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The concept of going 'green' and 'cold' has led to utilizing renewable resources for the synthesis of microbial biosurfactants that are both patient and eco-friendly. In this review, we shed light on the potential and regulatory aspects of biosurfactants in pharmaceutical applications and how they can significantly contribute to novel concepts for the Coronavirus 2019 (COVID-19) vaccine and future treatment. We emphasize that more specific guidelines should be formulated to regulate the approval of biosurfactants for human use. It is also crucial to implement a risk-based approach from the early research and development (R&D) phase in addition to establishing more robust standardized techniques and assays to evaluate the characteristics of biosurfactants.

This « Magnum Opus » emphasizes that serendipity is a corner stone in research. The paths of discovery and innovation often result from the interdisciplinarity of scientific areas that are a priori disconnected from each other. In the 1970s, fundamental discoveries in cell biology led to unexpected advances in galenic pharmacy with the emergence of nanotechnologies for the intracellular delivery of non diffusing molecules. As well, fluorescein-loaded polyacrylamide nanocapsules were shown to deliver this fluorescent agent precisely into cellular lysosomes which represented a seminal observation. However, due to the lack of biodegradability of this carrier polymer, this approach was still far from therapeutic application. The use of cyanoacrylates as surgical glue inspired us to use this material in the design of the first biodegradable nanoparticles for human use. Capable of transporting compounds with anti-tumor activity, these polyalkylcyanoacrylate nanoparticles demonstrated the unexpected property of overcoming multi-drug resistance. This discovery led to the development of a nanomedicine that has completed phase III clinical trials for the treatment of resistant hepatocarcinoma. Going beyond the state-of-the art, a step ahead in the nanomedicine field was the drug « squalenoylation » technology, which represents a shift from the « physical » to the « chemical » encapsulation paradigm. The bioconjugation of anticancer and other drugs to squalene, a natural and biocompatible lipid, enabled a dramatic increase in drug payload, and eliminated the so-called « burst release » of drug: Two major drawbacks commonly associated with drug nanoencapsulation. The drug « squalenoylation » approach resulted in a generic nanomedicine platform with broad pharmacological applications.

Elimination of fluoride from water sample is an imperative stimulus for the betterment of society. Based on WHO policy, the fluoride level superior than 1.5 miligram/litre causes dental and bone scarcity to living entities. In order to prevent these issues, the proper deflouridation technique was chosen. In the present investigations highlighted the elimination percentage of Fluoride from water with the aid of low-cost material, rice husk. Various physical and chemical deflouridation methods were developed to treat high concentrations of fluoride in ground water. Those deflouridation methods need to be built which this will be cost-efficient, and biodegradable. Rice husk is used to detoxify fluoride-rich water and making it safe for human use. 0.5 g/100 mL of adsorbent accomplished 87% of fluoride removal.

The accuracy with which preclinical studies performed on infrahuman mammals predict the efficacy and safety of potential new therapeutics intended for human use is a topic of interest and concern to preclinical scientists, physicians, veterinarians, regulators, and patients everywhere. Factors that impact the potential accuracy of preclinical assessments of safety and efficacy in surrogate species for humans include substantial differences in the mechanisms of cardiac repolarization and excitation-contraction coupling, as well as in the isoforms of the heart’s contractile proteins. Some species are so similar to humans that they suffer the same spontaneous heart diseases – and yet so different that toxic doses of drugs or interventions that would be instantly fatal to a human have literally no effect on them. These differences are in part explained by the sometimes enormous differences in size and scale among species, and in part by genetic and biochemical differences that we have only recently begun to understand. In reviewing some of the more striking species differences and similarities in cardiovascular physiology, this paper hopes to stimulate interest in and inform the choices of scientists involved in surrogate model selection as they work to improve both the positive and negative predictive value of preclinical drug studies.

Summary This Perspective examines the status of large-scale cortical interfaces through the lens of potential applications to active implants for brain-machine interfaces. Examples of research and development in a still embryonic field are discussed from a neuroengineer’s perspective, touching on the design of scalable electrophysiological sensors with the ambition to access thousands of cortical points at near-cellular-level resolution. Important issues include microscale geometry of neural probes, design of implantable ultra-low-power electronics, implementation of high-data-rate wireless telemetry, and compatible device packaging—all requiring advanced solutions along a translational path for chronic human use.

Clinical trials of drug candidates intended to treat neurological conditions often fail because of the poor correlation between outcomes in humans and other animal models. Microphysiological systems offer a potential alternative to or a synergetic approach with animal testing by using human cells assembled in three-dimensional morphologies that are representative of human tissues and organs. The recent advances in microphysiological models of neurological disorders are reviewed here in terms of models used to quantify drug distribution and drug engagement and function. We find that the complexity of microphysiological models continues to increase, but only few neurological conditions have been modeled with the purpose of testing pharmacological traits of candidate drugs. Much more effort appears to have been devoted to models that recapitulate drug distribution, particularly across vascular barriers, and models involving barrier modifications as a result of patient-specific neurological conditions have started to emerge. Based on the current trend, microphysiological models of neurological disorders have the capacity to become a useful tool in the preclinical testing of drugs for human use.

Automated synthesis of a radiopharmaceutical 3-((2-fluoro-4-(5-(2′-methyl-2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl) (methyl-11C)amino)propanoic acid ([11C]CS1P1) for PET imaging sphingosine-1 phosphate receptor 1 (S1P1) was accomplished by a two-step-one-pot procedure in a Siemens CTI methylation automated module using TR-19 cyclotron. The synthesis of [11C]CS1P1 was successfully validated under current Good Manufacturing Practices (cGMP) conditions, resulting in a consistent average radiochemical yield of ∼15%, molar activity of ∼3129 GBq/μmol (decay corrected to end of bombardment, EOB), and radiochemical purity > 95%. The radiopharmaceutical product meets all quality control criteria for human use for an Investigational New Drug (IND) application to permit human studies.

