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Introduction: The main purpose of this study was comparing median time (TTR, time to reimbursement) between the first Agenzia Italiana del Farmaco (AIFA) pricing and reimbursement (P&R) dossier’s evaluation and patient access in Italy and to observe the key P&R negotiation results for all new active substances approved by the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use between January 2014 and December 2019. We analysed the different factors influencing TTR. Methods: A panel of medicines for human use approved by the EMA in the period 2014-2019 was considered. All information about authorisation and reimbursement in Italy, including timelines and results from the negotiation, were gathered through EMA and Italian Official Journal databases. Results: Of 213 new active substances approved from January 2014 to December 2019, 137 obtained reimbursement in Italy, with a median TTR of 7.6 months (228 days). Even if orphan designation, oncology indication, application of Managed Entry Agreements (MEAs; both outcome and financial based) or a discount did not show an impact on TTR, recognition of full innovativeness (n = 27; 20%) was associated with a reduction of 1 month in median TTR. Interestingly, drugs reimbursed with a lower price/daily defined dose showed a reduced TTR (−22%). Conclusions: Even if the lack of impact of some negotiation conditions was predictable (e.g. oncology indication or orphan status) or the application of a MEA helped to manage possible uncertainties, it did not lead to a quicker completion of the negotiation procedure. Likewise, full innovative drugs showed a shorter TTR underlying the AIFA commitment in recognising, promoting and rewarding innovation.

Dairy and fermented foods are common sources of dietary branched-chain fatty acids (BCFA) of chain lengths C13-C18 serving a putative prebiotic role and a component of human integument. Few studies have reported on nonfermented plant-derived BCFA in human diets or cosmetics. A three-ion monitoring method was adapted to confirm branch position of ultratrace (

Eventually there may be a broadly acceptable, even perfected, substitute for the human host requirement for direct feeding experiments by arthropods, most notably mosquitoes. However, for now, direct and indirect feeding on human volunteers is an important, if not essential, tool in vector biology research (VBR). This article builds on the foundational publication by Achee et al. (2015) covering considerations for the use of human participants in VBR pursuits. The authors introduced methods involving human participation in VBR, while detailing human-landing collections (catches) as a prime example. Benedict et al. (2018) continued this theme with an overview of human participation and considerations for research that involves release of mosquito vectors into the environment. In this study, we discuss another important aspect of human use in VBR activities: considerations addressing studies that require an arthropod to feed on a live human host. Using mosquito studies as our principal example, in this study, we discuss the tremendous importance and value of this approach to support and allow study of a wide variety of factors and interactions related to our understanding of vector-borne diseases and their control. This includes establishment of laboratory colonies for test populations, characterization of essential nutrients that contribute to mosquito fitness, characterization of blood-feeding (biting) behavior and pathogen transmission, parameterization for modeling transmission dynamics, evaluation of human host attraction and/or agents that repel, and the effectiveness of antivector or parasite therapeutic drug studies.

Los productos farmacéuticos se evalúan de acuerdo con los requisitos establecidos en cada país para aceptar su registro sanitario. La regulación sanitaria debe de cumplirse para que estos medicamentos puedan comercializarse. Estas especificaciones dependen de lo que las normativas consideran indispensable en cada caso. Esta situación complica la elaboración de etiquetas para su distribución en diferentes países. El objetivo de esta investigación fue facilitar el cumplimiento de la regulación de etiquetado de medicamentos mediante la verificación de requisitos para Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panamá, Perú, Chile, Bolivia, Colombia, Ecuador, Paraguay, Uruguay, República Dominicana, Cuba, Trinidad y Tobago, Jamaica, Aruba, Curaçao y Guyana. Para ello, se realizó una recopilación y una revisión de las regulaciones (reglamentos, normas y leyes de inscripción de medicamentos para uso humano) de las entidades reglamentarias de estos países. La información encontrada se seleccionó y se resumió. Con dicho resumen, se creó una comparación de requisitos para cada una de las regiones mencionadas. Al realizar una revisión de las regulaciones sobre etiquetado de los diversos países se encontró que sus requisitos no están homologados en las regiones centroamericana, Caribe y sudamericana.

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.

Background: An estimated 1 million patients require cardiac implantable electronic devices (CIEDs) but go without annually. This disparity exists in low-to-middle-income nations largely owing to the cost of CIED hardware. Humanitarian reuse of CIEDs has been shown to be safe and feasible. However, recent publications have raised concern that promotion of CIED reuse may foster a CIED “black market,” to the dismay of manufacturers, regulators, and clinicians alike. Objective: To determine if unregulated CIED sales for potential human use is a real issue by investigating unregulated public online CIED sale listings in the United States of America. Methods: An observational study was undertaken over 6 months using multiple internet search engines from May 1 to November 1, 2019. We cataloged usable CIEDs (still in packaging, manufactured

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.

Modern human need for medicines is so extensive that it is thought to be a deep evolutionary behavior. There is abundant evidence from our Paleolithic and later prehistoric past, of survival after periodontal disease, traumas, and invasive medical treatments including trepanations and amputations, suggesting a detailed, applied knowledge of medicinal plant secondary compounds. Direct archeological evidence for use of plants in the Paleolithic is rare, but evidence is growing. An evolutionary context for early human use of medicinal plants is provided by the broad evidence for animal self-medication, in particular, of non-human primates. During the later Paleolithic, there is evidence for the use of poisonous and psychotropic plants, suggesting that Paleolithic humans built on and expanded their knowledge and use of plant secondary compounds.

