Enhancing intestinal anastomotic healing using butyrate: Systematic review and meta-analysis of experimental animal studies.

BACKGROUND: Despite advancements in surgical technique and perioperative care, intestinal anastomoses still have a 10-15 per cent risk of leakage, which results in considerable morbidity and/or mortality. Recent animal studies have suggested that administration of butyrate to the anastomotic site results in enhanced anastomotic strength, which may prevent leakage. This systematic review and meta-analysis summarises current evidence concerning the effect of butyrate administration on anastomotic healing and will form a scientific basis for the development of new research into this subject. METHODS: Animal studies on the effect of butyrate-based interventions in models of intestinal anastomotic healing were systematically retrieved from online databases. Bibliographical data, study characteristics and outcome data were extracted, and internal validity of the studies was assessed. Outcomes studied through meta-analysis concerned: anastomotic strength, anastomotic leakage, collagen metabolism and general histologic parameters of wound healing. RESULTS: A comprehensive search and selection identified 19 relevant studies containing 41 individual comparisons. Design and conduct of most experiments were poorly reported resulting in an unclear risk of bias. Meta-analyses showed that butyrate administration significantly increases anastomotic strength (SMD 1.24, 0.88 to 1.61), collagen synthesis (SMD 1.44, 0.72 to 2.15) and collagen maturation, making anastomoses less prone to leakage in the early postoperative period (OR 0.37, 0.15 to 0.93). CONCLUSION: This systematic review and meta-analysis shows that there is potential ground to investigate the use of butyrate in clinical trials to prevent anastomotic leakage in intestinal surgery. However, more research is necessary to define the best application form, dosage and administration route.

The effect of age on resilience of health-related quality of life among polytrauma patients: a cross-sectional multicenter study.

PURPOSE: The aim of this study was to determine the impact of age on patient-reported health-related quality of life (HRQoL) and the capacity to show resilience-i.e., the ability to adapt to stressful adverse events-after sustaining a polytrauma. METHODS: A cross-sectional multicenter cohort was conducted between 2013 and 2016 that included surviving polytrauma patients (ISS ≥ 16). HRQoL was obtained by the Short Musculoskeletal Function assessment and EuroQol (SMFA and EQ-5D-5L). The effect of age on HRQoL was tested with linear regression analysis. Next, the individual scores were compared with age- and sex-matched normative data to determine whether they showed resilience. Multivariate binary logistic regression was used to assess the effect of age on reaching the normative threshold of the surveys, correcting for several confounders. RESULTS: A total of 363 patients responded (57%). Overall, patients had a mean EQ-5D-5L score of 0.73. With higher age, scores on the SMFA subscales "upper extremity dysfunction," "lower extremity dysfunction" and "daily activities" significantly dropped. Only 42% of patients were classified as being resilient, based on the EQ-5D-5L score. Patients aged 60-69 showed the highest resilience (56%), and those aged 80 + showed the lowest resilience (0%). CONCLUSION: Sustaining a polytrauma leads to a serious decline in HRQoL. Aging is associated with a decline in the physical components of HRQoL. No clear relationship with age was seen on the non-physical components of quality of life. Octogenarians, and to a lesser extent septuagenarians and tricenarians, showed to be very vulnerable groups, with low rates of resilience after surviving a polytrauma.

Translational validity and methodological underreporting in animal research: A systematic review and meta-analysis of the Fragile X syndrome (Fmr1 KO) rodent model.

Predictive models are essential for advancing knowledge of brain disorders. High variation in study outcomes hampers progress. To address the validity of predictive models, we performed a systematic review and meta-analysis on behavioural phenotypes of the knock-out rodent model for Fragile X syndrome according to the PRISMA reporting guidelines. In addition, factors accountable for the heterogeneity between findings were analyzed. The knock-out model showed good translational validity and replicability for hyperactivity, cognitive and seizure phenotypes. Despite low replicability, translational validity was also found for social behaviour and sensory sensitivity, but not for attention, aggression and cognitive flexibility. Anxiety, acoustic startle and prepulse inhibition phenotypes, despite low replicability, were opposite to patient symptomatology. Subgroup analyses for experimental factors moderately explain the low replicability, these analyses were hindered by under-reporting of methodologies and environmental conditions. Together, the model has translational validity for most clinical phenotypes, but caution must be taken due to low effect sizes and high inter-study variability. These findings should be considered in view of other rodent models in preclinical research.