The determination of biomarkers in sewage samples is a useful tool to monitor the consumption of contaminants of human use evolving to wastewater-based epidemiology (WBE). Solid-phase extraction (SPE) followed by high specific and sensitive determination techniques such as liquid chromatography with mass spectrometry–based detection is usually used for the determination of the low concentration of these biomarkers in such complex samples. The different SPE sorbents and the variables involved in the SPE protocol such as sample loading, washing, and elution solvent are critically reviewed from studies dealing with WBE. Moreover, the results in form of extraction recoveries and matrix effect achieved are discussed. At the end, the review intents to overview the different possibilities of SPE when applied in WBE.

Discovering new therapeutics for human viral diseases is important for combatting emerging infectious viruses and omnipresent circulating viruses as well as those that can become resistant to the drugs we currently have available. The innate host defense peptide (HDP) repertoire present in animals is a wealth of potential antimicrobial agents that could be mined to meet these needs. While much of the body of research regarding HDPs is in the context of bacteria, there is increasing evidence that they can be an effective source for antivirals. Peptides can be identified in a number of ways, including eco-conservation-minded approaches. Those shown to have antiviral properties can be modified to exhibit desired properties as the relationship between structure and function is elucidated and then developed into therapeutics for human use. This review looks at the discovery and therapeutic potential of HDPs for human viral infections.

Biosensors consist of a biocatalyst that can detect a biological element and a transducer which can convert the combination event of the biocatalyst and the biological element into a detectable parameter. The biocatalyst can be biomolecules like, enzyme, DNA, RNA, metabolites, cells, oligonucleotides etc., and the transducers can be electrochemical, optical, piezoelectric, acoustics, calorimetric etc. In disease diagnostics biosensors utilizing immobilized cells, enzymes, nucleic acids have come into the field in recent years. Nanobiosensors exploiting the ultrasmall size and unique properties have also been used for engineering disease diagnostic biosensors. The use of biosensors can rapidly assess the health status, onset of the disease and its progression and can help to plan treatment for many diseases with the aid of multidisciplinary combination of chemistry, medical science and nanotechnology. The devices are cost effective, highly sensitive, rapid, user friendly and can be produced in bulk for human use. This review focuses on the different biosensors for the diagnosis of three major diseases like diabetes, cardiovascular disease and cancer.

Urdu abstract: آج پوری دنیا پانی کی کمی کا شکار ہے اس لیے بہت سے ممالک میں پانی کی کمی کے خطرے سے نمٹنے کے لیے استعمال شدہ پانی کو دوبارہ قابل استعمال بنایا جارہا ہے ۔ گندے پانی کو زراعت میں استعمال کرنے کا رواج دو ہزار سال پہلے کے زمانے میں ہوتا تھا، جب یونان میں فصلوں کی آب پاشی اس طرح کےآلودہ و گندے پانی سے ہوا کرتی تھی لیکن پانی کے بحران نے حالیہ ادوار میں اس رواج کو بہت فروغ دیاہے۔ ویسے بھی گندا پانی 99 فیصد پانی ہے۔ باقی ایک فیصد ایسی چیزوں پر مشتمل ہے جو انسانی یا حیوانی استعمال کی وجہ سے پانی میں شامل ہو گئی ہیں۔ ایسے پانی میں گندگی و غلاظت کے علاوہ بہت زیادہ مضر صحت اشیاء اور نجاستیں بھی شامل ہوتی ہیں۔ اسلام بحیثیت دین نہ صرف ہر مسئلے کا مکمل حل پیش کرتا ہے بلکہ دنیاوی زندگی کے ہر پہلو سے متعلق مکمل رہنمائی بھی فراہم کرتا ہے۔ اس لیے مذکورہ بالا مسئلہ کے بارے میں بھی شریعت اسلامیہ میں مکمل رہنمائی موجود ہے اور متقدمین و متاخرین نے اس مسئلہ کے بارے میں اپنی آراء پیش کی ہیں۔ ان سطور میں مسئلہ زیر بحث کی شرعی حیثیت کو واضح کیا جائے گا۔ English abstract: Water is the precious blessing of Allah Almighty which is found everywhere in the world. Hence, its usefulness is neglected, and it is wasted unreasonably. Due to its excessive use and human activities, the water sources are becoming polluted too. The rivers, streams and watercourses are too polluted for human use. This situation created water scarcity in the world. Pakistan is also facing acute water deficiency and it will soon become a water stress country from water scarcity state. It demands appropriate measures to treat water as a precious wealth and to use it carefully so that coming generations will not have to face the music. One of those measures is to clean the wastewater so that water scarcity could be eliminated. This paper examines the wastewater treatment in Islamic perspective. In this research, the viewpoints of four Imams regarding water purification have been elaborated and suggestion have been enlightened in brief.

Resource extraction is an activity that humans can undertake in relation to land, resources, or elements of the earth. Mining, forestry, drilling for oil, and fracking all entail extraction. On its face, it describes the act of taking, from nature, resources for human use, typically non-renewable resources. But ‘extractivism’ connotes not an activity, but a relation: here, the concept does not turn on the type of resource taken, but on the underlying political economy. That is, extractivism is a particular way of relating to nature. The term is not reserved for fossil fuels and mineral extraction; neither would it apply to the extraction of those materials in all contexts and circumstances.