ObjectiveTo identify the presence of unapproved pharmaceutical drugs in over-the-counter dietary supplements marketed to improve memory and cognitive function.MethodsSupplements were identified by searching 2 supplement databases for products labeled as containing omberacetam, aniracetam, phenylpiracetam, or oxiracetam, 4 drugs not approved for human use in the United States. Products were purchased online and analyzed using nontargeted liquid chromatography-quadrupole time-of-flight mass spectrometry methods.ResultsIn the 10 products tested, omberacetam and aniracetam were detected along with 3 additional unapproved drugs (i.e., phenibut, vinpocetine and picamilon). By consuming recommended serving sizes, consumers could be exposed to pharmaceutical-level dosages of drugs including a maximum of 40.6 ± 0.4 mg omberacetam (typical pharmacologic dose of 10 mg), 502 ± 0.8 mg of aniracetam (typical pharmacologic dose 200–750 mg), 15.4 ± 0.3 mg of phenibut (typical pharmacologic dose 250–500 mg), 4.3 ± 0.1 mg of vinpocetine (typical pharmacologic dose 5–40 mg), and 90.1 ± 0.7 mg of picamilon (typical pharmacologic dose 50–200 mg). Several detected drugs were not declared on the label, and several declared drugs were not detected in the products. For those products with drug quantities provided on the labels, 75% (9/12) of declared quantities were inaccurate. Consumers could be exposed to up to four-fold greater than pharmaceutical dosages and as many as 4 unapproved drugs when using individual products.ConclusionsOver-the-counter cognitive enhancement supplements may contain multiple unapproved drugs. The health effects of consuming untested combinations of unapproved drugs at unpredictable dosages without clinician oversight in supplements are unknown.

Several different vaccines have been produced for human use to prevent the highly pathogenic H5N1 influenza. Some studies reported that the clinical effectiveness of influenza vaccines in older adults may be lower than in younger adults. In this study, a meta-analysis of the immunogenicity of H5N1 influenza vaccines in elderly adults was performed. Database search was conducted in EMBASE, PubMed, the Cochrane Library, Chinese VIP, Wanfang and CBM. A total of 3951 elderly adults from 10 articles were included in the meta-analysis. Compared to a single dose, two doses of H5N1 vaccines resulted in the higher seroconversion and seroprotection. For all groups treated with adjuvanted vaccines, there were significant increases (1.55- to 2.16-fold) in the seroconversion rates (SCRs) and seroprotection rates (SPRs) after two immunizations. Oil-in-water emulsion (OE)-adjuvanted 7.5 μg vaccine caused higher antibody responses than 3.75 μg of vaccine (SCR: risk ratio (RR) = 1.26 (1.19, 1.33); SPR: RR = 1.25 (1.14, 1.36)). Elderly adults exhibited slightly lower antibody responses only when given 7.5 μg of OE-adjuvanted vaccine (SCR: RR = 1.06 (1.01, 1.11)) than younger adults. After treatment with the 7.5 μg of OE-adjuvanted vaccines, the most commonly reported adverse events were injection site pain, swelling and erythema, with the incidence of 32%, 3% and 2%, respectively, and no serious adverse events were found. These data demonstrate that two doses of 7.5 µg of OE-adjuvanted H5N1 vaccine are well tolerated and induce a robust antibody response in elderly adults.

Demands for certified reference materials of osmium mono-element standard solutions are increasing to obtain reliable results in chemical instrument analyses. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) issues the Guideline for Elemental Impurities (Q3D) and lists osmium as an elemental impurity to be measured. There are few reports on osmium standards although osmium is widely used as a catalyst and needed to measure. In the present paper, potential titration paths were explored to determine the mass fraction of osmium traceable to the International System of Units. Three stoichiometric reactions were examined to assay osmium compounds, and the availability was discussed. The presented discussions will contribute to establish first osmium mono-element standard solutions characterized by a metrologically valid procedure.

Food and Drug Administration (FDA) has approved a drug product (Spritam®) and many medical devices manufactured by three-dimensional printing (3DP) processes for human use. There is immense potential to print personalized medicines using 3DP. Many 3DP methods have been reported in the literature for pharmaceutical applications. However, selective laser sintering (SLS) printing has remained least explored for pharmaceutical applications. There are many advantages and challenges in adopting a SLS method for fabrication of personalized medicines. Solvent-free nature, availability of FDA approved thermoplastic polymer/excipients (currently used in hot melt-extrusion process), minimal/no post-processing step, etc. are some of the advantages of the SLS printing process. Major challenges of the technology are requirement of at least one thermoplastic component in the formulation and thermal stability of drug and excipients. This review provides an overview of the SLS printing method, excipient requirements, process monitoring, quality defects, regulatory aspects, and potential pharmaceutical applications.

