The efficacy of cognitive–behavioral therapy for older adults with ADHD: a randomized controlled trial

Older adults with ADHD exhibit significant functional impairment, yet there is little research to guide clinicians in evidence-based care of these adults. This study examined response to treatment in older adults who participated in a previous study of the efficacy of cognitive–behavioral treatment (CBT) in adult ADHD. It was hypothesized that older adults would respond less well to CBT than younger adults, given the cognitive demands of the treatment. As described in the original publication, 88 adults who met DSM-IV criteria for ADHD were randomized to receive either a manualized 12-week CBT group intervention targeting executive dysfunction or a parallel Support group. In the current study, outcomes for 26 adults, aged 50 or older, were compared with those of 55 younger adults with respect to inattentive symptoms assessed on a structured interview by a blind clinician, as well as on ratings by self and/or collateral on measures of attention, executive dysfunction, and comorbidity. Contrary to the hypothesis, older and younger adults were equally responsive to CBT on measures of attention. The older adults also responded as well to Support as to CBT on several outcome measures. The results provide preliminary evidence that CBT is an effective intervention for older adults with ADHD. The unexpected response to support highlights a possible age-specificity of effective therapeutic intervention that requires further investigation.     

Traumeel S® for pain relief following hallux valgus surgery: a randomized controlled trial

Background

In spite of recent advances in post-operative pain relief, pain following orthopedic surgery remains an ongoing challenge for clinicians. We examined whether a well known and frequently prescribed homeopathic preparation could mitigate post-operative pain.

Method

We performed a randomized, double blind, placebo-controlled trial to evaluate the efficacy of the homeopathic preparation Traumeel S^® in minimizing post-operative pain and analgesic consumption following surgical correction of hallux valgus. Eighty consecutive patients were randomized to receive either Traumeel tablets or an indistinguishable placebo, and took primary and rescue oral analgesics as needed. Maximum numerical pain scores at rest and consumption of oral analgesics were recorded on day of surgery and for 13 days following surgery.

Results

Traumeel was not found superior to placebo in minimizing pain or analgesic consumption over the 14 days of the trial, however a transient reduction in the daily maximum post-operative pain score favoring the Traumeel arm was observed on the day of surgery, a finding supported by a treatment-time interaction test (p = 0.04).

Conclusions

Traumeel was not superior to placebo in minimizing pain or analgesic consumption over the 14 days of the trial. A transient reduction in the daily maximum post-operative pain score on the day of surgery is of questionable clinical importance.

Trial Registration

This study was registered at ClinicalTrials.gov. # NCT00279513     

Resistance exercise improves muscle strength,health status and pain intensity in fibromyalgia—a randomized controlled trial

IntroductionFibromyalgia (FM) is characterized by persistent widespread pain, increased pain sensitivity and tenderness. Muscle strength in women with FM is reduced compared to healthy women. The aim of this study was to examine the effects of a progressive resistance exercise program on muscle strength, health status, and current pain intensity in women with FM.MethodsA total of 130 women with FM (age 22–64 years, symptom duration 0–35 years) were included in this assessor-blinded randomized controlled multi-center trial examining the effects of progressive resistance group exercise compared with an active control group. A person-centred model of exercise was used to support the participants’ self-confidence for management of exercise because of known risks of activity-induced pain in FM. The intervention was performed twice a week for 15 weeks and was supervised by experienced physiotherapists. Primary outcome measure was isometric knee-extension force (Steve Strong®), secondary outcome measures were health status (FIQ total score), current pain intensity (VAS), 6MWT, isometric elbow-flexion force, hand-grip force, health related quality of life, pain disability, pain acceptance, fear avoidance beliefs, and patient global impression of change (PGIC). Outcomes were assessed at baseline and immediately after the intervention. Long-term follow up comprised the self-reported questionnaires only and was conducted after 13–18 months. Between-group and within-group differences were calculated using non-parametric statistics.ResultsSignificant improvements were found for isometric knee-extension force (p = 0.010), health status (p = 0.038), current pain intensity (p = 0.033), 6MWT (p = 0.003), isometric elbow flexion force (p = 0.02), pain disability (p = 0.005), and pain acceptance (p = 0.043) in the resistance exercise group (n = 56) when compared to the control group (n = 49). PGIC differed significantly (p = 0.001) in favor of the resistance exercise group at post-treatment examinations. No significant differences between the resistance exercise group and the active control group were found regarding change in self-reported questionnaires from baseline to 13–18 months.ConclusionsPerson-centered progressive resistance exercise was found to be a feasible mode of exercise for women with FM, improving muscle strength, health status, and current pain intensity when assessed immediately after the intervention.