Industrial contaminants such as dyes and intermediates are released into water bodies, making the water unfit for human use. At the same time large amounts of food wastes accumulate near the work places, residential complexes etc. polluting the air due to putrefaction. The need of the hour lies in finding innovative solutions for dye removal from wastewater streams. In this context, the article emphasizes adoption or conversion of food waste materials, an ecological nuisance, as adsorbents for the removal of dyes from wastewaters. Adsorption, being a well-established technique, the review critically examines the specific potential of food waste constituents as dye adsorbents. The efficacy of food waste-based adsorbents is examined, besides addressing the possible adsorption mechanisms and the factors affecting phenomenon such as pH, temperature, contact time, adsorbent dosage, particle size, and ionic strength. Integration of information and communication technology approaches with adsorption isotherms and kinetic models are emphasized to bring out their role in improving overall modeling performance. Additionally, the reusability of adsorbents has been highlighted for effective substrate utilization. The review makes an attempt to stress the valorization of food waste materials to remove dyes from contaminated waters thereby ensuring long-term sustainability.

Superparamagnetic iron oxide nanoparticles (SPION) are available since many years and some of them are already approved for human use. New applications are currently emerging and the field is moving from the use of SPION as simply contrast agents, to more complex structures optimized in terms of core, size, shape and coating for different imaging modalities (e.g. MRI vs MPI), and different theranostic applications. Prof. Krishnan M. Kannan has greatly contributed to our understanding of the role of each of these parameters in shaping SPIO best function. Some of these developments are discussed in this short review just as examples. More recently, new cell-based SPIO constructs have also been optimized, moving the field from engineering the nanoparticles to the generation of hybrids cell-nanoparticle constructs. These developments have requested additional SPIO optimizations to maintain nanoparticles biocompatibility and properties and, at the same time, prevent cell damage and maintain cell functionality. Related examples from our lab are also discussed.

In recent years, there is renewed interest in the study of various hallucinogens for their potential therapeutic effects. In the United States of America (USA), the abuse potential assessment of a drug is carried out as part of the general safety and efficacy evaluation of a drug. Additionally, the abuse potential assessment is taken under consideration in determining if a drug needs to be subject to controls to minimize the abuse of the drug once on the market. This assessment is conducted for all new drugs with central nervous system (CNS) activity, that are chemically or pharmacologically similar to other drugs with known abuse potential, or drugs that produce psychoactive effects predictive of abuse, such as euphoria and hallucinations. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, with emphasis on hallucinogens. The paper discusses the role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs and its role in drug control, and provides an overview of the controlled status of hallucinogens and the requirements to conduct research with Schedule I substances in the USA. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Purpose Advances in methods designed to evaluate preclinical toxicity have not kept up with progress in regenerative medicine. Preclinical toxicity studies of regenerative therapies must be designed logically and should be flexible to accurately reflect toxicity of products under development. The purpose of this review is to discuss requirements of preclinical toxicity studies of this type developed in Japan. Methods We conducted MEDLINE and PubMed literature searches to identify recent reports relevant to regenerative medicine. Information regarding approved drugs and public announcements, including existing guidelines and guidance in Japan, was collected from the website of Japan's Ministry of Health, Labor and Welfare ( https://www.mhlw.go.jp/index.html ) and the Pharmaceuticals and Medical Devices Agency ( https://www.pmda.go.jp/ ). Findings Four cell therapy products have been developed and approved in Japan so far. The principal preclinical toxicity data submitted to regulatory authorities in the Pharmaceuticals and Medical Devices Agency in Japan are summarized here. The potential for tumor formation, a major concern in such clinical applications, is assessed in 3 ways: tumor-forming capacity of the original cell, quantitation of residual pluripotent stem cells in the product, and the possibility that a tumor will form at the product's engraftment site. Although gene therapy and oncolytic virus products are under development, these types of products are not yet approved in Japan. Guidelines relevant to the development of these products are now being created based on existing guidelines and considerations established by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Implications Because of cell tropism and heterologous immunity, animal species or strains useful for preclinical studies of regenerative therapies are often restricted. Nonetheless, preclinical toxicity studies must be designed to predict results relevant to humans.

The discovery and wide spread use of vaccines have saved millions of lives in the past few decades. Vaccine adjuvants represent an integral part of the modern vaccines. Despite numerous efforts, however, only a handful of vaccine adjuvants is currently available for human use. A comprehensive understanding of the mechanisms of action of adjuvants is pivotal to harness the potential of existing and new adjuvants in mounting desirable immune responses to counter human pathogens. Decomposing the host response to vaccines and its components at systems level has recently been made possible owing to the recent advancements in Omics technology and cutting edge immunological assays powered by systems biology approaches. This approach has begun to shed light on the molecular signatures of several human vaccines and adjuvants. This review is an attempt to provide an overview of the recent efforts in systems analysis of vaccine adjuvants that are currently in clinic.

Small and medium-sized enterprises (SMEs) are an important source of innovative medicines. Compared with their larger counterparts, they experience challenges as a result of insufficient human and financial resources that can hamper drug development and regulatory compliance. This analysis reviews the profile of major objections raised in marketing authorisation applications for medicines for human use submitted by SMEs to the European Medicines Agency (EMA) between 2011 and 2015 and their impact on the outcome of applications. It showed that SMEs experience challenges in the quality (e.g. manufacturing process validation and control and/or characterisation data of drug substance or drug product) and clinical sections of marketing authorisation applications (e.g. analysis or robustness of pivotal data or selection of submitted studies, study design issues and marginal or no clinical relevant efficacy), with deficiencies in demonstrating clinical efficacy representing the major eventual hurdles to authorisation.

