Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria

With the availability of new preventive and curative interventions, global malaria control has been strengthened significantly in recent years. Drugs effective in reducing malaria gametocytaemia might contribute to local elimination and possible long-term eradication. We here report on the effects of methylene blue (MB)-based malaria combination therapy on gametocytaemia during a randomised-controlled trial in Burkina Faso. An open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria was conducted in Nouna, north-western Burkina Faso. Children were randomised to MB-artesunate (AS), MB-amodiaquine (AQ), and AS-AQ (local standard of care). Overall follow-up was for 28 days, follow-up for gametocytaemia was for 14 days. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. Compared to AS-AQ, both MB-containing regimens were associated with significantly reduced gametocyte carrier rates during follow-up days 3, 7, and 14. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline. MB reveals pronounced gametocytocidal activity which appears to act against both existing and developing P. falciparum gametocytes. MB-based combination therapy thus has the potential to reduce transmission of P. falciparum malaria in endemic regions, which has important implications for future elimination and eradication strategies

Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated falciparum malaria

Besides existing artemisinin-based combination therapies, alternative safe, effective and affordable drug combinations against falciparum malaria are needed. Methylene blue (MB) was the first synthetic antimalarial drug ever used, and recent studies have been promising with regard to its revival in malaria therapy. The objective of this study was to assess the safety and efficacy of two MB-based malaria combination therapies, MB-artesunate (AS) and MB-amodiaquine (AQ), compared to the local standard of care, AS-AQ, in Burkina Faso. Open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria in Nouna, north-western Burkina Faso. Follow-up was for 28 days and analysis by intention-to-treat. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. No drug-related serious adverse events and no deaths occurred. MB-containing regimens were associated with mild vomiting and dysuria. No early treatment failures were observed. Parasite clearance time differed significantly among groups and was the shortest with MB-AS. By day 14, the rates of adequate clinical and parasitological response after PCR-based correction for recrudescence were 87% for MB-AS, 100% for MB-AQ (p = 0.004), and 100% for AS-AQ (p = 0.003). By day 28, the respective figure was lowest for MB-AS (62%), intermediate for the standard treatment AS-AQ (82%; p = 0.015), and highest for MB-AQ (95%; p<0.001; p = 0.03). MB-AQ is a promising alternative drug combination against malaria in Africa. Moreover, MB has the potential to further accelerate the rapid parasite clearance of artemisinin-based combination therapies. More than a century after the antimalarial properties of MB had been described, its role in malaria control deserves closer attention. ClinicalTrials.gov NCT00354380

Surgical versus dilational tracheostomy in patients with severe stroke: a SETPOINT2 post hoc analysis

Background Tracheostomy in mechanically ventilated patients with severe stroke can be performed surgically or dilationally. Prospective data comparing both methods in patients with stroke are scarce. The randomized Stroke-Related Early Tracheostomy vs Prolonged Orotracheal Intubation in Neurocritical Care Trial2 (SETPOINT2) assigned 382 mechanically ventilated patients with stroke to early tracheostomy versus extubation or standard tracheostomy. Surgical tracheostomy (ST) was performed in 41 of 307 SETPOINT2 patients, and the majority received dilational tracheostomy (DT). We aimed to compare ST and DT in these patients with patients. Methods All SETPOINT2 patients with ST were compared with a control group of patients with stroke undergoing DT (1:2), selected by propensity score matching that included the factors stroke type, SETPOINT2 randomization group, Stroke Early Tracheostomy score, patient age, and premorbid functional status. Successful decannulation was the primary outcome, and secondary outcome parameters included functional outcome at 6 months and adverse events attributable to tracheostomy. Potential predictors of decannulation were evaluated by regression analysis. Results Baseline characteristics were comparable in the two groups of patients with stroke undergoing ST (n = 41) and matched patients with stroke undergoing DT (n = 82). Tracheostomy was performed significantly later in the ST group than in the DT group (median 9 [interquartile range {IQR} 5–12] vs. 9 [IQR 4–11] days after intubation, p = 0.025). Patients with ST were mechanically ventilated longer (median 19 [IQR 17–24] vs.14 [IQR 11–19] days, p = 0.008) and stayed in the intensive care unit longer (median 23 [IQR 16–27] vs. 17 [IQR 13–24] days, p = 0.047), compared with patients with DT. The intrahospital infection rate was significantly higher in the ST group compared to the DT group (14.6% vs. 1.2%, p = 0.002). At 6 months, decannulation rates (56% vs. 61%), functional outcomes, and mortality were not different. However, decannulation was performed later in the ST group compared to the DT group (median 81 [IQR 66–149] vs. 58 [IQR 32–77] days, p = 0.004). Higher baseline Stroke Early Tracheostomy score negatively predicted decannulation. Conclusions In ventilated patients with severe stroke in need of tracheostomy, surgical and dilational methods are associated with comparable decannulation rate and functional outcome at 6 months. However, ST was associated with longer time to decannulation and higher rates of early infections, supporting the dilational approach to tracheostomy in ventilated patients with stroke

