) that compared at least two PPI regimens with different cumulative 72 hour doses; restriction of the previous analysis to patients who had EHT for high risk stigmata). Meta-regression analysis did not show any statistically significant associations between treatment effect (for the outcomes of mortality, rebleeding and surgical intervention) and the three study-level factors that were assessed (geographical location (Asia versus not Asia), route of PPI administration (intravenous versus oral), within-study ratio among the 72-hour cumulative doses of the two PPI regimens)., Authors' Conclusions: There is insufficient evidence for concluding superiority, inferiority or equivalence of high dose PPI treatment over lower doses in peptic ulcer bleeding.

1. The effects of the kappa-opioid agonist U50,488 on parturition were studied in the rat. 2. Given directly after the birth of the second pup U50,488 (5 mg or 10 mg kg-1, i.p.) delayed the birth of the subsequent 4 pups by ca. 100 min, acting like morphine (10 mg kg-1, i.p.). In controls given the vehicle i.p., the birth of the 4 pups after treatment took 45.4 +/- 4.6 min. The effects of U50,488 could be prevented by simultaneous naloxone injection (10 mg kg-1). Injection of either U50,488 or morphine at 1 mg kg-1, i.v. also significantly delayed parturition. The effects of U50,488 but not of morphine were fully prevented by preinjection with nor-binaltorphimine (0.5 mg kg-1, i.v.) showing selective kappa-opioid receptor-mediated inhibition by U50,488 of established parturition. 3. In rats with an indwelling jugular venous cannula, i.v. injection of U50,488 (5 mg kg-1) after the birth of the second pup slowed parturition in a similar way to i.p. injection and significantly reduced blood plasma oxytocin concentration measured by radioimmunoassay compared with vehicle-injected controls. 4. Bolus i.v. injections of oxytocin (4 mu once per 5 min) significantly reduced the delay in parturition caused by i.v. U50,488, but continuous i.v. infusion of oxytocin (4 mu 5 min-1) was less effective. 5. Since i.v. oxytocin did not immediately reverse the effects of U50,488 on parturition, direct effects of U50,488 on isometric uterine contractions in vitro were sought. U50,488 inhibited spontaneous or oxytocin-stimulated contractions of uteri from rats within 24 h after parturition in a dose-related manner; the inhibitory effect was not naloxone-reversible.6. Thus U50,488 inhibited established parturition in the rat in a Kappa-opioid selective manner by reducing oxytocin secretion. The inhibitory effect may well have been potentiated by a direct non-opioid depressant action on contractile activity of the uterus.