Coastal systems are constantly in flux, and feedback from monitoring is necessary to support decision making for effective sustainable natural resource management. Frequently natural resources are the ultimate target of management actions, but management programs work through the proximate step of regulating human behavior towards those resources. For example, a marine reserve is considered a conservation success when the abundance and diversity of organisms increase within reserve boundaries, all relative to existing trends that would have affected ecological communities in the absence of a reserve. Biological monitoring can assesses whether reserve management achieves these goals. However, when monitoring data are inconclusive or do not match expectations, managers face uncertainty in understanding why particular biological patterns occurred, whether a reserve is a biologically appropriate management strategy for the system, and what steps to take moving forward. Monitoring human behavior can provide information that may alleviate some uncertainty and help explain observed biological patterns. In this study we illustrate the utility of complimenting biological monitoring data with monitoring of human behavior. We used a before-after control-impact analysis to test for effects of a no-take reserve in the Gulf of California, Mexico on the density and biomass of seven fished species. We failed to detect a positive biological effect of the reserve, and found the density of five monitored species had declined. These results indicated that the reserve was not succeeding, but provided no insight into why. Evaluation of recreational angler use of the reserve provided a possible explanation: first, the frequency of angler visits to the study area was increasing over time. Second, the reserve reduced the propensity of anglers to visit the reserve, but not by enough to offset the overall increasing visitation trend. Biological and human use monitoring results in tandem indicated that a reserve could potentially be an effective conservation tool for the system, and allowed us to suggest modifications that could help the reserve succeed. Our work illustrates the necessity of monitoring human use changes alongside biological responses to a reserve for a holistic portrait of reserve functioning, providing a concrete example of the importance of human behavioral aspects of marine reserve success.

Spectrochemical elemental analysis of pharmaceuticals and raw materials used for their production will be in the nearest future an obligatory part of quality and safety control for compliance with new standards announced by the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH Q3D). The present paper surveys R&D articles and scientific papers devoted to determination of the elemental impurities by inductively coupled plasma optical emission spectrometry and mass spectrometry (ICP-OES and ICP-MS) in different pharmaceuticals products that have been published since 2000. In reference to recent changes described in the United States Pharmacopoeia (USP) general chapters and , different aspects of such measurements are presented, including appropriate sample preparation procedures, possible interferences and means of their avoidance, suitable calibration strategies and validation parameters that have to be assessed to prove reliability of the analytical results on the elemental impurities in pharmaceutical products.

In modern process management, the life cycle concept gains more and more importance. It focusses on the total costs of the process from invest to operation and finally retirement. Also for analytical procedures an increasing interest for this concept exists in the recent years. The life cycle of an analytical method consists of design, development, validation (including instrumental qualification, continuous method performance verification and method transfer) and finally retirement of the method. It appears, that also regulatory bodies have increased their awareness on life cycle management for analytical methods. Thus, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), as well as the United States Pharmacopeial Forum discuss the enrollment of new guidelines that include life cycle management of analytical methods. The US Pharmacopeia (USP) Validation and Verification expert panel already proposed a new General Chapter 〈1220〉 "The Analytical Procedure Lifecycle" for integration into USP. Furthermore, also in the non-regulated environment a growing interest on life cycle management is seen. Quality-by-design based method development results in increased method robustness. Thereby a decreased effort is needed for method performance verification, and post-approval changes as well as minimized risk of method related out-of-specification results. This strongly contributes to reduced costs of the method during its life cycle.

In Antarctica, waste is generated mainly during scientific research programmes and related logistics. In this study, the impact of wastewater on the western shore of Admiralty Bay was investigated during austral summer in 2017 and 2019. A range of physicochemical parameters and the presence of selected trace metals, formaldehyde and different groups of surfactants were determined in wastewater coming from Arctowski Station and in nearby coastal waters. The presence of selected trace metals (e.g., Cr: 2.7–4.4 μg/L; Zn: 15.2–37.3 μg/L; and Ni: 0.9–23.3 μg/L) and the sums of cationic (0.3–1.5 mg/L), anionic (3.1–1.7 mg/L), and non-ionic (0.6–2.4 mg/L) surfactants in wastewater indicated the potential influence of anthropogenic factors on sea water. The determined surfactants are found in many hygiene products that end up in the waste water tank after human use and, if untreated, can be released into surface waters with discharge. In addition, the levels of some trace metals indicate that they cannot come only from natural sources, but are the result of human activity. The reported data show disturbances in the marine environment caused by non-treated wastewater discharge, e.g. by comparing the obtained results from the values of the no observed effect concentrations (NOECs) on selected Antarctic bioindicators, and provide information for the implementation of proper wastewater treatment at any Antarctic station in the future.

Intense human use and high construction density in coastal areas are stressors to sandy beaches. Pollution by marine debris is a major problem on beaches worldwide. This study pioneered an assessment of marine debris characterization over time on beaches with different levels of access. In two periods and seasons, marine debris was sampled on nine sandy beaches of Rio de Janeiro, grouped by levels of access. The general marine debris density has decreased over time, accompanied by an improvement in public cleaning mechanisms. The most important predictor for the majority of marine debris items is related to accessibility; beaches with restricted access showed a reduction in the abundance of most items. High marine debris densities, even on beaches with restricted access, showed that all evaluated beaches can be sinks for marine debris circulating in marine waters. Beach cleaning strategy improvements will be inefficient unless integrated marine debris management is implemented.

The rate of infections caused by resistant bacteria to the antimicrobials available for human use grows exponentially every year, which generates major impacts on human health and the world economy. In the last two decades, human beings can witness the expressive increase in the Science and Technology worldwide, and areas such as Health Sciences have benefited from these advances in favor of human health, such as the advent of Pharmaceutical Nanotechnology as an important approach applied for bacterial infections treatment with resistance profile to available antibiotics. This review of the scientific literature brings the applicability of nanotechnology-based lipid systems as an innovative tool in the improvement of bacterial infections treatment. Important studies involving the use of liposomes, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, microemulsions and lipid nanocapsules were verified in the period from 2000 to 2020, where important scientific results were found and will serve as a basis for the use of these systems to remain in constant updating. This manuscript shows the use of these drug delivery systems as potential vehicles for antibacterial compounds, which opens a new hope in the complement of the antibacterial therapeutic arsenal. Important studies developed in the last 20 years are present in this review, and thus guarantees an update on the use of these drug delivery systems for researchers from different areas of Health Sciences.