Seroprevalence of Measles-, Mumps-, and Rubella-specific antibodies in the German adult population – cross-sectional analysis of the German Health Interview and Examination Survey for Adults (DEGS1)

Background: The WHO European Region targets the elimination of measles, rubella, and the congenital rubella syndrome and welcomes mumps elimination via the joint MMR vaccine. In a push towards this elimination goal, Germany introduced a recommendation on MMR vaccination for adults in 2010 to prevent increasing numbers of measles cases among adults and to strengthen herd immunity. Methods: The prevalence of anti-measles, -mumps, and -rubella IgG antibodies was analysed in 7,115 participants between the ages of 18 and 79 years in the German Health Interview and Examination Survey. Risk factors of seronegativity of adults born 1970 or later were determined. Findings: The seroprevalence of anti-measles IgG antibodies was more than 97% in adults born before 1965 and less than 90% in adults born afterwards. Prevalence and GMTs declined with later years of birth. Seronegativity was associated with two-sided migration background and region of residence in East Germany. For anti-mumps IgG antibodies, the seroprevalence was less than 90% in almost all age groups. Prevalence and GMTs declined with later years of birth. Seronegativity was not associated with any socio-demographic factor. Anti-rubella IgG seropositivity was found in more than 90% of adults born before 1985. GMTs declined in younger age groups. Seronegativity was associated with birth between 1980 and 1993 and male gender. High socio-economic status lowered the odds of being seronegative. Interpretation: These data reinforce the implementation of the vaccination recommendation for adults and provide the basis for further evaluation of this measure. Funding: The Federal Ministry of Health, Germany.Peer Reviewe

In vivo investigation of open-pored magnesium scaffolds LAE442 with different coatings in an open wedge defect

The magnesium alloy LAE442 showed promising results as a bone substitute in numerous studies in non-weight bearing bone defects. This study aimed to investigate the in vivo behavior of wedge-shaped open-pored LAE442 scaffolds modified with two different coatings (magnesium fluoride (MgF2, group 1)) or magnesium fluoride/calcium phosphate (MgF2/CaP, group 2)) in a partial weight-bearing rabbit tibia defect model. The implantation of the scaffolds was performed as an open wedge corrective osteotomy in the tibia of 40 rabbits and followed for observation periods of 6, 12, 24, and 36 weeks. Radiological and microcomputed tomographic examinations were performed in vivo. X-ray microscopic, histological, histomorphometric, and SEM/EDS analyses were performed at the end of each time period. µCT measurements and X-ray microscopy showed a slight decrease in volume and density of the scaffolds of both coatings. Histologically, endosteal and periosteal callus formation with good bridging and stabilization of the osteotomy gap and ingrowth of bone into the scaffold was seen. The MgF2 coating favored better bridging of the osteotomy gap and more bone-scaffold contacts, especially at later examination time points. Overall, the scaffolds of both coatings met the requirement to withstand the loads after an open wedge corrective osteotomy of the proximal rabbit tibia. However, in addition to the inhomogeneous degradation behavior of individual scaffolds, an accumulation of gas appeared, so the scaffold material should be revised again regarding size dimension and composition