Burn-Induced Local and Systemic Immune Response: Systematic Review and Meta-Analysis of Animal Studies.

Because burn injuries are often followed by a derailed immune response and excessive inflammation, a thorough understanding of the occurring reactions is key to preventing secondary complications. This systematic review, which includes 247 animal studies, shows the postburn response of 14 different immune cell types involved in immediate and long-term effects in both wound tissue and circulation. Peripheral blood neutrophil and monocyte numbers increased directly after burns, whereas thrombocyte numbers increased near the end of the first week. However, lymphocyte numbers were decreased for at least 2 weeks. In burn wound tissue, neutrophil and macrophage numbers accumulated during the first 3 weeks. Burns also altered cellular functions because we found an increased migratory potential of leukocytes, impaired antibacterial activity of neutrophils, and enhanced inflammatory mediator production by macrophages. Neutrophil surges were positively associated with burn size and were highest in rats. Altogether, this comprehensive overview of the temporal immune cell dynamics shows that unlike normal wound healing, burn injury induces a long-lasting inflammatory response. It provides a fundamental research basis to improve experimental set-ups, burn care, and outcomes.

Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks.

The workshop titled "Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks" was co-organized by the Evidence-based Toxicology Collaboration and the European Food Safety Authority (EFSA) and hosted by EFSA at its headquarters in Parma, Italy on October 2 and 3, 2019. The goal was to explore integration of systematic review with mechanistic evidence evaluation. Participants were invited to work on concrete products to advance the exploration of how evidence-based approaches can support the development and application of adverse outcome pathways (AOP) in chemical risk assessment. The workshop discussions were centered around three related themes: 1) assessing certainty in AOPs, 2) literature-based AOP development, and 3) integrating certainty in AOPs and non-animal evidence into decision frameworks. Several challenges, mostly related to methodology, were identified and largely determined the workshop recommendations. The workshop recommendations included the comparison and potential alignment of processes used to develop AOP and systematic review methodology, including the translation of vocabulary of evidence-based methods to AOP and vice versa, the development and improvement of evidence mapping and text mining methods and tools, as well as a call for a fundamental change in chemical risk and uncertainty assessment methodology if to be conducted based on AOPs and new approach methodologies (NAM). The usefulness of evidence-based approaches for mechanism-based chemical risk assessments was stressed, particularly the potential contribution of the rigor and transparency inherent to such approaches in building stakeholders' trust for implementation of NAM evidence and AOPs into chemical risk assessment.

A systematic review and meta-analysis on the use of fibrin glue in peripheral nerve repair: Can we just glue it?

BACKGROUND: Within the field of peripheral nerve surgery, the use of fibrin glue as an alternative to conventional microsurgical suture repair is becoming increasingly popular. Advantages of fibrin glue for nerve reconstruction include technical ease of use, less tissue manipulation, and shorter operation times. Although fibrin glue seems a promising alternative to conventional microsurgical repair, further insight into the outcomes of nerve recovery is essential. OBJECTIVE: To summarize the current literature on the use of fibrin glue for peripheral nerve repair and compare these results with outcomes following conventional suture repair. METHODS: A systematic search in Embase, MEDLINE, Web of Science, Cochrane, and Google Scholar databases was performed. The search included animal, cadaveric, and human studies assessing outcomes following peripheral nerve repair using fibrin glue. Data on outcomes were subdivided into functional outcomes, electrophysiology, histopathology, biomechanical outcomes, and operation times. We calculated standardized mean differences and combined these in a random effects model to estimate the overall effect. RESULTS: From a total of 2057 references, 37 animal, two cadaveric, and four human studies were included. Fibrin glue repairs resulted in similar functional and electrophysiology outcomes and shorter operation times than suture repairs. However, fibrin glue alone resulted in lower strength and more dehiscence. No dehiscence was reported when fibrin glue was combined with one or two sutures. Yet, we also found that methodological details were poorly reported in animal studies, resulting in an unclear risk of bias. This should be taken into consideration when interpreting the results. CONCLUSION: The results indicate that nerve regeneration may be similar in fibrin glue repairs and suture repairs. Combining fibrin glue with one or two positional sutures allows for a precise realignment of the nerve fibers and seems to provide sufficient strength to prevent dehiscence.