Trial registration

ClinicalTrials.gov identification number: {"type":"clinical-trial","attrs":{"text":"NCT01226784","term_id":"NCT01226784"}}NCT01226784, Oct 21, 2010.     

Effects of daily iron supplementation in primary-school–aged children: systematic review and meta-analysis of randomized controlled trials

Background:

Anemia is an important public health and clinical problem. Observational studies have linked iron deficiency and anemia in children with many poor outcomes, including impaired cognitive development; however, iron supplementation, a widely used preventive and therapeutic strategy, is associated with adverse effects. Primary-school–aged children are at a critical stage in intellectual development, and optimization of their cognitive performance could have long-lasting individual and population benefits. In this study, we summarize the evidence for the benefits and safety of daily iron supplementation in primary-school–aged children.

Methods:

We searched electronic databases (including MEDLINE and Embase) and other sources (July 2013) for randomized and quasi-randomized controlled trials involving daily iron supplementation in children aged 5–12 years. We combined the data using random effects meta-analysis.

Results:

We identified 16 501 studies; of these, we evaluated 76 full-text papers and included 32 studies including 7089 children. Of the included studies, 31 were conducted in low- or middle-income settings. Iron supplementation improved global cognitive scores (standardized mean difference 0.50, 95% confidence interval [CI] 0.11 to 0.90, p = 0.01), intelligence quotient among anemic children (mean difference 4.55, 95% CI 0.16 to 8.94, p = 0.04) and measures of attention and concentration. Iron supplementation also improved age-adjusted height among all children and age-adjusted weight among anemic children. Iron supplementation reduced the risk of anemia by 50% and the risk of iron deficiency by 79%. Adherence in the trial settings was generally high. Safety data were limited.

Interpretation:

Our analysis suggests that iron supplementation safely improves hematologic and nonhematologic outcomes among primary-school–aged children in low- or middle-income settings and is well-tolerated.An estimated 25% of school-aged children worldwide are anemic.¹ Iron deficiency is thought to account for about half of the global cases of anemia² and is associated with inadequate dietary iron and, in developing settings, hookworm and schistosomiasis.³ In developed settings, anemia is prevalent among disadvantaged populations, including newly arrived refugees, indigenous people⁴ and some ethnic groups (e.g., Hispanic people in the United States).^5,6 About 3% of primary-school–aged children in Canada are anemic.⁷ Programs to address anemia are constrained by concerns that iron supplements cause adverse effects, including an increased risk of infections such as malaria in endemic areas.⁸In observational studies, iron deficiency has been associated with impaired cognitive and physical development. It has been estimated that each 10 g/L decrement in hemoglobin reduces future intelligence quotient (IQ) by 1.73 points.⁹ However, observational data are susceptible to confounding,¹⁰ and a causal relation between iron deficiency and cognitive impairment has not been confirmed.¹¹ Randomized controlled trials should overcome confounding, but results of trials examining this question have not agreed.Optimizing cognitive and physical development in primary-school–aged children could have life-long benefits.¹² However, anemia-control recommendations must balance safety and efficacy. We performed a systematic review of the effects of daily iron supplementation, a commonly used strategy to combat anemia,² in primary-school–aged children. We examined cognitive, growth and hematologic outcomes and adverse effects across all settings.     

