3Rs as part of preclinical neuropsychiatric translational crisis, and ARRIVE guidelines as part of solution

2019 ◽  
Vol 31 (6) ◽  
pp. 348-349 ◽  
Author(s):  
Aage Kristian Olsen Alstrup ◽  
Christian Sonne
Keyword(s):  
Systematic Reviews ◽  
Clinical Studies ◽  
Animal Studies ◽  
Brain Diseases ◽  
Preclinical Research ◽  
Experimental Animals ◽  
Accurate Reporting

AbstractObjective:The ongoing translational and reproducibility crisis dominates preclinical research today as results from animal studies often disappoint when transferred to human clinical studies. This problem is especially relevant in the field of brain diseases and translational neuropsychiatry.Methods:Here, we discuss if the 3R concept could be part of the translational crisis.Results:The focus has been on the second R, which is to reduce the variation between the experimental animals, so that the number of animals per study can be reduced. However, the risk of obtaining false results has also increased. We, therefore, recommend that researchers use a broader perspective as also suggest by Russell and Burch who founded the 3Rs when considering the 3R concept, which involves the translational aspects described in detail in their 3R book from 1959.Conclusion:This may together with systematic reviews and well-designed and well-performed animal studies and accurate reporting of the results indeed contribute to solving the translational crisis in preclinical research.

scholarly journals The impact of conducting preclinical systematic reviews on researchers and their research: A mixed method case study

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260619
Author(s):  
Julia M. L. Menon ◽  
Merel Ritskes-Hoitinga ◽  
Pandora Pound ◽  
Erica van Oort
Keyword(s):  
Systematic Reviews ◽  
Animal Studies ◽  
Research Field ◽  
Structured Interviews ◽  
Preclinical Research ◽  
Subsequent Work ◽  
Dutch Health ◽  
Funding Scheme ◽  
The Impact

Background Systematic reviews (SRs) are cornerstones of evidence-based medicine and have contributed significantly to breakthroughs since the 1980’s. However, preclinical SRs remain relatively rare despite their many advantages. Since 2011 the Dutch health funding organisation (ZonMw) has run a grant scheme dedicated to promoting the training, coaching and conduct of preclinical SRs. Our study focuses on this funding scheme to investigate the relevance, effects and benefits of conducting preclinical SRs on researchers and their research. Methods We recruited researchers who attended funded preclinical SR workshops and who conducted, are still conducting, or prematurely stopped a SR with funded coaching. We gathered data using online questionnaires followed by semi-structured interviews. Both aimed to explore the impact of conducting a SR on researchers’ subsequent work, attitudes, and views about their research field. Data-analysis was performed using Excel and ATLAS.ti. Results Conducting preclinical SRs had two distinct types of impact. First, the researchers acquired new skills and insights, leading to a change in mindset regarding the quality of animal research. This was mainly seen in the way participants planned, conducted and reported their subsequent animal studies, which were more transparent and of a higher quality than their previous work. Second, participants were eager to share their newly acquired knowledge within their laboratories and to advocate for change within their research teams and fields of interest. In particular, they emphasised the need for preclinical SRs and improved experimental design within preclinical research, promoting these through education and published opinion papers. Conclusion Being trained and coached in the conduct of preclinical SRs appears to be a contributing factor to many beneficial changes which will impact the quality of preclinical research in the long-term. Our findings suggest that this ZonMw funding scheme is helpful in improving the quality and transparency of preclinical research. Similar funding schemes should be encouraged, preferably by a broader group of funders or financers, in the future.

Comparative Chemical, Biological and Clinical Studies of 99mTc-Glucoheptonate and 99mTc-Dimercaptosucci- nate as Used in Renal Scintigraphy

1979 ◽  
Vol 18 (01) ◽  
pp. 40-45 ◽  
Author(s):  
M. Malešević ◽  
Lj. Stefanović ◽  
N. Vanlić-Razumenić
Keyword(s):  
Clinical Studies ◽  
Gamma Camera ◽  
Radiochemical Purity ◽  
Renal Cortex ◽  
Renal Scintigraphy ◽  
Time Intervals ◽  
Experimental Animals ◽  
Dynamic Studies

The renal radiopharmaceutical preparations 99mTc-DMS and 99mTc-GH were examined chemically, biologically and clinically. Both preparations are of high radiochemical purity. The biodistribution of both preparations was examined in experimental animals at different time intervals, from 15 min to 4 hr; the percentage of incorporation of 99mTc-DMS into kidneys is much higher (29.4% to 52.0%) than that of 99mTc-GH (12.80% to 22.20%). Both preparations accumulate to a greater extent in the renal cortex than in the medulla.The most suitable time for renal scintigraphy for "mTc-DMS is 90-150 min while for 99mTc-GH it is 60-90 min. It is concluded that 99mTc-DMS is more suitable for static scintigrams on the scanner and 99mTc-GH for dynamic studies with the gamma camera.