Strong Gametocytocidal Effect of Methylene Blue-Based Combination Therapy against Falciparum Malaria: A Randomised Controlled Trial

With the availability of new preventive and curative interventions, global malaria control has been strengthened significantly in recent years. Drugs effective in reducing malaria gametocytaemia might contribute to local elimination and possible long-term eradication. We here report on the effects of methylene blue (MB)-based malaria combination therapy on gametocytaemia during a randomised-controlled trial in Burkina Faso.An open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria was conducted in Nouna, north-western Burkina Faso. Children were randomised to MB-artesunate (AS), MB-amodiaquine (AQ), and AS-AQ (local standard of care). Overall follow-up was for 28 days, follow-up for gametocytaemia was for 14 days.The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. Compared to AS-AQ, both MB-containing regimens were associated with significantly reduced gametocyte carrier rates during follow-up days 3, 7, and 14. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline.MB reveals pronounced gametocytocidal activity which appears to act against both existing and developing P. falciparum gametocytes. MB-based combination therapy thus has the potential to reduce transmission of P. falciparum malaria in endemic regions, which has important implications for future elimination and eradication strategies.(ClinicalTrials.gov) NCT00354380

In vivo investigation of open-pored magnesium scaffolds LAE442 with different coatings in an open wedge defect

The magnesium alloy LAE442 showed promising results as a bone substitute in numerous studies in non-weight bearing bone defects. This study aimed to investigate the in vivo behavior of wedge-shaped open-pored LAE442 scaffolds modified with two different coatings (magnesium fluoride (MgF2, group 1)) or magnesium fluoride/calcium phosphate (MgF2/CaP, group 2)) in a partial weight-bearing rabbit tibia defect model. The implantation of the scaffolds was performed as an open wedge corrective osteotomy in the tibia of 40 rabbits and followed for observation periods of 6, 12, 24, and 36 weeks. Radiological and microcomputed tomographic examinations were performed in vivo. X-ray microscopic, histological, histomorphometric, and SEM/EDS analyses were performed at the end of each time period. µCT measurements and X-ray microscopy showed a slight decrease in volume and density of the scaffolds of both coatings. Histologically, endosteal and periosteal callus formation with good bridging and stabilization of the osteotomy gap and ingrowth of bone into the scaffold was seen. The MgF2 coating favored better bridging of the osteotomy gap and more bone-scaffold contacts, especially at later examination time points. Overall, the scaffolds of both coatings met the requirement to withstand the loads after an open wedge corrective osteotomy of the proximal rabbit tibia. However, in addition to the inhomogeneous degradation behavior of individual scaffolds, an accumulation of gas appeared, so the scaffold material should be revised again regarding size dimension and composition

Magnesium Alloys for Open-Pored Bioresorbable Implants

If bone defects occur, the body’s own healing mechanism can close them below a critical size; for larger defects, bone autografts are used. These are typically cut from the same person’s hip in a second surgery. Consequently, the risk of complications, such as inflammations, rises. To avoid the risks resulting from the second surgery, absorbable, open-pored implants can be used. In the present study, the suitability of different magnesium alloys as absorbable porous bone substitute material has been investigated. Using the investment casting process with its design flexibility, the implant’s structure can be adapted to the ideal pore geometry with respect to bone ingrowth behavior. Different magnesium alloys (Mg-La2, LAE442, and ZX61) were studied and rated in terms of their degradation rate, bone ingrowth behavior, biocompatibility, and resorbability of the individual alloying elements

Children of Mentally III Parents at Risk Evaluation (COMPARE): Design and Methods of a Randomized Controlled Multicenter Study—Part I