Improving general flexibility with a mind-body approach: a randomized, controlled trial using neuro emotional Technique®

General flexibility is a key component of health, well-being, and general physical conditioning. Reduced flexibility has both physical and mental/emotional etiologies and can lead to musculoskeletal injuries and athletic underperformance. Few studies have tested the effectiveness of a mind-body therapy on general flexibility. The aim of this study was to investigate if Neuro Emotional Technique? (NET), a mind-body technique shown to be effective in reducing stress, can also improve general flexibility. The sit-and-reach test (SR) score was used as a measure of general flexibility. Forty-five healthy participants were recruited from the general population and assessed for their initial SR score before being randomly allocated to receive (a) two 20-minute sessions of NET (experimental group); (b) two 20-minute sessions of stretching instruction (active control group); or (c) no intervention or instruction (passive control group). After intervention, the participants were reassessed in a similar manner by the same blind assessor. The participants also answered questions about demographics, usual water and caffeine consumption, and activity level, and they completed an anxiety/mood psychometric preintervention and postintervention. The mean (SD) change in the SR score was +3.1 cm (2.5) in the NET group, +1.2 cm (2.3) in the active control group and +1.0 cm (2.6) in the passive control group. Although all the 3 groups showed some improvement, the improvement in the NET group was statistically significant when compared with that of either the passive controls (p = 0.015) or the active controls (p = 0.021). This study suggests that NET could provide an effective treatment in improving general flexibility. A larger study is required to confirm these findings and also to assess longer term effectiveness of this therapy on general flexibility.     

Effect of mivacurium 200 and 250 μg/kg in infants during isoflurane anesthesia: a randomized controlled trial [ISRCTN07742712]

Background  

Infants usually respond differently to a neuromuscular relaxant compared to children or adults. Isoflurane is commonly used as an anesthetic gas in infants. In an RCT design, we investigated whether a dose of mivacurium 250 μg/kg results in faster onset of action than 200 μg/kg in infants under isoflurane anesthesia. Spontaneous recovery times and cardiovascular response were also evaluated.     

Biomarkers of pulmonary hypertension in patients with scleroderma: a case–control study

IntroductionSignificant pulmonary vascular disease is a leading cause of death in patients with scleroderma, and early detection and early medical intervention are important, as they may delay disease progression and improve survival and quality of life. Although several biomarkers have been proposed, there remains a need to define a reliable biomarker of early pulmonary vascular disease and subsequent development of pulmonary hypertension (PH). The purpose of this study was to define potential biomarkers for clinically significant pulmonary vascular disease in patients with scleroderma.MethodsThe circulating growth factors basic fibroblast growth factor, placental growth factor (PlGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor, and soluble VEGF receptor 1 (sFlt-1), as well as cytokines (interleukin [IL]-1β IL-2, IL-4, IL-5, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor-α, and interferon-γ), were quantified in patients with scleroderma with PH (n = 37) or without PH (n = 40). In non-parametric unadjusted analyses, we examined associations of growth factor and cytokine levels with PH. In a subset of each group, a second set of earlier samples, drawn 3.0±1.6 years earlier, were assessed to determine the changes over time.ResultssFlt-1 (p = 0.02) and PlGF (p = 0.02) were higher in the PH than in the non-PH group. sFlt-1 (ρ = 0.3245; p = 0.01) positively correlated with right ventricular systolic pressure. Both PlGF (p = 0.03) and sFlt-1 (p = 0.04) positively correlated with the ratio of forced vital capacity to diffusing capacity for carbon monoxide (DLCO), and both inversely correlated with DLCO (p = 0.01). Both PlGF and sFlt-1 levels were stable over time in the control population.ConclusionsOur study demonstrated clear associations between regulators of angiogenesis (sFlt-1 and PlGF) and measures of PH in scleroderma and that these growth factors are potential biomarkers for PH in patients with scleroderma. Larger longitudinal studies are required for validation of our results.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0712-4) contains supplementary material, which is available to authorized users.     

Comparison of two different folic acid doses with methotrexate – a randomized controlled trial (FOLVARI Study)