The water of the three springs in the village of Tarjla (located in the area of Bartala, eastern Mosul) is characterized by different physical and chemical properties depending on the results of the laboratory tests of (NTU, EC, TDS, TH, PH) and major ions (Na+, Ca+2, Mg+2, Cl-, ) for six selected water samples for the study area. This difference did not remain constant, but changed with the flow of water to the neighboring villages (Sheikh Amir, Shaquli, Karemlesh), where the percentages of physical and chemical concentrations have changed in terms of the increase and decrease of some water samples. This is due to the time factor and the water contact of some of the soils and rocks that encountered their flow as well as exposure to the sun. The purpose of the research is to study the quality of springs water to determine its suitability for different uses. Using the Piper and Stiff classifications, the water quality is calcium-bicarbonate, the calcium ion predominates over the rest of the positive ions and the bicarbonate ion prevails over the rest of the negative ions, this indicates that spring number (1) and spring number (3) are derived from the Fat'ha formation deposits, which contain limestone and gypsum rocks that contain high concentrations of sulphates. The spring number (2) is derived from the Injana formation and modern sediments that is hydraulically connected with each other and can be considered one reservoir. By comparing the results of laboratory tests with the international standards, it was found that the water of spring number (2) is suitable for human use, and that the water of spring’s number (1) and (3) are not suitable for human use because they contain a high proportion of sulfur ions. All water samples are suitable for agricultural and animal use and very good to excellent

Synthesizing engineered bacteriophages (phages) for human use has potential in various applications ranging from drug screening using a phage display to clinical use using phage therapy. However, the engineering of phages conventionally involves the use of an

[18F]6-fluoro-L-DOPA ([18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) and high molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.

Objectives The main objective of the present work is to develop a simple, precise, specific and stability method indicating reverse phase high performance liquid chromatography method for simultaneous estimation of teneligliptin and metformin in bulk and tablet dosage form. Materials and methods The analysis was performed with a Kromasil C18 column (250×4.6 mm, 5 μm) at 30°C using buffer: acetonitrile: methanol (65:25:10, v/v/v) as mobile phase. The detection was carried out with a flow rate of 1.0 mL/min at 254 nm. Results The retention time of teneligliptin and metformin was 2.842 min and 2.017 min, respectively. The linearity range was 5-30 μg/mL for teneligliptin and 125-750 μg/mL for metformin. The forced degradation studies were performed as per the guidelines of the The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use under acidic, alkaline, oxidative, thermal, photostability, and neutral conditions. Conclusion This method was successfully validated for all the parameters and could detect the the correct amounts of active drug substance in formulations that are available in the market. This developed method in the present study could be successfully employed for the simultaneous estimation of teneligliptin and metformin in bulk and tablet dosage form.

Background: Limited safety information has been described in the peer-reviewed literature for callus-softening products containing potassium hydroxide. Methods: This pilot human use study evaluated the safety and effectiveness of a commercially available callus softener, containing less than 10% potassium hydroxide by weight. Baseline callused skin was scored (grade 1–4) on each study participant’s feet (n = 10). Participants’ feet were soaked and then a licensed manicurist applied a callus softener product to the right foot, which remained on callused skin for 3 to 5 minutes (no callus softener was applied to the participant’s left foot). Both feet were then wiped with a wet towel, and a foot rasp was used to file the callused skin, beginning on the left foot. Callused skin was scored and participants’ feet were evaluated by a physician immediately after use, 1 day after use, and 1 week after use for the presence or absence of skin irritation, adverse skin reactions, and chemical burns. Results: No adverse events were reported by study participants or the physician for all evaluation time points. Each participant’s highest callus grade score on the treated foot either improved or remained the same following product use (compared to baseline). Mean callus grade scores were 1.75 at baseline, 1.55 immediately after use, 1.25 1 day after use, and 1.50 1 week after use. Conclusions: Results from this pilot study suggest that callus-softening products containing less than 10% potassium hydroxide are likely to be safe and effective products under intended use scenarios of 3- to 5-minute application times, as dictated by product label instructions.

The discovery of insulin in 1921 – due to the efforts of the Canadian research team based in Toronto – has been a landmark achievement in the history of medicine. Lives of people with diabetes were changed forever, considering that in the pre-insulin era this was a deadly condition. Insulin, right after its discovery, became the first hormone to be purified for human use, the first to be unraveled in its amino acid sequence and to be synthetized by DNA-recombinant technique, the first to be modified in its amino acid sequence to modify its duration of action. As such the discovery of insulin represents a pivotal point in medical history. Since the early days of its production, insulin has been improved in its pharmacokinetic and pharmacodynamic properties in the attempt to faithfully reproduce diurnal physiologic plasma insulin fluctuations. The evolution of insulin molecule has been paralleled by evolution in the way the hormone is administered. Once-weekly insulins will be available soon, and glucose-responsive “smart” insulins start showing their potential in early clinical studies. The first century of insulin as therapy was marked by relentless search for better formulations, a search that has not stopped yet. New technologies may have, indeed, the potential to provide further improvement of safety and efficacy of insulin therapy and, therefore, contribute to improvement of the quality of life of people with diabetes.

Bioanalysis describes quantitative estimation of chemicals or drug substances as well as their metabolic products in large variety of bio-samples. It is an integrated technique that has been employed in preclinical stages of drug-discovery process to further support the clinical phases of drug discovery. However, a bioanalytical method must be optimized, characterized, and validated following documented procedures according to United States Pharmacopeia (USP)/International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines to comply with the regulatory guidelines and acceptance criteria. Bioanalytical studies should therefore provide accurate and reproducible estimation of drugs or metabolites in biological samples at great level of sensitivity, selectivity, and specificity. In this chapter, various advanced techniques commonly employed in bioanalysis have been summarized. Different techniques of extraction and an array of advanced hyphenated techniques are employed for the evaluation of bioanalytes in biofluids, with improved analytical specificity and sensitivity. The applications of bioanalysis in biomedical, pharmaceutical, and other allied areas have been systematically reviewed in this chapter.