Despite uncertainty about its clinical benefit, ivermectin has been used for COVID 19, even in prophylaxis. The European Medicines Agency (EMA) has advised against its use for the prevention or treatment of COVID-19 outside randomised clinical trials. Although the potential negative environmental effects of ivermectin have been widely recognised when used in veterinary medicine, scarce attention has been devoted to the potential ecotoxicological impact of human use. We believe is time to include One Health's philosophy in our daily practice. In the specific case of ivermectin & COVID 19, environmental aspects should also be on the table.

Introduction: In 2019, the Italian Supreme Court established that hemp cannot be commercialized for human use, when the “psychotropic effect” of the product or its “offensiveness” can be demonstrated. The aim of the present study is to assess Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) blood concentrations after smoking cannabis with a low percentage of Δ9-THC, also referred as “light cannabis”, and its effects on young adults’ vigilance, cognitive and motor skills. Materials and methods: Eighteen young adults consumed three light cannabis cigarettes containing 400 mg of inflorescences each, with a percentage of 0.41% of Δ9-THC and of 12.41% of CBD. Blood samples were collected before the experiment (t0), after each light cannabis cigarette (t1→t3), 60 (t4) and 120 (t5) minutes after the beginning of the experiment. Five performance tasks and a subjective scale were employed for measuring cognitive and psychomotor performances the day before the experiment (TT0) and after the third cigarette (TT1). Results: Mean (SD) concentrations (ng/ml) were 1.0 (0.8) in t1, 1.2 (0.9) in t2, 1.0 (0.8) in t3, 0.6 (0.4) in t4 and 0.3 (0.3) in t5 for Δ9-THC; 10.5 (10.3) in t1, 10.3 (13.2) in t2, 15.1 (14.8) in t3, 9.9 (9.2) in t4 and 5.7 (5.7) in t5 for CBD. No significant differences were observed between TT0 and TT1 for all performed psychomotor performance task. None of the subjects declared to feel “high” after the experiment. Discussion: All study participants reported that a higher number of cigarettes, corresponding in this study to 1200 mg of herbal product, could hardly be consumed by smoking in a recreational setting. Δ9-THC and CBD concentrations showed a high inter-subject variability, and the average concentrations were lower than those previously reported. Toxicological results showed a decrease of Δ9-THC and CBD after the third light cannabis cigarette, and a Δ9-THC /CBD ratio always

Background We aimed to develop a process using three-dimensional (3D) printing to create bioengineered tracheal grafts (BETGs) for reconstruction of anterior tracheal defects in a large-animal model (porcine) that would have translational relevance for potential human use. Methods Preoperative computed tomographic scans were used to create virtual 3D models of the animal airways. Anatomically scaled tracheal grafts were subsequently developed using 3D-printed polycaprolactone and extracellular matrix. A 4-cm anterior tracheal defect (about 50% of the length of the subject trachea) was surgically created in 4-week-old female Yorkshire pigs and reconstructed using the customized grafts. Gross and microscopic analyses of the grafts were performed. Results The BETGs were implanted in 7 animals. There was adequate graft–native trachea size match at the operation. The trachea was successfully reconstructed in all cases. Gross examination at autopsy showed a structurally intact, well-incorporated graft. Histologic evaluation showed respiratory mucosal coverage and vascularity of the graft. Five of 7 animals outlived the 3-month study period. The animals had approximately 100% growth during the study period. Conclusions We report of a 3D-printed BETG to repair long-segment anterior tracheal defects in a large-animal model. Although the study duration is short, this work presents an efficient strategy for tracheal graft bioengineering with potential translational relevance for human use.

Botanicals used in dietary supplements industry can have toxicology concerns related to endpoint gaps that cannot be fully resolved by a history of use, or existence of conflicting safety data. However, traditional toxicological studies on botanicals are scientifically and pragmatically challenging due to testing of complex mixtures of constituents, cost, time, and animal usage. Alternatively, we developed an in silico decision-tree approach to address data gaps and inform need for further studies by toxicologically evaluating the chemical composition of botanicals. Following advanced multi-detector analytical characterization of a botanical, each chemical constituent is: (a.) quantitatively benchmarked against similar constituents in commonly consumed foods or botanicals with well-established safety profiles, (b.) systematically evaluated for toxicity data utilizing structure-activity relationships, and, (c.) compared to established thresholds of toxicological concern in absence of safety data or structural analogs. Finally, where safety endpoint gaps are identified which cannot be resolved without additional in vitro or in vivo studies, the botanical compositional data are critical to inform on study design. Results with three herbal preparations demonstrate the utility of this novel approach to identify potential hazards and establish safe human use levels for botanicals in a cost efficient and informative manner that minimizes animal use.

The aim of this paper is to discuss the representation of spatiality in the interaction between humans and the environment. The work focuses on the movement and relations involved in these past and present interactions. Theoretical reflections are based on the study of the human use of Butia palm trees in Uruguay. A variety of techniques were used to carry out an ethnographic work that proposes an exercise for the representation of spatiality. The dialogue among these different ways of representing diachronic spatiality in human-palm relationships aims to critically analyse the use of participatory mapping in land management. We propose a non-aerial representation of the spatiality of human-palm relationships with implications on the discussions on the hegemonic ways of representing space.

Evidence of human use of opium dates back as far as the sixth millennium BCE. Ancient societies through the Renaissance period created a variety of opium products, proliferating its common use and subsequent addiction. Because the active moiety was not known at this time, the potency of these opium concoctions could neither be predicted nor controlled. The first step in identifying opium's active ingredient, morphine, was its chemical isolation in the early 1800s by Wilhelm Sertürner. The subsequent elucidation of morphine's chemical formula and Sir Robert Robinson's derivation of morphine's structural formula, which won him the 1947 Nobel Prize in Chemistry, round out 150 years of the incremental advances in our chemical understanding of morphine. Nevertheless, our attempts to synthesize morphine, despite our advanced knowledge in synthetic chemistry, are still no match for the plant-based extraction of morphine from the poppy plant. The status quo remains problematic socially, economically, and politically; the relationships between the countries laboriously growing poppy plants to extract morphine and those countries importing these painkillers are unstable at best. In this study, we contrast the cumulative scientific discoveries that have led to our current chemical knowledge of morphine with the centuries-old natural method of morphine production that still dominates the opioid market today.