Animal studies for the evaluation of in situ tissue-engineered vascular grafts - a systematic review, evidence map, and meta-analysis.

Vascular in situ tissue engineering (TE) is an approach that uses bioresorbable grafts to induce endogenous regeneration of damaged blood vessels. The evaluation of newly developed in situ TE vascular grafts heavily relies on animal experiments. However, no standard for in vivo models or study design has been defined, hampering inter-study comparisons and translational efficiency. To provide input for formulating such standard, the goal of this study was to map all animal experiments for vascular in situ TE using off-the-shelf available, resorbable synthetic vascular grafts. A literature search (PubMed, Embase) yielded 15,896 studies, of which 182 studies met the inclusion criteria (n = 5,101 animals). The reports displayed a wide variety of study designs, animal models, and biomaterials. Meta-analysis on graft patency with subgroup analysis for species, age, sex, implantation site, and follow-up time demonstrated model-specific variations. This study identifies possibilities for improved design and reporting of animal experiments to increase translational value.

Guidance document on Good Cell and Tissue Culture Practice 2.0 (GCCP 2.0).

Good Cell and Tissue Culture Practice (GCCP) 2.0 is an updated guidance document from GCCP 1.0 (published by ECVAM in 2005), which was developed for practical use in the laboratory to assure the reproducibility of in vitro (cell-based) work. The update in the guidance was essential as cell models have advanced dramatically to more complex culture systems and need more comprehensive quality management to ensure reproducibility and high-quality scientific data. This document describes six main principles to consider when performing cell culture including characterization and maintenance of essential characteristics, quality management, documentation and reporting, safety, education and training, and ethics. The document does not intend to impose detailed procedures but to describe potential quality issues. It is foreseen that the document will require further updates as the science and technologies evolve over time.

Osteoblast-osteoclast co-cultures: A systematic review and map of available literature.

Drug research with animal models is expensive, time-consuming and translation to clinical trials is often poor, resulting in a desire to replace, reduce, and refine the use of animal models. One approach to replace and reduce the use of animal models is to use in vitro cell-culture models. To study bone physiology, bone diseases and drugs, many studies have been published using osteoblast-osteoclast co-cultures. The use of osteoblast-osteoclast co-cultures is usually not clearly mentioned in the title and abstract, making it difficult to identify these studies without a systematic search and thorough review. As a result, researchers are all developing their own methods, leading to conceptually similar studies with many methodological differences and, as a consequence, incomparable results. The aim of this study was to systematically review existing osteoblast-osteoclast co-culture studies published up to 6 January 2020, and to give an overview of their methods, predetermined outcome measures (formation and resorption, and ALP and TRAP quantification as surrogate markers for formation and resorption, respectively), and other useful parameters for analysis. Information regarding these outcome measures was extracted and collected in a database, and each study was further evaluated on whether both the osteoblasts and osteoclasts were analyzed using relevant outcome measures. From these studies, additional details on methods, cells and culture conditions were extracted into a second database to allow searching on more characteristics. The two databases presented in this publication provide an unprecedented amount of information on cells, culture conditions and analytical techniques for using and studying osteoblast-osteoclast co-cultures. They allow researchers to identify publications relevant to their specific needs and allow easy validation and comparison with existing literature. Finally, we provide the information and tools necessary for others to use, manipulate and expand the databases for their needs.

The poly(I:C)-induced maternal immune activation model; a systematic review and meta-analysis of cytokine levels in the offspring.