Vaccine adjuvants are products or substances coadministered with poorly immunogenic antigens to boost their immune response. Adjuvants such as aluminum salts and Freund's complete and incomplete emulsion adjuvants were some of the early discovered adjuvants about a century ago. Discovery of safe, highly purified, but less immunogenic antigens via innovation in recombinant DNA technology in the early 1980s led to the need for more potent vaccine adjuvants as well as the basis for understanding how adjuvants work. The past few decades of adjuvant research have unraveled mechanisms of adjuvant action resulting in a more focused research on developing of novel adjuvants catering to the desired characteristic immune response. Based on their direct function and interaction with cells, adjuvants can be broadly classified as particulate adjuvants and immune potentiators. Particulate adjuvants help in “delivery” of the antigen to the antigen-presenting cells, whereas immune potentiators broadly work by directly activating the local innate immune system via receptors on antigen-presenting cells to trigger an antigen-specific immune response. Despite the vast history of adjuvant use, very few are approved by the FDA for human use. Increasing knowledge and research on understanding the fundamentals of the desired immune response should facilitate rational development of novel adjuvants. Advancing novel adjuvants requires a careful amalgamation of formulation science, toxicology, and a thorough understanding of immunological aspects. In this chapter, we have reviewed the heritage of vaccine adjuvants, the current status of adjuvant development, and future considerations for developing novel adjuvants.

The Irrawaddy dolphin (Orcaella brevirostris) is an imperiled Southeast Asian coastal and freshwater mammal species. Throughout their range, Irrawaddy dolphins face numerous anthropogenic threats including gillnet entanglement, habitat degradation, and boat disturbance (e.g. noise). Five subpopulations, four of which are freshwater, are classified as Critically Endangered on the International Union for the Conservation of Nature’s (IUCN) Red List of Threatened Species and the species as a whole is classified as Vulnerable. It is thought that most subpopulations are small and declining. Little is known about this species’ habitat preferences, life history, or movement. The subpopulation in the Gulf of Thailand is one that has yet to be evaluated and thus provides an ideal research subject to increase the body of knowledge on this rare and little-studies species. In Chapter 1, we analyzed stable isotopes of carbon and nitrogen using ANOVA and MANOVA to investigate regional subpopulation structure and ontogenetic patterns in the Gulf of Thailand and the Andaman Sea. We further used a mixing model (MixSIAR) to determine diet in two sites in the eastern Gulf of Thailand by comparing stable isotopes of dolphins to those of potential prey species. Limited age and sex structure was discovered. However, stable isotope ratios in Irrawaddy dolphins varied significantly by region (eastern Gulf, northern Gulf, western Gulf, Andaman Sea), suggesting distinct geographic groups. Mixing models revealed that the group within the eastern Gulf is primarily piscivorous, consuming mainly ponyfish, mackerel, gizzardshad, and scad, and secondarily crustacean-eating. Cephalopods make up a smaller proportion of the overall diet. Slight differences were found between the two study sites within the eastern Gulf, suggesting weak sub-regional structure, perhaps driven by resource partitioning. In Chapter 2, we used a hurdle model to evaluate the habitat of Irrawaddy dolphins in the eastern Gulf of Thailand. We found that depth and temperature are significant predictors of dolphin presence and group size, respectively. Depth had a positive relationship with dolphin presence probability up to around 10.5 meters, at which the relationship became negative. Dolphin group size was significantly negatively correlated with temperature. We further identified two primary locations of dolphin occurrence probability (combined high presence and large group size probabilities), one large region in the center of the study area and a smaller region in the south. Finally, in Chapter 3, we used binomial and negative binomial GLMs to model fishing effort in three locations in the eastern Gulf of Thailand. We further compared these results to the results from Chapter 2 to determine where dolphins were more likely to encounter fishing vessels and gear.