Among the several new provisions foreseen by the EU Regulation (R) 2014/536 on Clinical Trials (CTs) repealing Directive (D) 2001/20/EC, this article focuses on the identification of possible critical points leading to potential incongruences regarding Good Clinical Practice (GCP). EU D foresees the obligation to be in compliance with GCP detailed guidelines, while the R foresees the obligation to be in compliance only with the GCP principles. Many of the GCP detailed aspects have been transposed in the R and the R provides to be in compliance with GCP quality standards. Nevertheless, other GCP aspects, which have direct or indirect ethical implication in CTs, will not be mandatory in the EU.

White sharks (Carcharodon carcharias) are attracted to and scavenge on floating whale carcasses. However, little is known about how stranded whale carcasses may affect their behaviour. With increasing whale populations and beach stranding events, sharks may be attracted to nearshore waters at carcass sites, increasing the potential conflict with human use. Here, we used aerial drones to assess whether white shark behaviour around stranded whale carcasses differs from their behaviour away from carcasses. We quantified white shark behaviour by measuring swim speed, net velocity, straightness and sinuosity of shark tracks, as well as the total length of each shark. White sharks in the vicinity of whale carcasses travelled at 0.46 m s−1 (±0.06 SD) faster, were 0.26 m (±0.15 SD) longer, swam tracks that were 0.15 (±0.11 SD) lower on the straightness index, and showed more sinuous tracks by 0.07 (±0.02 SD), compared to sharks away from a carcass. The presence of a stranded whale carcass may, therefore, significantly altered the behaviour and size of white sharks close to shore. As white shark activity increases in a relatively small nearshore area, which was indicated by decreased straightness and increased sinuosity, there may be an elevated risk of shark interactions with water users in the vicinity of stranded whale carcasses.

Biologics, both monoclonal antibodies (mAbs) and fusion proteins, have revolutionized the practice of medicine. This year marks the 30th anniversary of the Food and Drug Administration approval of the first mAb for human use. In this review, we examine the biotechnological breakthroughs that spurred the explosive development of the biopharmaceutical mAb industry, as well as how critical lessons learned about human immunology informed the development of improved biologics. We also discuss the most common mechanisms of action of currently approved biologics and the indications for which they have been approved to date.

The establishment of protected areas is a key strategy for preserving biodiversity. However, human use of protected areas can cause disturbance to wildlife, especially in areas that allow hunting and if humans are accompanied by dogs (Canis familiaris). We used citizen-science run camera traps to investigate how humans, dogs and coyotes (Canis latrans) used 33 protected areas and analyzed behavioral responses by three prey species: white-tailed deer (Odocoileus virginianus), eastern gray squirrel (Sciurus carolinensis) and northern raccoon (Procyon lotor). We obtained 52,863 detections of native wildlife, 162,418 detections of humans and 23,332 detections of dogs over 42,874 camera nights. Most dogs (99%) were on the trail, and 89% of off-trail dogs were accompanied by humans. Prey avoided dogs, humans and coyotes temporally, but did not avoid them spatially, or greatly increase vigilance. Our results indicate that humans are perceived as a greater risk than coyotes, and this increases when dogs accompany their owners. The concentration of dogs on the trail with their owners, and relatively minor behavioral impacts on prey, contrasts the strong negative ecological effects found in studies of free-ranging dogs. We found dog management to be effective: prohibiting dogs in protected areas reduced their use of an area by a factor of 10 and leash laws increased leashing rates by 21%. Although millions of dogs use natural areas in North America each year, regulations enacted by protected areas combined with responsible management of dog behavior greatly reduce the ecological impact of man's best friend.

The combined effects of global climate change and increased anthropogenic use of free water are likely to cause decreases in availability and surface area of water in arid environments. Climate change and water loss are predicted to alter community dynamics, but identifying mechanisms underlying differential responses of species remains a critical conservation challenge. Bats drink in flight and rely on accessible water sources, yet the ability to access water is a function of flight maneuverability. By reducing the size of water sources (to simulate predicted water loss due to climate change/increased human use), we demonstrated species-specific responses by desert bats based on differences in morphology and flight maneuverability. Under natural conditions, less-maneuverable bats selected larger water sources while maneuverable bats exhibited no preference. When we experimentally reduced surface area, larger, less-maneuverable bats experienced a 69% decrease in the proportion of drinking attempts that were successful ( p

Nucleic acid-based vaccines are being developed as a means to combine the positive attributes of both live-attenuated and subunit vaccines. Viral vectors and plasmid DNA vaccines have been extensively evaluated in human clinical trials and have been shown to be safe and immunogenic, although none have yet been licensed for human use. Recently, mRNA based vaccines have emerged as an alternative approach. They promise the flexibility of plasmid DNA vaccines, without the need for electroporation, but with enhanced immunogenicity and safety. In addition, they avoid the limitations of anti-vector immunity seen with viral vectors, and can be dosed repeatedly. This review highlights the key papers published over the past few years and summarizes prospects for the near future.