The maternal polyinosinic:polycytidylic acid (poly(I:C)) animal model is frequently used to study how maternal immune activation may impact neuro development in the offspring. Here, we present the first systematic review and meta-analysis on the effects of maternal poly(I:C) injection on immune mediators in the offspring and provide an openly accessible systematic map of the data including methodological characteristics. Pubmed and EMBASE were searched for relevant publications, yielding 45 unique papers that met inclusion criteria. We extracted data on immune outcomes and methodological characteristics, and assessed the risk of bias. The descriptive summary showed that most studies reported an absence of effect, with an equal number of studies reporting an increase or decrease in the immune mediator being studied. Meta-analysis showed increased IL-6 concentrations in the offspring of poly(I:C) exposed mothers. This effect appeared larger prenatally than post-weaning. Furthermore, poly(I:C) administration during mid-gestation was associated with higher IL-6 concentrations in the offspring. Maternal poly(I:C) induced changes in IL-1ß, Il-10 and TNF-α concentrations were small and could not be associated with age of offspring, gestational period or sampling location. Finally, quality of reporting of potential measures to minimize bias was low, which stresses the importance of adherence to publication guidelines. Since neurodevelopmental disorders in humans tend to be associated with lifelong changes in cytokine concentrations, the absence of these effects as identified in this systematic review may suggest that combining the model with other etiological factors in future studies may provide further insight in the mechanisms through which maternal immune activation affects neurodevelopment.

Effects of Radiofrequency Electromagnetic Field (RF-EMF) exposure on male fertility and pregnancy and birth outcomes: Protocols for a systematic review of experimental studies in non-human mammals and in human sperm exposed in vitro.

BACKGROUND: Radiofrequency Electromagnetic Fields (RF-EMF) at environmental level have been reported to induce adverse effects on the male reproductive system and developing embryos. However, despite the number of experiments conducted since the 1970s, the diversity of testing approaches and exposure conditions, inconsistencies among results, and dosimetric flaws have not yet permitted a solid assessment of the relationship between RF-EMF exposure and such effects, warranting a more systematic and methodologically rigorous approach to the evaluation of available data. OBJECTIVES: This study aims at evaluating the effects of RF-EMF exposure on male fertility and pregnancy outcomes by a systematic review (SR) of experimental studies, conducted in compliance with international guidelines. The evidence will be organized into three streams: 1) Studies evaluating the impact of RF-EMF on the male reproductive system of experimental mammals; 2) studies evaluating the impact of RF-EMF on human sperm exposed in vitro; 3) studies evaluating the impact of RF-EMF on adverse pregnancy, birth outcomes and delayed effects in experimental mammals exposed in utero. STUDY ELIGIBILITY AND CRITERIA: Eligible studies will include peer-reviewed articles reporting of original results about effects of controlled exposures to RF-EMF in the frequency range 100 kHz-300 GHz on the selected outcomes without any language or year-of-publication restrictions. Eligible studies will be retrieved by calibrated search strings applied to three electronic databases, PubMed, Scopus and EMF Portal and by manual search of the list of references of included papers and published reviews. STUDY APPRAISAL AND SYNTHESIS METHOD: The internal validity of the studies will be evaluated using the Risk of Bias (RoB) Rating Tool developed by National Toxicology Program/Office of Health Assessment and Translation (NTP/OHAT) integrated with input from the SYRCLE RoB tool. Given sufficient commensurate data, meta-analyses will be performed, otherwise narrative syntheses will be produced. Finally, the certainty of the effects of RF-EMF exposure on male fertility and pregnancy and birth outcomes will be established following GRADE. FUNDING: The study is financially supported by the World Health Organization. REGISTRATION: OSF Registration DOI https://doi.org/10.17605/OSF.IO/7MUS3; PROSPERO CRD42021227729, CRD42021227746.

Effects of joint and nerve mobilisation on neuroimmune responses in animals and humans with neuromusculoskeletal conditions: a systematic review and meta-analysis.