IntroductionThere is reasonable evidence that folic acid 5–10 mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). However, this is based on studies conducted with lower MTX dosage than used currently. It is unclear whether higher doses of folic acid may be better in reducing toxicity.MethodsThis was a double-blind randomized controlled trial of 24 weeks duration. To be eligible, patients should have rheumatoid arthritis (1987 American College of Rheumatology criteria), be 18–75 years of age, not be on MTX and have active disease as defined by ‘Modified Disease Activity Score using three variables’ (DAS28(3)) > 3.2. MTX was started at 10 mg/week and escalated to 25 mg/week by 12 weeks. Folic acid was given at a dose of 10 mg (FA10) or 30 mg per week (FA30). Co-primary endpoints were incidence of toxicity (undesirable symptoms and laboratory abnormalities) and change in disease activity by 24 weeks. Intention-to-treat and per-protocol analyses were performed.ResultsAmong 100 patients enrolled, 51 and 49 were randomized to FA10 and FA30 respectively. By 24 weeks, there were 6 patient withdrawals in either group and mean(±SD) dose of MTX was 22.8 ± 4.4 and 21.4 ± 4.6 mg per week (p = 0.1). Frequency of patients with undesirable symptoms was non-significantly lower by 7.4 % (95 % confidence interval −27.4 to 12.7 %) in FA10 compared to FA30. There was also no difference in frequency of transaminitis (>Upper limit of normal (ULN)) (42.6, 45.7 %, p = 0.7) or transminitis as per primary endpoint (>2xULN) (10.6, 8.7 %, p = 1.0) or cytopenias (4.3, 4.3 %, p = 0.9). There was no difference in the primary end-point of occurrence of any adverse effect (symptom or laboratory) in FA10 and FA30 (46.8, 54.3 %, p = 0.5). At 24 weeks, DAS28(3) declined in both groups by a similar extent (−1.1 ± 1.0, −1.3 ± 1.0, p = 0.2) and ‘European League Against Rheumatism’ good or moderate response occurred in 56.9 and 67.4 % (p = 0.3).ConclusionsEven with the high doses of MTX used in current practice, there was no additional benefit (or harm) of a higher dose of folic acid (30 mg/week) over a usual dose (10 mg/week).

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01583959","term_id":"NCT01583959"}}NCT01583959 Registered 15 March 2012     

Safety and efficacy of granulocyte–colony-stimulating factor administration following autologous intramuscular implantation of bone marrow mononuclear cells: a randomized controlled trial in patients with advanced lower limb ischemia

Background aimsThe aim was to investigate the therapeutic effect of granulocyte–colony-stimulating factor (G-CSF) administration following implantation of autologous bone marrow mononuclear cells (BM MNC) for patients with lower limb ischemia.MethodsThe design was a randomized controlled trial. Fifteen patients with severe chronic limb ischemia were treated with autologous BM MNC [without G-CSF (MNC–G-CSF) or combined with G-CSF administration for 5 days following transplantation (MNC+G-CSF)].ResultsAll clinical parameters, including ankle brachial index, visual analog scale and pain-free walking distance, showed a mean improvement from baseline, which was measured at 4 and 24 weeks after transplantation in both groups. However, in three (20%) patients, the clinical course did not improve and limb salvage was not achieved. No significant difference was observed among the patients treated in the MNC–G-CSF and MNC+G-CSF groups. No severe adverse reactions were reported during the study period. No relationship was observed between both the numbers of viable MNC or CD34⁺ cells and the clinical outcome.ConclusionsAutologous transplantation of BM MNC into ischemic lower limbs is safe, feasible and efficient for patients with severe peripheral artery disease. However, the administration of G-CSF following cell transplantation does not improve the effect of BM MNC implantation and therefore would not have any beneficial value in clinical applications of such cases.     

Knowledge translation in child welfare—improving educational outcomes for children at risk: study protocol for a hybrid randomized controlled pragmatic trial

Background

In Norway, a disproportionately high number of children receiving Child Welfare Services (CWS) struggle academically and drop out of school. Academic attainment is one of the strongest protective factors against societal marginalization. The present study is part of a knowledge translation project in collaboration with local CWS with the aim to develop, implement, and evaluate Enhanced Academic Support (EAS) for primary school children in CWS.

Methods/design

The study is a mixed-methods hybrid type 2 randomized, controlled pragmatic trial. The participants are approximately 120 children whose families receive support measures from three child welfare agencies in and around Oslo, Norway, and practitioners from these agencies. Families are randomly assigned to either the EAS condition or “business as usual” support. Primary outcomes are math and reading skills, parental involvement in school, and intervention fidelity. Questionnaires and academic tests are administered at baseline, post-intervention (after 6 months), and at follow-up (after 12 months). Implementation drivers are assessed before and after the trial period, and intervention fidelity is monitored during the trial through checklists and structured telephone interviews. Semi-structured interviews and focus groups are conducted after the trial.