A vaccine is an immunogen, the administration of which is intended to stimulate the immune system to result in the prevention, amelioration, or therapy of any disease or infection (US Food and Drug Administration. Guidance for Industry: content and format of chemistry, manufacturing, and controls information and establishment description information for a vaccine or related product). A vaccine may be a live attenuated preparation of microorganisms, inactivated (killed) whole organisms, living irradiated cells, crude fractions, or purified immunogens, including those derived from recombinant DNA in a host cell, conjugates formed by covalent linkage of components, synthetic antigens, polynucleotides (such as the plasmid DNA vaccines), living vectored cells expressing specific heterologous immunogens, or cells pulsed with immunogen. Vaccines are highly complex products that differ from small molecule drugs because of the biological nature of the source materials such as those derived from microorganisms as well as the various cell substrates from which some are derived. Regardless of the technology used, because of their complexities, vaccines must undergo extensive characterization and testing. Special expertise and procedures are needed for their manufacture, control, and regulation. The Food and Drug Administration (FDA) is the National Regulatory Authority (NRA) in the United States responsible for assuring quality, safety, and effectiveness of all human medical products, including vaccines for human use.The Center for Biologics Evaluation and Research (CBER) within the US FDA is responsible for overseeing the regulation of therapeutic and preventative vaccines against infectious diseases. Authority for the regulation of vaccines resides in Section 351 of the Public Health Service Act and specific sections of the Federal Food, Drug, and Cosmetic Act (FD&C). Vaccines are regulated as biologics and licensed based on the demonstration of safety and effectiveness. The vaccine development process can be divided into two major categories: those events that are not under the regulatory authority of the FDA and are exploratory in nature and those events that are subject to regulatory authority by the FDA. Exploratory events or research and development cover basic research drug discovery processes that occur before the sponsor submits an investigational new drug application (IND) to the FDA. There are four main stages of vaccine development under the purview of regulatory authorities: preclinical, clinical (IND), licensing, and post-licensure. Throughout their life cycle from preclinical evaluation to post-licensure lot release testing, vaccines are subject to rigorous testing and oversight by manufacturers and NRAs. In this chapter an overview of the regulatory evaluation and testing requirements for vaccines is presented.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 3 million people and causing a severe economic crisis. This extraordinary situation prompted entities in government, industry, and academia to work together at unprecedented speed to develop safe and effective vaccines. Indeed, vaccines of multiple types have been generated in record time, and many have been evaluated in clinical trials. Of these, messenger RNA (mRNA) vaccines have emerged as lead candidates due to their speed of development and high degree of safety and efficacy. To date, two mRNA vaccines have received approval for human use, providing proof of the feasibility of this next-generation vaccine modality. This review gives a detailed overview about the types of mRNA vaccines developed for SARS-CoV-2, discusses and compares preclinical and clinical data, gives a mechanistic overview about immune responses generated by mRNA vaccination, and speculates on the challenges and promising future of this emergent vaccine platform. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Antimicrobial use (AMU) is one of the major drivers of emerging antimicrobial resistance (AMR). Surveillance of AMU, a pillar of AMR stewardship (AMS), helps devise strategies to mitigate AMR. This descriptive, longitudinal retrospective study quantified the trends in human antibiotic utilization between 2010 and 2016 using data on all antibiotics imported for systemic human use into Tanzania's mainland. Regression and time series analyses were used to establish trends in antibiotics use. A total of 12,073 records for antibiotics were retrieved, totaling 154.51Daily Defined Doses per 1,000 inhabitants per day (DID) with a mean (± standard deviation) of 22.07 (±48.85) DID. The private sector contributed 93.76%% of utilized antibiotics. The top-ranking antibiotics were amoxicillin, metronidazole, tetracycline, ciprofloxacin and cefalexin. The DDIs and percentage contribution of these antibiotics were 53.78 (34.81%), 23.86 (15.44), 20.53 (13.29), 9.27 (6.0) and 6.94 (4.49), respectively. The time series model predicted significant increase in utilization(p-value =0.002). The model forecasted that by 2022, the total antibiotics consumed would reach 89.6 DIDs, corresponding to a 13-fold increase compared to 2010. Government intervention to curb inappropriate antibiotic utilization to mitigate the rising threat of antibiotic resistance should focus on implementing AMS programs in pharmacies and hospitals in Tanzania.

Plants produce interesting secondary metabolites that are a valuable source of both medicines for human use, along with significant advantages for the manufacturer species. The active compounds which lead to these instrumental effects are generally secondary metabolites produced during various plant growth phases, which provide the host survival advantages while affecting human health inadvertently. Different chemical classes of secondary metabolites are biosynthesized by the plant type III polyketide synthases (PKSs). They are simple homodimeric proteins with the unique mechanistic potential to produce a broad array of secondary metabolites by utilizing simpler starter and extender units. These PKS derived products are majorly the precursors of some important secondary metabolite pathways leading to products such as flavonoids, stilbenes, benzalacetones, chromones, acridones, xanthones, cannabinoids, aliphatic waxes, alkaloids, anthrones, and pyrones. These secondary metabolites have various pharmaceutical, medicinal and industrial applications which make biosynthesizing type III PKSs an important tool for bioengineering purposes. Because of their structural simplicity and ease of manipulation, these enzymes have garnered interest in recent years due to their application in the generation of unnatural natural polyketides and modified products in the search for newer drugs for a variety of health problems. The following review covers the biosynthesis of a variety of type III PKS-derived secondary metabolites, their biological relevance, the associated enzymes, and recent research.

The number of diseases has greatly increased in the last decades in addition to the global pandemic that affected everyone’s life and killed a lot of humans. With this increase, the use of masks has greatly increased as well. Modern masks have various problems and can be inconvenient to keep all day long. One of its worst problems is that they cause the fogging up of eyeglasses. Many products have tried to solve this problem, but none was completely successful. This paper aims to design a new mask that tackles this problem in an innovative way by optimizing the airflow of warm breath to exit the mask from the sides instead of going upward. The mask is for human use and can be adopted by global standards.