Anterior Cruciate Ligament Mechanoreceptors and their Potential Importance in Remnant-Preserving Reconstruction: A Review of Basic Science and Clinical Findings

2017 ◽  
Vol 31 (08) ◽  
pp. 736-746 ◽  
Author(s):  
Jonathan Kosy ◽  
Vipul Mandalia
Keyword(s):  
Anterior Cruciate Ligament ◽  
Posterior Cruciate Ligament ◽  
Clinical Studies ◽  
Basic Science ◽  
Animal Studies ◽  
Cruciate Ligament ◽  
Meta Analysis ◽  
Future Research ◽  
Remnant Preservation ◽  
Anterior Cruciate

AbstractMechanoreceptors, within the anterior cruciate ligament (ACL), are believed to have importance in proprioception, contributing to dynamic knee stability. The potential for reinnervation of the ACL graft is one of the proposed advantages of remnant-preserving reconstruction. The aim of this review is to summarize advances in the basic science underpinning this function, alongside recent clinical studies, to define the current role for remnant-preservation.A comprehensive systematic review was performed using PubMed and Medline searches. Studies were analyzed with particular focus placed on the methodology used to either identify mechanoreceptors or test proprioception.Contemporary work, using immunohistological staining, has shown mechanoreceptors primarily within proximity to the bony attachments of the ACL (peripherally in the subsynovial layer). The number of these receptors has been shown to decrease rapidly, following rupture, with adhesion to the posterior cruciate ligament slowing this decline. Recent studies have shown proprioceptive deficits, in both the injured and contralateral knees, with the clinical relevance of findings limited by testing methodology and the small differences found. The advantages of remnant-preservation, seen primarily in animal studies, have not been shown in systematic reviews or meta-analysis of clinical studies.The potential for reinnervation of the graft is likely time-dependent and reliant on continued loading of the remnant. Therefore, current clinical use and future research should focus on preserving remnants within 6 months of injury that remain loaded by adherence to the posterior cruciate ligament. Subsequent testing should account for central neurological changes and focus on clinically relevant outcomes.

scholarly journals A Cell-Based Approach to Dental Pulp Regeneration Using Mesenchymal Stem Cells: A Scoping Review

2021 ◽  
Vol 22 (9) ◽  
pp. 4357
Author(s):  
Sahng G. Kim
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Scoping Review ◽  
Clinical Studies ◽  
Dental Pulp ◽  
Animal Studies ◽  
Risk Of Bias ◽  
Pulp Regeneration

Despite the recent explosion of investigations on dental pulp regeneration using various tissue engineering strategies, the translation of the findings from such studies into therapeutic applications has not been properly achieved. The purpose of this scoping review was to systematically review the efficacy of mesenchymal stem cell transplantation for dental pulp regeneration. A literature search was conducted using five electronic databases from their inception to January 2021 and supplemented by hand searches. A total of 17 studies, including two clinical trials and 15 animal studies using orthotopic pulp regeneration models, were included for the review. The risk of bias for the individual studies was assessed. This scoping review demonstrated that the regeneration of vascularized pulp-like tissue was achieved using the stem cell transplantation strategy in animal models. Autologous cell transplantation in two clinical studies also successfully regenerated vascularized vital tissue. Dental pulp stem cell subpopulations, such as mobilized dental pulp stem cells, injectable scaffolds such as atelocollagen, and a granulocyte-colony forming factor, were the most commonly used for pulp regeneration. The overall risk of bias was unclear for animal studies and was moderate or judged to raise some concerns for clinical studies. More high-quality clinical studies are needed to further determine the safety and efficacy of the stem cell transplantation strategy for dental pulp regeneration.