Several animal and human studies revealed that joint and nerve mobilisations positively influence neuroimmune responses in neuromusculoskeletal conditions. However, no systematic review and meta-analysis has been performed. Therefore, this study aimed to synthesize the effects of joint and nerve mobilisation compared with sham or no intervention on neuroimmune responses in animals and humans with neuromusculoskeletal conditions. Four electronic databases were searched for controlled trials. Two reviewers independently selected studies, extracted data, assessed the risk of bias, and graded the certainty of the evidence. Where possible, meta-analyses using random effects models were used to pool the results. Preliminary evidence from 13 animal studies report neuroimmune responses after joint and nerve mobilisations. In neuropathic pain models, meta-analysis revealed decreased spinal cord levels of glial fibrillary acidic protein, dorsal root ganglion levels of interleukin-1ß, number of dorsal root ganglion nonneuronal cells, and increased spinal cord interleukin-10 levels. The 5 included human studies showed mixed effects of spinal manipulation on salivary/serum cortisol levels in people with spinal pain, and no significant effects on serum ß-endorphin or interleukin-1ß levels in people with spinal pain. There is evidence that joint and nerve mobilisations positively influence various neuroimmune responses. However, as most findings are based on single studies, the certainty of the evidence is low to very low. Further studies are needed.

A Systematic Review to Compare Chemical Hazard Predictions of the Zebrafish Embryotoxicity Test With Mammalian Prenatal Developmental Toxicity.

Originally developed to inform the acute toxicity of chemicals on fish, the zebrafish embryotoxicity test (ZET) has also been proposed for assessing the prenatal developmental toxicity of chemicals, potentially replacing mammalian studies. Although extensively evaluated in primary studies, a comprehensive review summarizing the available evidence for the ZET's capacity is lacking. Therefore, we conducted a systematic review of how well the presence or absence of exposure-related findings in the ZET predicts prenatal development toxicity in studies with rats and rabbits. A two-tiered systematic review of the developmental toxicity literature was performed, a review of the ZET literature was followed by one of the mammalian literature. Data were extracted using DistillerSR, and study validity was assessed with an amended SYRCLE's risk-of-bias tool. Extracted data were analyzed for each species and substance, which provided the basis for comparing the 2 test methods. Although limited by the number of 24 included chemicals, our results suggest that the ZET has potential to identify chemicals that are mammalian prenatal developmental toxicants, with a tendency for overprediction. Furthermore, our analysis confirmed the need for further standardization of the ZET. In addition, we identified contextual and methodological challenges in the application of systematic review approaches to toxicological questions. One key to overcoming these challenges is a transition to more comprehensive and transparent planning, conduct and reporting of toxicological studies. The first step toward bringing about this change is to create broad awareness in the toxicological community of the need for and benefits of more evidence-based approaches.

Quantifying single-cell ERK dynamics in colorectal cancer organoids reveals EGFR as an amplifier of oncogenic MAPK pathway signalling.

Direct targeting of the downstream mitogen-activated protein kinase (MAPK) pathway to suppress extracellular-regulated kinase (ERK) activation in KRAS and BRAF mutant colorectal cancer (CRC) has proven clinically unsuccessful, but promising results have been obtained with combination therapies including epidermal growth factor receptor (EGFR) inhibition. To elucidate the interplay between EGF signalling and ERK activation in tumours, we used patient-derived organoids (PDOs) from KRAS and BRAF mutant CRCs. PDOs resemble in vivo tumours, model treatment response and are compatible with live-cell microscopy. We established real-time, quantitative drug response assessment in PDOs with single-cell resolution, using our improved fluorescence resonance energy transfer (FRET)-based ERK biosensor EKAREN5. We show that oncogene-driven signalling is strikingly limited without EGFR activity and insufficient to sustain full proliferative potential. In PDOs and in vivo, upstream EGFR activity rigorously amplifies signal transduction efficiency in KRAS or BRAF mutant MAPK pathways. Our data provide a mechanistic understanding of the effectivity of EGFR inhibitors within combination therapies against KRAS and BRAF mutant CRC.