Acyclovir (ACV) is an effective and selective antiviral drug, and the study of its toxicology and the use of appropriate detection techniques to control its toxicity at safe levels are extremely important for medicine efforts and human health. This review discusses the mechanism driving ACV’s ability to inhibit viral coding, starting from its development and pharmacology. A comprehensive summary of the existing preparation methods and synthetic materials, such as 5-aminoimidazole-4-carboxamide, guanine and its derivatives, and other purine derivatives, is presented to elucidate the preparation of ACV in detail. In addition, it presents valuable analytical procedures for the toxicological studies of ACV, which are essential for human use and dosing. Analytical methods, including spectrophotometry, high performance liquid chromatography (HPLC), liquid chromatography/tandem mass spectrometry (LC-MS/MS), electrochemical sensors, molecularly imprinted polymers (MIPs), and flow injection–chemiluminescence (FI-CL) are also highlighted. A brief description of the characteristics of each of these methods is also presented. Finally, insight is provided for the development of ACV to drive further innovation of ACV in pharmaceutical applications. This review provides a comprehensive summary of the past life and future challenges of ACV.

Rainwater harvesting is the art and science of capturing rain for human use. This study analysed rainfall data for the Regional Hospital's catchment area to ascertain potential harvestable rainfall. Assessment of the buildings and their respective roof areas were also done to determine the possible roof catchment areas. The potential rainwater that could be harvested from the different blocks within the hospital range between 3,306.18 -9,943.45m3. The potential total average rainwater that could be harvested from the different blocks within the hospital catchment area of 51,939.11m2 is 53,524.29 m3 per annum. According to data collected from the GWCL, the monthly and yearly demand of water by the hospital are 3,146 m3 and 337,752m3 respectively, which is lower than the total potential rainwater that could be harvested per annum of 53, 524.29m3 . This implies that there would be an excess water of 15,772.29m3 . Theoretically, it means that harvested and stored rainwater could meet the water needs of the hospital. Keywords: Rainwater harvesting (RWH); Water storage; Organizational water usage

This paper describes a previously unknown mikiri well in the Simpson dune field. This site was abandoned about 500-600 years ago and does not feature in ethnographic records for this region. We argue that its abandonment was most likely due to failure of the well caused by a fall in the local watertable. The Simpson Desert is one of the major sand-ridge deserts of the world, but current views of the chronology of human use of this vast dune field rest on only a handful of radiocarbon ages (n=12). The radiocarbon ages for this mikiri, and its surroundings, add to this limited dataset. We plot all available radiocarbon ages from archaeological sites in the dune field showing that occupation of this mikiri coincided with a widespread increase in use of the dune field during the last millennium, at about the time the Wangkanguru people in the dune field were becoming linguistically distinct from the Arabana to the west.

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.

Street furniture is an independent discipline. It addresses detailed solutions of products designed for human use in an exterior environment. Based on present-day studies, senior citizens constitute the fastest growing segment of the population. The sample element with defined ergonomic parameters has been defined by analyzing the standard and most used component of street furniture - bench, by the comparison of used materials and chosen construction. During the comparison and the subsequent conclusions, a great emphasis was placed on the functionality and durability of the individual components. The categories of street furniture have been based on the study of production programs of mainstream furniture manufacturers in Europe, and on the research of factors influencing street furniture. With the basic material of the supporting structure, the sitting and leaning sections and based on the measurements and defining of materials, a sample construction design has been proposed, and supporting element of concrete, steel and wooden constructions including their surface treatment has been described. info:eu-repo/semantics/openAccess

A high-performance liquid chromatography method employing a diode-array detector and mass spectrometry detector was developed, validated and implemented for determining Synephrine, Caffeine, Clenbuterol, Nandrolone, Testosterone and Methylhexaneamine in Nutritional supplements. The use of Nutritional supplements is widespread. Hazards relating to concentration, composition, individual contaminants, supplements interactions as well as positive doping results among athletes present increasing concerns regarding nutritional supplement consuming. The proposed method was validated according to the International Conference on the Harmonization of the Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) standards. The proposed method observed to be accurate, linear, precise, sensitive, required minimal sample preparation and uncomplicated mobile phase. The implementation of the proposed method on nine commercial supplements shows that inaccurate labeling for some supplements regarding the concentration of the ingredients.

The chemical environment, and the natural resources available in which our species has evolved has been crucial for the establishment of our medical practices. Here we present a brief review of the insights provided by chemical ecology to understand the evolution of medical practices since ancestral hominids to modern humans, as well as their implications for the search for new drugs of natural origin. Like for any other mammal, ecological and evolutionary processes have shaped how we relate to plant and animal chemicals, whether to avoid, transform and/or explore these compounds according to our needs. In addition, culture has played a key role in the way these chemicals are perceived by people and how they can be processed by different modes of use for ingestion, as well as providing cultural significance for their use (in medicine, for example) or their rejection altogether.

Current cardiovascular magnetic resonance imaging techniques provide an exquisite assessment of the structure and function of the heart and great vessels, but their ability to assess the molecular processes that underpin changes in cardiac function in health and disease is limited by inherent insensitivity. Hyperpolarized magnetic resonance is a new technology which overcomes this limitation, generating molecular contrast agents with an improvement in magnetic resonance signal of up to five orders of magnitude. One key molecule, hyperpolarized [1-13C]pyruvate, shows particular promise for the assessment of cardiac energy metabolism and other fundamental biological processes in cardiovascular disease. This molecule has numerous potential applications of clinical relevance and has now been translated to human use in early clinical studies. This review outlines the principles of hyperpolarized magnetic resonance and key potential cardiovascular applications for this new technology. Finally, we provide an overview of the pipeline for forthcoming hyperpolarized agents and their potential applications in cardiovascular disease.