Objectives: Mental disorders are frequent, associated with disability-adjusted life years, societal, and economic costs. Children of parents with a mental illness (COPMI) are at an increased risk to develop disorders themselves. The transgenerational transmission of mental disorders has been conceptualized in a model that takes parental and family factors, the social environment (i.e., school, work, and social support), parent-child-interaction and possible child outcomes into account. The goal of the “Children of Mentally Ill Parents At Risk Evaluation” (COMPARE) study will thus be twofold: (1) to establish the efficacy and cost-effectiveness of a high-quality randomized controlled trial (RCT) with the aim of interrupting the intergenerational transmission of mental disorders in COPMI, (2) to test the components of the trans-generational transmission model of mental disorders. Methods: To implement a randomized controlled trial (RCT: comparison of parental cognitive behavioral therapy/CBT with CBT + Positive Parenting Program) that is flanked by four add-on projects that apply behavioral, psychophysiological, and neuro-imaging methods to examine potential moderators and mediators of risk transmission (projects COMPARE-emotion/-interaction/-work/-school). COMPARE-emotion targets emotion processing and regulation and its impact on the transgenerational disorder transmission; COMPARE-interaction focuses especially on the impact of maternal comorbid diagnoses of depression and anxiety disorders and will concentrate on different pathways of the impact of maternal disorders on socio-emotional and cognitive infant development, such as parent-infant interaction and the infant's stress regulation skills. COMPARE-work analyzes the transmission of strains a person experiences in one area of life to another (i.e., from family to work; spill-over), and how stress and strain are transmitted between individuals (i.e., from parent to child; cross-over). COMPARE-school focuses on the psychosocial adjustment, school performance, and subjective well-being in COPMI compared to an adequate control group of healthy children. Results: This study protocol reports on the interdisciplinary approach of COMPARE testing the model of the transgenerational transmission of mental disorders. Conclusion: The combination of applied basic with clinical research will facilitate the examination of specific risk transmission mechanisms, promotion, dissemination and implementation of results into a highly important but largely neglected field. Clinical Trial Registration: DRKS-ID: DRKS00013516 (German Clinical Trials Register, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013516)

Intravenous versus epidural analgesia to reduce the incidence of gastrointestinal complications after elective pancreatoduodenectomy (the PAKMAN trial, DRKS 00007784): study protocol for a randomized controlled trial

Background: Despite substantial improvements in surgical and anesthesiological practices leading to decreased mortality of less than 5 % at high-volume centers, pancreatic surgery is still associated with high morbidity rates of up to 50 %. Attention is increasingly directed toward the optimization of perioperative management to reduce complications and enhance postoperative recovery. Currently, two different strategies for postoperative pain management after pancreatoduodenectomy are being routinely used: patient-controlled intravenous analgesia and thoracic epidural analgesia. Evidence is lacking to assess which strategy entails fewer postoperative complications. Methods/design: The PAKMAN trial is designed as an adaptive, pragmatic, randomized, controlled, multicenter, open-label, superiority trial with two parallel study groups. A total of 370 patients scheduled for elective pancreatoduodenectomy will be randomized after giving written informed consent, and 278 patients are needed for analysis. Patients with chronic pancreatitis, severe chronic obstructive pulmonary disease (COPD), American Society of Anesthesiologists (ASA) physical status classification ≥ IV, or chronic pain syndrome will be excluded. The group A intervention includes intraoperative general anesthesia and postoperative patient-controlled intravenous analgesia; the group B intervention comprises combined intraoperative general anesthesia and epidural analgesia with postoperative epidural analgesia. The primary endpoint of this trial is a composite of the gastrointestinal complications (delayed gastric emptying, pancreatic fistula, biliary leak, gastrointestinal bleeding, and postoperative ileus) up to postoperative day 30. The aim is to investigate whether the frequency of gastrointestinal complications following pancreatoduodenectomy can be reduced by 15 % using postoperative, patient-controlled intravenous analgesia compared with epidural analgesia. Discussion: Several previous studies investigating the two different strategies for postoperative pain management have mainly focused on their effectiveness in pain control. However, the PAKMAN trial is the first to compare them with regard to their impact on the surgical endpoint “postoperative gastrointestinal complications” after pancreatoduodenectomy. Trial registration: German Clinical Trials Register, DRKS0000778