Discussion

This hybrid study has two implications. (1) The effects of providing EAS to children in child welfare will be investigated. The study also explores how each core component of the intervention and the use of specific adaptations, implementation drivers, and other important child-level covariates moderate the overall effects. The results can provide valuable knowledge about how to deliver precise and effective academic support to increase academic skills and prevent dropout. In turn, this can promote academic completion and well-being, outcomes that are beneficial for both children and society at large. (2) The study also evaluates the feasibility of applying an Integrated Knowledge Translation model designed to develop, implement, and evaluate research-supported practice in health, care, and welfare services in less time than is usually the case. If deemed successful, this model will provide an efficient collaborative approach to translate the best available evidence into effective evidence-based practice, applicable in effectiveness research and quality improvement efforts.

Trial registration

ISRCTN, ISRCTN38968073. Registered on 18 September 2017.  https://doi.org/10.1186/ISRCTN38968073.

     

Amelioration of human osteoarthritis symptoms with topical ‘biotherapeutics’: a phase I human trial

Osteoarthritis (OA) treatments presently rely on analgesics, which manage pain but fail to restore imbalances between catabolic and anabolic processes that underlie OA pathogenesis. Recently, biologic (biotherapeutic) drugs, which alter the activity of catabolic agents such as nitric oxide and inflammatory cytokines in ways, allowing tissue regeneration, were evaluated for efficacy in OA treatment. These studies failed to demonstrate dramatic abatement of OA symptoms by these drugs, but suggested strategies by which biologic agents might be used to treat OA. The present review summarizes current understanding of OA pathogenesis and evolving treatments. Preliminary evaluations of a novel biotherapeutic strategy are presented here. Twenty OA patients receiving sour topical cherry seed extract (SCE), an inducer of heme oxygenase-1 (HO-1), a major physiological protectant against oxidative stress exhibited significantly decreased joint pain and activation of CD4+ T cells expressing inflammatory cytokines (p < 0.05), significantly decreased peripheral blood C-reactive protein (CRP), and increased leukocyte HO-1 (p < 0.05) in comparison with ten placebo-treated patients. SCE inhibits joint-damaging inflammatory mediator production. This agent therefore meets the main criterion for classification as a “biotherapeutic,” or “biologic” agent. The negligible toxicity and low cost of such materials make them promising contributors to OA treatment, sustainable within resource limitations of a wide range of patients.     

“As du Coeur” study: a randomized controlled trial on quality of life impact and cost effectiveness of a physical activity program in patients with cardiovascular disease

Background

Physical activity programs (PAP) in patients with cardiovascular disease require evidence of cost-utility. To assess improvement in health-related quality of life (QoL) and reduction of health care consumption of patients following PAP, a randomized trial was used.

Methods

Patients from a health insurance company who had experienced coronary artery disease or moderate heart failure were invited to participate (N?=?1891). Positive responders (N?=?50) were randomly assigned to a progressively autonomous physical activity (PAPA) program or to a standard supervised physical activity (SPA) program. The SPA group had two supervised sessions per week over 5?months. PAPA group had one session per week and support to aid habit formation (written tips, exercise program, phone call). To measure health-related quality of life EQ-5D utility score were used, before intervention, 6?months (T6) and 1 year later. Health care costs were provided from reimbursement databases.

Results

Mobility, usual activities and discomfort improved significantly in both group (T6). One year later, EQ-5D utility score was improved in the PAPA group only. Total health care consumption in the intervention group decreased, from a mean of 4097 euros per year before intervention to 2877 euros per year after (p?=?0.05), compared to a health care consumption of 4087 euros and 4180 euros per year, in the total population of patients (N?=?1891) from the health insurance company. The incremental cost effectiveness ratio was 10,928 euros per QALYs.

Conclusion

A physical activity program is cost-effective in providing a better quality of life and reducing health care consumption in cardiovascular patients.

Trial registration

ISRCTN77313697, retrospectively registered on 20 November 2015.