Fluorine-18 labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([18 F]FDPA) is a potent and selective radiotracer for positron-emission tomography (PET) imaging of the translocator protein 18 kDa (TSPO). Our previous in vitro and in vivo evaluations have proven that this tracer is promising for further human translation. Our study addresses the need to streamline the automatic synthesis of this radiotracer to make it more accessible for widespread clinical evaluation and application. Here, we successfully demonstrate a one-step radiolabeling of [18 F]FDPA based on a novel spirocyclic iodonium ylide (SCIDY) precursor using tetra-n-butyl ammonium methanesulfonate (TBAOMs), which has demonstrated the highest radiochemical yields and molar activity from readily available [18 F]fluoride ion. The nucleophilic radiofluorination was completed on a GE TRACERlab FX2 N synthesis module, and the formulated [18 F]FDPA was obtained in nondecay corrected (n.d.c) radiochemical yields of 15.6 ± 4.2%, with molar activities of 529.2 ± 22.5 GBq/μmol (14.3 ± 0.6 Ci/μmol) at the end of synthesis (60 minutes, n = 3) and validated for human use. This methodology facilitates efficient synthesis of [18 F]FDPA in a commercially available synthesis module, which would be broadly applicable for routine production and widespread clinical PET imaging studies.

When utilizing [18F]tetrabutylammonium fluoride ([18F]TBAF) in the synthesis of 18F-labeled radiotracers for clinical positron emission tomography (PET) imaging, it is necessary to confirm that residual TBA levels in formulated doses do not exceed established specifications (≤2.6 mg per patient dose). Historically this has been accomplished using HPLC, but this is time consuming for short-lived PET radiotracers and limited by the need for expensive equipment. This motivated us to introduce a TLC spot test for determining residual TBA, and we have developed a new method which employs the Dragendorff reagent. Herein we report details of the TLC method and use it to quantify residual TBA in different formulations of 6-[18F]fluoro-DOPA.

The aim of present review is to provide an insight on FDA updates in it’s own words on coronavirus disease 2019. The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Studies were carried out to determine asbestos fiber levels in cosmetic (talc powder) and non-cosmetic (gauze pad, plastic filler and ceiling tiles) products sold in market outlets within Enugu, metropolis, Enugu State, Nigeria, using standard established procedures. The samples were pretreated based on its physical make-up and the asbestos fiber levels determined using scanning electron microscopy (SEM) with energy dispersing spectroscopy techniques. The mean range of asbestos fiber was, 0.02 - 0.06; 0.01 - 0.05; 0.01 - 0.04 and 0.03 - 0.06 f/cc for talc powder, gauze pads, plastic filler and ceiling tile samples respectively. The mean levels of asbestos fibers in the studied samples were within the recommended permissible limits. The samples contain asbestos fiber in the following decreasing order: ceiling tiles > talc powders > gauze pads > plastic fillers. Asbestos fiber was found present in the investigated local and foreign items sold in market outlets within the metropolis. This study shows that despite the ban on the use of asbestos in the industry in the manufacture of items meant for human use, its enforcement appears weak and lethargic and this could portend health danger especially in the use of produced items with high asbestos fiber friability such as talc powder.

Glandular trichomes are epidermal outgrowths that are the site of biosynthesis and storage of large quantities of specialized metabolites. Besides their role in the protection of plants against biotic and abiotic stresses, they have attracted interest owing to the importance of the compounds they produce for human use; for example, as pharmaceuticals, flavor and fragrance ingredients, or pesticides. Here, we review what novel concepts investigations on glandular trichomes have brought to the field of specialized metabolism, particularly with respect to chemical and enzymatic diversity. Furthermore, the next challenges in the field are understanding the metabolic network underlying the high productivity of glandular trichomes and the transport and storage of metabolites. Another emerging area is the development of glandular trichomes. Studies in some model species, essentially tomato, tobacco, and Artemisia, are now providing the first molecular clues, but many open questions remain: How is the distribution and density of different trichome types on the leaf surface controlled? When is the decision for an epidermal cell to differentiate into one type of trichome or another taken? Recent advances in gene editing make it now possible to address these questions and promise exciting discoveries in the near future.