This paper presents the results obtained from the study of the bivalves recovered during the archaeological excavations in the Vestibulo chamber of Nerja Cave (Malaga, southern Spain) carried out by Professor Francisco Jorda Cerda between 1983 and 1987. These excavations recovered the archaeological record of the sequence from the Gravettian to the Neolithic. The mollusc remains from the Vestibulo chamber of Nerja Cave record constitute an extraordinary collection, composed of more than 136000 specimens which correspond to more than 78 kg. In this work, only marine bivalves were studied. The bivalve remains are more than 124000 specimens, corresponding to more than 65 kg from 31 taxa. More than 115000 of these specimens (59 kg) are derived from the shell midden dated to GS 1. The archaeological record of Nerja Cave is distinguished by the abundant presence of human-provided marine and continental molluscs with a high presence of bivalves. Marine bivalves increased clearly from the LGM to the mid-Holocene, and the human inhabitants of the cave accumulated an important shell midden in the contact between MIS 2 and MIS 1.

Mutations resulting in reduced signaling of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis are associated with increased life and health-span across model organisms. Similar findings have been noted in human cohorts with functional mutations in the somatotropic axis, suggesting that this pathway may also be relevant to human aging and protection from age-related diseases. While epidemiological data indicates that low circulating IGF-1 level may protect aging populations from cancer, results remain inconclusive regarding most other diseases. We propose that studies in humans and animals need to consider differences in sex, pathway function, organs, and time-specific effects of GH/IGF-1 signaling in order to better define the role of the somatotropic axis in aging. Agents that modulate signaling of the GH/IGF-1 pathway are available for human use, but before they can be implemented in clinical studies that target aging and age-related diseases, researchers need to address the challenges discussed in this review.

The evidence presented in this paper is a first effort to contextualize aspects related to the sourcing, production and uses of red paint during the second millennium BC in Northern Peru. The site tested was Gramalote, a fishing settlement of the Peruvian North Coast. The results show that the inhabitants of this settlement had access to a local source of hematite but they also used cinnabar that came from a distant region located in the Southern Highlands. Based on the abundance of lithic and bone tools, shell containers and ceramic seal stamps, the authors of this article study the process behind the production of this painting. Using physicochemical techniques such as Portable X-ray fluorescence (XRF) technology complemented with structural analysis through X-ray diffraction, applying conventional and synchrotron radiation on selected samples, the authors look at issues related to sourcing, production and uses of the red pigment. In addition, isotopic analysis helped to determine the provenience of cinnabar which is also the earliest evidence of human use of this mineral in the Andean region. Temporal and contextual distributions of these artifacts are analyzed to understand the manipulation and uses of the red paint. Finally, this study also gives a glimpse of the symbolic meaning red pigment could have played in the daily life of a second millennium BC maritime community on the Pacific coast of Peru.

In the Northern coast of Rio de Janeiro State is located the major urban centers of the oil and gas industry of Brazil. The intense urbanization in recent decades caused an increase in human use of the coastal areas, which is constantly impacted by agricultural, industrial and wastewater discharges. Franciscana dolphin (Pontoporia blainvillei) is a small cetacean that inhabits coastal regions down to a 30 m depth. This species is considered the most threatened cetacean in the Western South Atlantic Ocean. This study investigated the levels of 52 PCB congeners and 9 PBDE congeners in liver of nine individuals found stranded or accidentally caught between 2011 and 2012 in the Northern coast of Rio de Janeiro. PCB mean levels ranged from 208 to 5543 ng g(-1) lw and PBDEs mean concentrations varied between 13.84 and 36.94 ng g(-1) lw. Contamination patterns suggest the previous use of Aroclor 1254, 1260 and penta-BDE mixtures in Brazil. While still few studies have assessed the organic contamination in cetaceans from the Southern Hemisphere, including Brazil, the levels found in this study could represent a health risk to these endangered species.

Cardiac pacemakers are a critical management option for patients with rhythm disorders. Current efforts to develop leadless pacemakers have two primary goals: to reduce lead-associated post-procedural morbidity and to avoid the surgical scar associated with placement. After extensive studies on animal models and technological advancements, these devices are currently under investigation for human use. Herein, we review the evidence from animal studies and the technological advancements that have ushered in the era of use in humans. We also discuss different leadless pacemakers currently under investigation, along with limitations and future developments of this innovative concept.

Automated production of a promising radiopharmaceutical (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([(18)F]VAT) for the vesicular acetylcholine transporter(VAChT) was achieved using a two-step procedure in a current Good Manufacturing Practices fashion. The production of [(18)F]VAT was accomplished in approximately 140 min, with radiochemical yield of ~15.0% (decay corrected), specific activity>111 GBq/µmol, radiochemical purity>99% and mass of VAT ~3.4 μg/batch (n>10). The radiopharmaceutical product meets all quality control criteria for human use, and is suitable for clinical PET studies of VAChT.

The present study elucidates the development of an accurate, precise and simple simultaneous estimation method for the routine analysis of Betamethasone Valerate (BV) and Tazarotene (TZ). This combination is widely used in the treatment of psoriasis. No method has been reported so far for the simultaneous estimation of BV and TZ in topical dosage forms. The method proposed by this study for the quantification of BV and TZ is the Absorption factor method. The developed method was validated as per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline. The validated method was found to be linear in a concentration range of 10-38 μg/mL and 4-14 μg/mL for BV and TZ respectively with a regression coefficient0.990. The method was validated for accuracy and precision which revealed the recovery of99.80% with RSD2.0. The method was found to be precise with RSD2% for inter and intraday. The developed method was employed for quantification of BV and TZ in lipid based nanocarriers formulation and their in-vitro drug release samples. Further, the developed method was successfully applied for the estimation of BV and TZ in the ex-vivo skin matrix. This showed that the method can sensitively determine the drugs in aqueous and biological samples.