Applying evidence-based methods to the development and use of adverse outcome pathways

The workshop "Application of evidence-based methods to construct mechanistic frameworks for the development and use of non-animal toxicity tests" was organized by the Evidence-based Toxicology Collaboration and hosted by the Grading of Recommendations Assessment, Development and Evaluation Working Group on June 12, 2019. The purpose of the workshop was to bring together international regulatory bodies, risk assessors, academic scientists, and industry to explore how systematic review methods and the adverse outcome pathway framework could be combined to develop and use mechanistic test methods for predicting the toxicity of chemical substances in an evidence-based manner. The meeting covered the history of biological frameworks, the way adverse outcome pathways are currently developed, the basic principles of systematic methodology, including systematic reviews and evidence maps, and assessment of cer­tainty in models, and adverse outcome pathways in particular. Specific topics were discussed via case studies in small break-out groups. The group concluded that adverse outcome pathways provide an important framework to support mechanism-based assessment in environmental health. The process of their development has a few challenges that could be addressed with systematic methods and automation tools. Addressing these challenges will increase the transparency of the evidence behind adverse outcome pathways and the consistency with which they are defined; this in turn will increase their value for supporting public health decisions. It was suggested to explore the details of applying systematic methods to adverse outcome pathway development in a series of case studies and workshops.

Animal models for cystic fibrosis: a systematic search and mapping review of the literature. Part 2: nongenetic models.

Various animal models are available to study cystic fibrosis (CF). These models may help to enhance our understanding of the pathology and contribute to the development of new treatments. We systematically searched all publications on CF animal models. Because of the large number of models retrieved, we split this mapping review into two parts. Previously, we presented the genetic CF animal models. In this paper we present the nongenetic CF animal models. While genetic animal models may, in theory, be preferable for genetic diseases, the phenotype of a genetic model does not automatically resemble human disease. Depending on the research question, other animal models may thus be more informative.We searched Pubmed and Embase and identified 12,303 unique publications (after duplicate removal). All references were screened for inclusion by two independent reviewers. The genetic animal models for CF (from 636 publications) were previously described. The non-genetic CF models (from 189 publications) are described in this paper, grouped by model type: infection-based, pharmacological, administration of human materials, xenografts and other. As before for the genetic models, an overview of basic model characteristics and outcome measures is provided. This CF animal model overview can be the basis for an objective, evidence-based model choice for specific research questions. Besides, it can help to retrieve relevant background literature on outcome measures of interest.

Immune responses to azacytidine in animal models of inflammatory disorders: a systematic review.

Inflammatory disorders like diabetes, systemic lupus erythematodes, inflammatory lung diseases, rheumatoid arthritis and multiple sclerosis, but also rejection of transplanted organs and GvHD, form a major burden of disease. Current classes of immune suppressive drugs to treat these disorders are never curative and side effects are common. Therefore there is a need for new drugs with improved and more targeted modes of action. Potential candidates are the DNA methyl transferase inhibitor 5-azacytidine (Aza) and its derivative 5-aza 2'deoxycitidine (DAC). Aza and DAC have been tested in several pre-clinical in vivo studies. In order to obtain an overview of disorders for which Aza and/or DAC can be a potential treatment, and to find out where information is lacking, we systematically reviewed pre-clinical animal studies assessing Aza or DAC as a potential therapy for distinct inflammatory disorders. Also, study quality and risk of bias was systematically assessed. In the 35 identified studies, we show that both Aza and DAC do not only seem to be able to alleviate a number of inflammatory disorders, but also prevent solid organ rejection and GvHD in in vivo pre-clinical animal models. Aza/DAC are known to upregulate FOXP3, a master transcription factor for Treg, in vitro. Seventeen studies described the effect on Treg, of which 16 studies showed an increase in Treg. Increasing Treg therefore seems to be a common mechanism in preventing inflammatory disorders by Aza/DAC. We also found, however, that many essential methodological details were poorly reported leading to an unclear risk of bias. Therefore, reported effects might be an overestimation of the true effect.

Genetic variants and expression changes in urgency urinary incontinence: A systematic review.