scholarly journals Influence of immunological nutrition on treatment of patients with oncological profile

2018 ◽  
Vol 1 (1) ◽  
pp. 19-24
Author(s):  
M. O. Katrichenko ◽  
I. I. Lisnyi
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Clinical Studies ◽  
Animal Studies ◽  
Immune Cell ◽  
Laboratory Data ◽  
Vital Role ◽  
Biologically Active ◽  
Protective Effects ◽  
Immunological Reactions

In the reviewed article, we consider epidemiological and laboratory data that confirm the protective effects of biologically active nutrients in our diet for various diseases. Along with various factors such as alcohol, smoking, nutrition plays a vital role in influencing the patient’s immune response by transforming cells or by preventing, or acceleration of malignancy. Many data suggest that immunoactive nutrients control inflammatory and precancerous reactions in immune cells. Immunoprophylaxis is usually associated with modulation of the immune response when inflamed, thereby improving clinical outcomes. Different nutrients, including glutamine, arginine, vitamins, minerals and long-chain fatty acids, are important components of immunological nutrition. Clinical studies associated with these substances show different results with minimal effect. However, some studies have shown that these nutrients may have immunomodulatory effects that can reduce the risk of developing cancer. Pre-clinical studies claim that most of these nutrients have a positive effect in the complex treatment of cancer patients. In this article, we will consider the effect of the above nutrients on the immune system in patients of oncologic profile. Recent evidences suggest that immunological nutrition plays an important role in the development of cancer and its progression. Data from animal studies have clearly shown that the use of immunomodulatory nutrients isolated from food, by launching a cascade of immunological reactions, can detect and eliminate the tumor. Although the technology has evolved to such an extent that we can study each individual cytokine or function of the immune cell, it is difficult to demonstrate the powerful role of the immune system in preventing or treating cancer due to the complexity of the tumor cell or heterogeneity in different patients' populations. However, the study sheds light on interactions in immune responses and cancer development, prevention and therapeutic strategies that involve modulation through biologically active agents.

scholarly journals 10 Final Report on the Safety Assessment of Cholesterol

1986 ◽  
Vol 5 (5) ◽  
pp. 491-516 ◽  
Keyword(s):  
Clinical Studies ◽  
Safety Assessment ◽  
Final Report ◽  
Experimental Animals ◽  
Normal Metabolism ◽  
Hair Care ◽  
Uvb Exposure ◽  
High Doses ◽  
Skin Irritants

Cholesterol is used as an emulsifier in cosmetic skin and hair care products and eye and face makeup formulations at concentrations up to 5%. The normal metabolism and excretion of Cholesterol is well documented in man and experimental animals. Cholesterol is not a significant dermal or ocular irritant. Cholesterol does not appear to have any genotoxic activity in bacterial or mammalian cell in vitro mutagenic and transformation assays. High doses of Cholesterol were teratogenic in rats. Cholesterol has not been established as a promoter, cocarcinogen, or total carcinogen. Clinical studies to evaluate the safety of topically applied Cholesterol were restricted to products formulated with the ingredient. Most products were moisturizers containing 1.4% Cholesterol. The highest concentration of Cholesterol tested (6%) was evaluated in a modified prophetic test (110 subjects) and an RIPT (45 subjects); both assays had UVA and UVB exposure incorporated into the protocols. The Cholesterol-containing products were minimal to mild primary and cumulative skin irritants but not sensitizers or photosensitizers.

scholarly journals Can prospective systematic reviews of animal studies improve clinical translation?

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Pandora Pound ◽  
Merel Ritskes-Hoitinga
Keyword(s):  
Clinical Trials ◽  
Systematic Reviews ◽  
Animal Studies ◽  
Poor Quality ◽  
Human Studies ◽  
Clinical Knowledge ◽  
Safety And Efficacy ◽  
High Quality Evidence ◽  
Animal Data