Resumen Contexto: El agua es esencial para la vida y la conservación de su calidad es vital. La cantidad de agua dulce existente en la Tierra es limitada, y su calidad está sometida a una presión constante. Esta problemática hace necesario generar herramientas que permitan medir los impactos potenciales que causan las actividades humanas sobre el recurso hídrico. Por ello, esta investigación determina la huella hídrica en la zona costera de San Blas, México. Método: Este trabajo estima la huella de agua en la zona costera del municipio de San Blas, Nayarit (México), a partir del método de escasez de agua, que tiene lugar cuando la demanda supera el suministro de agua dulce en un área determinada. Este método considera el índice de estrés hídrico en su cálculo. Resultados: La huella de agua para cuantificar el volumen total del líquido utilizado por los habitantes resulta inferior al promedio nacional. De esta manera, la zona de estudio no presenta estrés hídrico, ya que la extracción de agua no ha superado su disponibilidad. Conclusiones: La huella hídrica por el método de escasez puede considerarse como un indicador de la proporción de extracciones anuales y disponibilidad de agua; permite realizar comparaciones de la presión a la que está sometido el recurso hídrico entre zonas, regiones y países. Además, puede contribuir a la planificación de la distribución y gestión del agua en uso agrícola y urbano, en regiones como este estudio, donde el área de uso agrícola supera el 35 %. La estimación de la huella hídrica presentada en este trabajo considera la relación entre la extracción de agua dulce para uso humano y su disponibilidad total de agua en una región dada (WSI), el volumen distribuido y el porcentaje de cobertura de agua potable del área en estudio. Abstract Context: Water is essential for life and conservation of water quality is vital. The amount of fresh water on earth is limited and its quality is subject to constant pressure. This problem makes it necessary to present tools that allow quantifying the possible impacts generated by human activities in this resource. Therefore, this research determines the water footprint in the coastal area of San Blas, Mexico. Method: This work estimates the water footprint in the coastal area of he municipality of San Blas, Nayarit, Mexico, according to the method of water scarcity that occurs when demand exceeds the supply of fresh water in a given area. This method considers the water stress index in its calculation. Results: The result shows that the water footprint to quantify the total volume of water used by the inhabitants is less than the national average. In this way, the study area does not present water stress, since the extraction of water has not exceeded its availability. Conclusions: The water footprint by the scarcity method can be considered as an indicator of the proportion of annual withdrawals and water availability; It allows comparisons of the pressure to which the water resource is subjected between zones, regions and countries. In addition, it can contribute to the planning of the distribution and management of water in agricultural and urban use, in regions such as this study, where the area of agricultural use exceeds 35%. The estimation of the water footprint presented in this work considers the relationship between the extraction of fresh water for human use and its total water availability in a given region (WSI), the volume distributed and the percentage of drinking water coverage of the area in study.

Objective: A simple, selective, sensitive, specific, and spectrophotometric method has been developed for the detection of imatinib mesylate in pure form and formulations. Methods: The analytical condition was optimized for the drug, carried out as per the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Results: The drug shows absorption at 232.0 nm and obeyed beers law in the wide concentration range from 0.5 to 4.0 μg/ml. The lower limit of detection was found to be 0.331 μg/ml and the limit of quantification to be 1.004 μg/ml. The regression equation was found to be y = 0.08x. The precision of the method was found to be 99.04%±0.527% and the percentage of drug recovered by this method is 100.13%±1.375%. Conclusion: The method is simple and suitable for determination for imatinib mesylate in pure and pharmaceutical preparation.

Vaccines are biological preparations that improve immunity to particular diseases and form an important innovation of 19th century research. It contains a protein that resembles a disease-causing microorganism and is often made from weak or killed forms of the microbe. Vaccines are agents that stimulate the body's immune system to recognize the antigen. Now, a new form of vaccine was introduced which will have the power to mask the risk side of conventional vaccines. This type of vaccine was produced from plants which are genetically modified. In the production of edible vaccines, the gene-encoding bacterial or viral disease-causing agent can be incorporated in plants without losing its immunogenic property. The main mechanism of action of edible vaccines is to activate the systemic and mucosal immunity responses against a foreign disease-causing organism. Edible vaccines can be produced by incorporating transgene in to the selected plant cell. At present edible vaccine are developed for veterinary and human use. But the main challenge faced by edible vaccine is its acceptance by the population so that it is necessary to make aware the society about its use and benefits. When compared to other traditional vaccines, edible vaccines are cost effective, efficient and safe. It promises a better prevention option from diseases.

Due to antimicrobial resistance and the adverse health effects that follow broad and inappropriate use of antibacterial agents, new classes of antibacterials with broad and strong bactericidal activity and safety for human use are urgently required globally, increasingly so with the onset of climate change. However, R&D in this field is known to be rarely profitable, unless a cost-effective, flexible, and convenient platform that ensures the production of workable candidate antibacterials can be developed. To address this issue, inorganic nanomaterials have been considered for their bactericidal activities, yet further investigations of composition crystalline modifications and/or surface biomaterial coatings are still required to provide effective and safe antibacterial nanoparticles. In this study, we developed a plug-in system comprising a spark plasma reactor and a flow heater under nitrogen gas flow to supply precursor inorganic nanoparticles (Cu-Te configuration) that can be modulated in-flight at different temperatures. From antibacterial and toxicological assays in both in vitro and in vivo models, bactericidal and toxicological profiles showed that the plug-in system-based platform can be used to identify key parameters for producing safe-by-design agents with antibacterial activity [>88% (in vitro) and >80% (in vivo) in antibacterial efficiency] and safety (>65% in in vitro viability and >60% in in vivo survival rate).

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 method of prohibiting khamar in the Qur'an is a way of educating a society by using a gradual approach. The first stage of the Qur'an provides an overview of the human use of dates and grapes, the second stage, the Qur'an in more detail Describes the advantages and disadvantages of drinking khamar. At these two stages, the Qur'an implements the concept of self-cultivation with logic, similarly on the resolving of game addiction. The stage that can be done by parents is to begin to explain to the child about what benefits and what the losses that children get from the game he played. Parents then make a deal with the child about the consequences of his actions in the form of rewards and punishment.

Did Arcadia actually exist as a place? How do species evolve? Would it be possible to harness and tame a whale for human use? Natural scientists and explorers pondered a range of fascinating – and ...