     

Vaccination of castration-resistant prostate cancer patients with TroVax (MVA–5T4) in combination with docetaxel: a randomized phase II trial

The attenuated vaccinia virus, modified vaccinia Ankara, has been engineered to deliver the tumor antigen 5T4 (TroVax^®). Here, we report results from a randomized open-label phase II trial in castration-resistant prostate cancer patients in which TroVax was administered in combination with docetaxel and compared against docetaxel alone. The aim was to recruit 80 patients (40 per arm), but the study was terminated early due to recruitment challenges. Therefore, this paper reports the comparative safety and immunological and clinical efficacy in 25 patients, 12 of whom were treated with TroVax plus docetaxel and 13 with docetaxel alone. 5T4-specific immune responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by CT and bone scan and by quantifying PSA concentrations. TroVax was well tolerated in all patients. Of 10 immunologically evaluable patients, 6 mounted 5T4-specific antibody responses. Patients treated with TroVax plus docetaxel showed a greater median progression-free survival of 9.67 months compared with 5.10 months for patients on the docetaxel alone arm (P = 0.097; HR = 0.31; 95 % CI 0.08–1.24). Importantly, a pre-treatment biomarker previously demonstrated to predict 5T4 immune response and treatment benefit showed a strong association with 5T4 antibody response and a statistically significant association with progression-free survival in patients treated with TroVax plus docetaxel, but not docetaxel alone.     

Prevention of catheter-related bladder discomfort – pudendal nerve block with ropivacaine versus intravenous tramadol: study protocol for a randomized controlled trial

BackgroundCatheter-related bladder discomfort (CRBD) is a common distressing symptom complex during the postoperative period, especially after urologic procedures with a relatively greater size urinary catheter. In this study, we will enroll male patients undergoing elective prostate surgery with urinary catheterization under general anesthesia, and we will compare the efficacy of pudendal nerve block (PNB) and intravenous tramadol in CRBD prevention.Methods/designThis trial is a prospective, randomized controlled trial that will test the superiority of bilateral PNB with 0.33 % ropivacaine compared with intravenous tramadol 1.5 mg/kg for CRBD prevention. A total of 94 male patients undergoing elective prostate surgery with urinary catheterization after anesthesia induction will be randomized to receive either bilateral PNB with 0.33 % ropivacaine (the PNB group) or intravenous tramadol 1.5 mg/kg (the tramadol group) after the completion of surgery. The primary outcome is the incidence of CRBD. The most important secondary outcome is the severity of postoperative CRBD, and other secondary outcomes include Numeric Rating Scale (NRS) score for postoperative pain; incidence of postoperative side effects such as postoperative nausea/vomiting, sedation, dizziness, and dry mouth; postoperative requirement for tramadol as a rescue treatment for CRBD and sufentanil as a rescue analgesic for postoperative pain; and NRS score for acceptance of an indwelling urinary catheter.DiscussionThis trial is planned to test the superiority of PNB with 0.33 % ropivacaine compared with intravenous tramadol 1.5 mg/kg. It may provide a basis for a new clinical practice for the prevention of CRBD.

Trial registration

ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT02683070","term_id":"NCT02683070"}}NCT02683070. Registered on 11 February 2016.

Electronic supplementary material

The online version of this article (doi:10.1186/s13063-016-1575-y) contains supplementary material, which is available to authorized users.     

Effect of a fixed-ratio (1:1:1) transfusion protocol versus laboratory-results–guided transfusion in patients with severe trauma: a randomized feasibility trial

Background:

Hemorrhage coupled with coagulopathy remains the leading cause of preventable in-hospital deaths among trauma patients. Use of a transfusion protocol with a predefined ratio of 1:1:1 (1 each of red blood cells [RBC], frozen plasma [FP] and platelets) has been associated with improved survival in retrospective studies in military and civilian settings, but such a protocol has its challenges and may increase the risk of respiratory complications. We conducted a randomized controlled trial to assess the feasibility of a 1:1:1 transfusion protocol and its effect on mortality and complications among patients with severe trauma.

Methods:

We included 78 patients seen in a tertiary trauma centre between July 2009 and October 2011 who had hypotension and bleeding and were expected to need massive transfusion (≥ 10 RBC units in 24 h). We randomly assigned them to either the fixed-ratio (1:1:1) transfusion protocol (n = 40) or to a laboratory-results–guided transfusion protocol (control; n = 38). The primary outcome, feasibility, was assessed in terms of blood product ratios and plasma wastage. Safety was measured based on 28-day mortality and survival free of acute respiratory distress syndrome.