AbstractSystematic reviews are powerful tools with the potential to generate high quality evidence. Their application to animal studies has been instrumental in exposing the poor quality of these studies, as well as a catalyst for improvements in study design, conduct and reporting. It has been suggested that prospective systematic reviews of animal studies (i.e. systematic reviews conducted prior to clinical trials) would allow scrutiny of the preclinical evidence, providing valuable information on safety and efficacy, and helping to determine whether clinical trials should proceed. However, while prospective systematic reviews allow valuable scrutiny of the preclinical animal data, they are not necessarily able to reliably predict the safety and efficacy of an intervention when trialled in humans. Consequently, they may not reliably safeguard humans participating in clinical trials and might potentially result in lost opportunities for beneficial clinical treatments. Furthermore, animal and human studies are often conducted concurrently, which not only makes prospective systematic reviews of animal studies impossible, but suggests that animal studies do not inform human studies in the manner presumed. We suggest that this points to a confused attitude regarding animal studies, whereby tradition demands that they precede human studies but practice indicates that their findings are often ignored. We argue that it is time to assess the relative contributions of animal and human research in order to better understand how clinical knowledge is actually produced.

An update on cefepime and its future role in combination with novel β-lactamase inhibitors for MDR Enterobacterales and Pseudomonas aeruginosa

2020 ◽  
Author(s):  
Burcu Isler ◽  
Patrick Harris ◽  
Adam G Stewart ◽  
David L Paterson
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Studies ◽  
Bacterial Infections ◽  
Animal Studies ◽  
Wide Spectrum ◽  
Clinical Development ◽  
Phase Iii ◽  
Lactam Antibiotic ◽  
Tract Infections

Abstract Cefepime, a wide-spectrum β-lactam antibiotic, has been in use for the treatment of serious bacterial infections for almost 25 years. Since its clinical development, there has been a dramatic shift in its dosing, with 2 g every 8 hours being preferred for serious infections to optimize pharmacokinetic/pharmacodynamic considerations. The advent of ESBLs has become a threat to its ongoing use, although future coadministration with β-lactamase inhibitors (BLIs) under development is an area of intense study. There are currently four new cefepime/BLI combinations in clinical development. Cefepime/zidebactam is generally active against MBL-producing Enterobacterales and Pseudomonas aeruginosa, in vitro and in animal studies, and cefepime/taniborbactam has activity against KPC and OXA-48 producers. Cefepime/enmetazobactam and cefepime/tazobactam are potential carbapenem-sparing agents with activity against ESBLs. Cefepime/enmetazobactam has completed Phase III and cefepime/taniborbactam is in Phase III clinical studies, where they are being tested against carbapenems or piperacillin/tazobactam for the treatment of complicated urinary tract infections. While these combinations are promising, their role in the treatment of MDR Gram-negative infections can only be determined with further clinical studies.

scholarly journals The Value of Case Reports in Systematic Reviews from Rare Diseases. The Example of Enzyme Replacement Therapy (ERT) in Patients with Mucopolysaccharidosis Type II (MPS-II)

2020 ◽  
Vol 17 (18) ◽  
pp. 6590
Author(s):  
Miguel Sampayo-Cordero ◽  
Bernat Miguel-Huguet ◽  
Andrea Malfettone ◽  
José Manuel Pérez-García ◽  
Antonio Llombart-Cussac ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Systematic Reviews ◽  
Rare Diseases ◽  
Clinical Studies ◽  
Case Reports ◽  
Mucopolysaccharidosis Type ◽  
Type Ii ◽  
Mucopolysaccharidosis Type Ii ◽  
Enzyme Replacement ◽  
Mps Ii

Background: Case reports are usually excluded from systematic reviews. Patients with rare diseases are more dependent on novel individualized strategies than patients with common diseases. We reviewed and summarized the novelties reported by case reports in mucopolysaccharidosis type II (MPS-II) patients treated with enzyme replacement therapy (ERT). Methods: We selected the case reports included in a previous meta-analysis of patients with MPS-II treated with ERT. Later clinical studies evaluating the same topic of those case reports were reported. Our primary aim was to summarize novelties reported in previous case reports. Secondary objectives analyzed the number of novelties evaluated in subsequent clinical studies and the time elapsed between the publication of the case report to the publication of the clinical study. Results: We identified 11 innovative proposals in case reports that had not been previously considered in clinical studies. Only two (18.2%) were analyzed in subsequent nonrandomized cohort studies. The other nine novelties (81.8%) were analyzed in later case reports (five) or were not included in ulterior studies (four) after more than five years from their first publication. Conclusions: Case reports should be included in systematic reviews of rare disease to obtain a comprehensive summary of the state of research and offer valuable information for healthcare practitioners.

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