AIM: To perform a systematic review summarizing the knowledge of genetic variants, gene, and protein expression changes in humans and animals associated with urgency urinary incontinence (UUI) and to provide an overview of the known molecular mechanisms related to UUI. METHODS: A systematic search was performed on March 2, 2020, in PubMed, Embase, Web of Science, and the Cochrane library. Retrieved studies were screened for eligibility. The risk of bias was assessed using the ROBINS-I (human) and SYRCLE (animal) tool. Data were presented in a structured manner and in the case of greater than five studies on a homogeneous outcome, a meta-analysis was performed. RESULTS: Altogether, a total of 10,785 records were screened of which 37 studies met the inclusion criteria. Notably, 24/37 studies scored medium-high to high on risk of bias, affecting the value of the included studies. The analysis of 70 unique genes and proteins and three genome-wide association studies showed that specific signal transduction pathways and inflammation are associated with UUI. A meta-analysis on the predictive value of urinary nerve growth factor (NGF) levels showed that increased urinary NGF levels correlate with UUI. CONCLUSION: The collective evidence showed the involvement of two molecular mechanisms (signal transduction and inflammation) and NGF in UUI, enhancing our understanding of the pathophysiology of UUI. Unfortunately, the risk of bias was medium-high to high for most studies and the value of many observations remains unclear. Future studies should focus on elucidating how deficits in the two identified molecular mechanisms contribute to UUI and should avoid bias.

Bioinorganic supplementation of calcium phosphate-based bone substitutes to improve in vivo performance: a systematic review and meta-analysis of animal studies.

Supplementation of CaP-based bone graft substitutes with bioinorganics such as strontium, zinc or silicon is an interesting approach to increase the biological performance in terms of bone regenerative potential of calcium phosphate (CaP)-based bone substitutes. However, the in vivo efficacy of this approach has not been systematically analyzed, yet. Consequently, we performed a systematic review using the available literature regarding the effect of bioinorganic supplementation in CaP-based biomaterials on new bone formation and material degradation in preclinical animal bone defect models and studied this effect quantitatively by performing a meta-analysis. Additional subgroup analyses were used to study the effect of different bioinorganics, animal model, or phase category of CaP-based biomaterial on bone formation or material degradation. Results show that bioinorganic supplementation increases new bone formation (standardized mean difference [SMD]: 1.43 SD, confidence interval [CI]: 1.13-1.73). Additional subgroup analysis showed that strontium, magnesium and silica significantly enhanced bone formation, while zinc did not have any effect. This effect of bioinorganic supplementation on new bone formation was stronger for DCPD or ß-TCP and biphasic CaPs than for HA or α-TCP (p < 0.001). In general, material degradation was slightly hindered by bioinorganic supplementation (mean difference [MD]: 0.84%, CI: 0.01-1.66), with the exception of strontium that significantly enhanced degradation. Overall, bioinorganic supplementation represents an effective approach to enhance the biological performance of CaP-based bone substitutes.

Recommendations for the conduct of systematic reviews in toxicology and environmental health research (COSTER).

BACKGROUND: There are several standards that offer explicit guidance on good practice in systematic reviews (SRs) for the medical sciences; however, no similarly comprehensive set of recommendations has been published for SRs that focus on human health risks posed by exposure to environmental challenges, chemical or otherwise. OBJECTIVES: To develop an expert, cross-sector consensus view on a key set of recommended practices for the planning and conduct of SRs in the environmental health sciences. METHODS: A draft set of recommendations was derived from two existing standards for SRs in biomedicine and developed in a consensus process, which engaged international participation from government, industry, non-government organisations, and academia. The consensus process consisted of a workshop, follow-up webinars, email discussion and bilateral phone calls. RESULTS: The Conduct of Systematic Reviews in Toxicology and Environmental Health Research (COSTER) recommendations cover 70 SR practices across eight performance domains. Detailed explanations for specific recommendations are made for those identified by the authors as either being novel to SR in general, specific to the environmental health SR context, or potentially controversial to environmental health SR stakeholders. DISCUSSION: COSTER provides a set of recommendations that should facilitate the production of credible, high-value SRs of environmental health evidence, and advance discussion of a number of controversial aspects of conduct of EH SRs. Key recommendations include the management of conflicts of interest, handling of grey literature, and protocol registration and publication. A process for advancing from COSTER's recommendations to developing a formal standard for EH SRs is also indicated.