Results:

Overall, a transfusion ratio of 1:1:1 was achieved in 57% (21/37) of patients in the fixed-ratio group, as compared with 6% (2/32) in the control group. A ratio of 1:1 (RBC:FP) was achieved in 73% (27/37) in the fixed-ratio group and 22% (7/32) in the control group. Plasma wastage was higher with the intervention protocol (22% [86/390] of FP units v. 10% [30/289] in the control group). The 28-day mortality and number of days free of acute respiratory distress syndrome were statistically similar between the groups.

Interpretation:

The fixed-ratio transfusion protocol was feasible in our study, but it was associated with increased plasma wastage. Larger randomized trials are needed to evaluate the efficacy of such a protocol in trauma care. Trial registration: ClinicalTrials.gov, no. {"type":"clinical-trial","attrs":{"text":"NCT00945542","term_id":"NCT00945542"}}NCT00945542A fixed-ratio (1:1:1) transfusion strategy is a resuscitation strategy for trauma patients that promotes the transfusion of red blood cells (RBC), plasma and platelets (PLT) at a 1:1:1 ratio while minimizing crystalloid infusion.¹ This balanced transfusion strategy aims to correct both the early coagulopathy of trauma and the volume status of patients in hemorrhagic shock, thus targeting preventable hemorrhage-related deaths.^2,3 Retrospective studies of the 1:1:1 transfusion protocol reported marked reductions in mortality based on retrospectively calculated ratios of plasma:PLT:RBC.^4–6 Methodologic limitations, particularly survivorship bias (where higher mortality was associated with low ratios of plasma and PLT to RBC in unsalvageable patients who died before 1:1:1 transfusion could be achieved), preclude any definitive conclusion on the potential benefit of a 1:1:1 transfusion strategy in terms of efficacy and safety.^7–10The 1:1:1 transfusion strategy has been widely adopted by trauma centres worldwide^11,12 and is being increasingly used in prehospital care and in the care of patients without traumatic injuries.^13–15 Widespread adoption of the strategy has significant resource and safety implications. Its full implementation requires access to thawed type AB plasma, which is chronically in short supply.¹⁶ In addition, because of the difficulty in predicting the need for massive transfusion (commonly defined as ≥ 10 RBC units in 24 h), the 1:1:1 transfusion protocol may lead to unnecessary exposure to blood components and an increased risk of acute respiratory distress syndrome, sepsis and multiple organ dysfunction.¹⁷We conducted a pilot randomized controlled trial comparing a 1:1:1 transfusion strategy with the standard of care at our institution (laboratory-results–guided transfusion; laboratory results are available for transfusion decisions throughout resuscitation) in trauma patients predicted to need massive transfusion. Our primary objective was to assess the feasibility and safety of the fixed-ratio protocol in patients with severe trauma.     

The effects of a low therapeutic dose of βCG fragment-lytic peptide conjugates on ovarian function and gonadotropin secretion in ewes: a randomized controlled trial

The main objective of this experiment was to determine and compare the effects of two lytic peptide conjugates, Phor21-?CG(ala) and ?CG(ala)-Phor21, at a low therapeutic dose (0.2 mg/kg body weight i.v.), on periovulatory ovarian and endocrine activity, and ensuing luteal function in an ovine experimental model. We hypothesized that the dense expression of LH/hCG receptors on the preovulatory follicle would present an appropriate target for the drugs and disrupt normal ovarian dynamics in sheep. Serum levels of reproductive hormones and ultrasonographic images were used for the assessment of periovulatory events following drug administration in 14 Rideau Arcott ewes; seven animals served as controls. Ovulations were synchronized with intravaginal progestogen-releasing sponges (medroxyprogesterone acetate, 60 mg) that were left in place for 12 days and a single i.m. injection of 750 IU of equine chorionic gonadotropin (eCG) given at sponge withdrawal. Both drugs were administered by i.v. injection 36 h post sponge removal/eCG injection, during the period of increasing LH responsiveness of potential ovulatory follicles and around the expected onset of the preovulatory surge of gonadotropins. No difference (p>0.05) was detected in the number of luteal structures per ewe in control versus treated animals during early luteogenesis. After drug administration, peak FSH concentrations were higher (p<0.05) in Phor21-?CG(ala)-treated compared to control ewes and circulating estradiol concentrations were lower (p<0.05) in ?CG(ala)-Phor21-treated animals. Mean serum progesterone concentrations were lower (p<0.05) in ?CG(ala)-Phor21-treated than control ewes during the luteal phase post-treatment. There were no differences (p>0.05) in the percentage of ewes that lambed or lamb characteristics between the three groups at lambing 9 months post-treatment. In summary, neither Phor21-?CG(ala) nor ?CG(ala)-Phor21 demonstrated adverse effects on the ovulatory process but the treatment with ?CG(ala)-Phor21 significantly depressed follicular and luteal steroidogenesis. With a lack of evidence for disruptive effects on endocrine function and fertility, these obsevations support the use of Phor21-?GG(ala) as a cancer pharmaceutical.     