Most artificial intelligence technologies are dual-use. They are incorporated into both peaceful civilian applications and military weapons systems. Most of the existing codes of conduct and ethical principles on artificial intelligence address the former while largely ignoring the latter. But when these technologies are used to power systems specifically designed to cause harm, the question must be asked as to whether the ethics applied to military autonomous systems should also be taken into account for all artificial intelligence technologies susceptible of being used for those purposes. However, while a freeze in investigations is neither possible nor desirable, neither is the maintenance of the current status quo. Comparison between general-purpose ethical codes and military ones concludes that most ethical principles apply to human use of artificial intelligence systems as long as two characteristics are met: that the way algorithms work is understood and that humans retain enough control. In this way, human agency is fully preserved and moral responsibility is retained independently of the potential dual-use of artificial intelligence technology.

The pollution of pharmaceuticals has attracted a lot of concerns during recent years. The goal of this study was to identify targets of ecological concern considering human use pharmaceuticals marketed in China. We constructed a database for 593 active pharmaceutical ingredients (APIs) by collecting their information on use and emission (e.g. production, human excretion, and removal by wastewater treatment) to calculated predicted environmental concentrations (PECs) by using an adapted European Medicines Agency method. PECs were comparable to the reported measurements for most APIs, demonstrating that the adapted method is reliable for the prioritization practice. Then PECs were compared to toxicity thresholds of three aquatic taxa (algae, daphnia, and fish). As a result, a total of 31 APIs, which were potentially risky and should be taken into consideration in future studies, were identified. Three APIs would pose a high risk with risk quotient (RQ) greater than 10. Six APIs were identified with moderate risks (1 RQ 10), and four of them were not reported before: rifaximin, griseofulvin, amikacin, and niclosamide. Of the 22 APIs with low risks (0.1 RQ 1), 17 have never been monitored previously in China and even worldwide. This study has yielded some probable antibiotics that should be considered as monitoring targets in China in the future.

Competition between human use and spring-dependent systems puts these systems in jeopardy. This study analyzed whether Florida springs have experienced reductions in springflow over the last century using time series data from state and federal agencies. Of 57 springs, 26 exhibited negative trends in springflow; these declines were correlated with population growth, with groundwater withdrawals, and to a lesser extent with rainfall. Even in a region with abundant rainfall, population growth has impacted spring integrity.

There are abundant data to suggest that the autologous transplantation of human progenitor cells is safe. However, the use of allogenic cells for human use has not been adequately researched and should not be considered safe at this time.

The morbidity of lifestyle-related diseases such as heart disease, cancer, and diabetes mellitus is increasing in industrialized countries including Japan each year, and dealing with this increased morbidity is a problem that needs prompt attention. Curcumin is a natural polyphenol derived from the root of Curcuma longa and has multiple actions, such as anti-inflammatory action, anti-cancer action, anti-oxidant action, anti-viral action, and cytoprotective action. It is expected that curcumin has therapeutic potency to prevent various lifestyle-related diseases. However, curcumin is not readily soluble in water and has an extremely low level of bioavailability. Over the past decade, preparation techniques such as nanoparticles and micelles have led to the development of highly absorbable curcumin preparations, paving the road for human use of curcumin. This article summarizes a number of basic studies and clinical trials involving curcumin and discusses the potential for clinical use of curcumin.

Although nanoparticles research is ongoing since more than 30 years, the development of methods and standard protocols required for their safety and efficacy testing for human use is still in development. The review covers questions on toxicity, safety, risk and legal issues over the lifecycle of inorganic nanoparticles for medical applications. The following topics were covered: (i) In vitro tests may give only a very first indication of possible toxicity as in the actual methods interactions at systemic level are mainly neglected; (ii) the science-driven and the regulation-driven approaches do not really fit for decisive strategies whether or not a nanoparticle should be further developed and may receive a kind of "safety label". (iii) Cost and time of development are the limiting factors for the drug pipeline. Knowing which property of a nanoparticle makes it toxic it may be feasible to re-engineer the particle for higher safety (safety by design). From the Clinical Editor: Testing the safety and efficacy of nanoparticles for human use is still in need of standardization. In this concise review, the author described and discussed the current unresolved issues over the application of inorganic nanoparticles for medical applications. (C) 2015 Elsevier Inc. All rights reserved.

Outdoor recreation is a widely recognized cultural ecosystem service. Ensuring that appropriate, high quality recreation opportunities are available requires, among other factors, knowledge of the environmental preferences of recreation users and spatial indicators of where those environmental features exist on the landscape and offer the potential to meet recreation goals. Diverse types of outdoor recreation exist, and different forms of recreation may be associated with different environmental features. The focus of this study is off-road vehicle (ORV) recreation. We demonstrate how readily available spatial environmental datasets, including high resolution image data provided within GoogleEarth, can be used to develop a cost-effective, objective indicator of ORV recreation across a landscape, which can inform management to provide desired recreation opportunities while protecting ecologically sensitive areas. ORV recreational tracks were delineated from GoogleEarth imagery throughout our study area in the Great Western Woodlands of Western Australia. In this region, ORV use is a popular recreation activity and a growing concern of conservation organizations, but is not yet actively managed. Most recreational ORV tracks in the study area are informal and user-created. Mapped ORV recreation tracks were used to model and map the environmental associations of ORV recreation. The pattern of existing tracks indicated associations between recreation and noteworthy environmental amenities in the study area such as the shores of salt lakes and rock outcrops with high ecological and cultural value. However, one of the most important determinants of ORV track presence was accessibility, especially proximity to a road. Access infrastructure, such as proximity to roads, is often used to proxy demand and use in expert-based spatial assessments of ecosystem services. The results of our empirical model underscore the importance of incorporating patterns of both supply (i.e., desired natural amenities) and demand (i.e., access) into ecosystem service assessments. In addition, when integrated with maps of environmental sensitivity and more detailed information about human use, the predictive map of areas providing potential recreation experiences can be used for comprehensive spatial planning of sustainable ORV recreation. One possibility suggested by our results is that careful planning and management of access routes may be an effective means to achieve sustainable ORV recreation.