A pilot study testing the feasibility of skin temperature monitoring to reduce recurrent foot ulcers in patients with diabetes – a randomized controlled trial

Background

Although monitoring foot skin temperatures has been associated with diabetic foot ulcer recurrence, no studies have been carried out to test the feasibility among European Caucasians. Moreover, the educational and/or motivational models that promote cognitive or psychosocial processes in these studies are lacking. Thus, we conducted a pilot randomized controlled trial to test the feasibility of monitoring foot skin temperatures in combination with theory-based counselling to standard foot care to reduce diabetic foot ulcer recurrence.

Methods

In a single-blinded nurse-led 1-year controlled trial, conducted at a hospital setting in Norway, 41 patients with diabetic neuropathy and previous foot ulcer were randomized to the intervention (n?=?21) or control groups (n?=?20). All participants were instructed in foot care and recording observations daily. Additionally, the intervention group was taught how to monitor and record skin temperature at baseline, and received counselling every third month supporting them to use the new treatment. Subjects observing temperature differences >2.0 °C between corresponding sites on the left and right foot on two consecutive days were asked to contact the study nurse and reduce physical activity. Fisher exact test was used to evaluate the effect of the intervention on the proportion of subjects with a foot ulcer. Kaplan-Meier survival analysis was performed to compare the two groups in regard to the time to development of a foot ulcer.

Results

In the intervention group, 67 % (n?=?14/21) monitored and recorded skin temperatures ≥80 % of the time while 70 % (n?=?14/20) of the controls recorded foot inspections. Foot ulcer incidence was 39 % (7/21) vs. 50 % (10/20) in the intervention and control groups, respectively (ns).

Conclusions

This feasibility study showed that the addition of counselling to promote self-monitoring of skin temperature to standard care to prevent recurrence of foot ulcer is feasible in patients with diabetes in Norway. Home skin temperature monitoring was performed as frequently by the intervention group as usual foot observations in the controls despite the extra effort required. We did not detect a difference in foot ulcer recurrence between groups, but our study may inform future full scale studies.

Trial registration

Clinicaltrials.gov NCT01269502

     

Apolipoprotein A-I infiltration in rheumatoid arthritis synovial tissue: a control mechanism of cytokine production?

The production of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) by monocytes is strongly induced by direct contact with stimulated T lymphocytes, and this mechanism may be critical in the pathogenesis of rheumatoid arthritis (RA). Apolipoprotein A-I (apoA-I) blocks contact-mediated activation of monocytes, causing inhibition of TNF-α and IL-1β production. This study examined the hypothesis that apoA-I may have a regulatory role at sites of macrophage activation by T lymphocytes in inflamed RA synovial tissue. Synovial tissue samples were obtained after arthroscopy from patients with early untreated RA or treated RA and from normal subjects. As determined by immunohistochemistry, apoA-I was consistently present in inflamed synovial tissue that contained infiltrating T cells and macrophages, but it was absent from noninflamed tissue samples obtained from treated patients and from normal subjects. ApoA-I staining was abundant in the perivascular areas and extended in a halo-like pattern to the surrounding cellular infiltrate. C-reactive protein and serum amyloid A were not detected in the same perivascular areas of inflamed tissues. The abundant presence of apoA-I in the perivascular cellular infiltrates of inflamed RA synovial tissue extends the observations in vitro that showed that apoA-I can modify contact-mediated macrophage production of TNF-α and IL-1β. ApoA-I was not present in synovium from patients in apparent remission, suggesting that it has a specific role during phases of disease activity. These findings support the suggestion that the biologic properties of apoA-I, about which knowledge is newly emerging, include anti-inflammatory activities and therefore have important implications for the treatment of chronic inflammatory diseases.