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The management of SARS-CoV-2 has not yet been clearly determined and is based on potential therapies evaluated during the SARS-CoV and MERS-CoV outbreaks. An emerging potential therapeutic approach currently being evaluated in numerous clinical trials is the remdesivir agent, which acts on COVID-19 by interfering with key steps in the virus replication cycle. It is considered a therapeutic option to be evaluated against COVID-19, based on data on its in vitro and in vivo activity against MERS-CoV and SARS-CoV coronaviruses. In this work, we provide an overview of remdesivir's discovery, mechanism of action, and the current studies exploring its clinical effectiveness. Recommendations for its use against COVID-19 infection are also summarized.

Graphical abstract, BV (bacterial vaginosis) influences 20%–40% of women but its etiology is still poorly understood. An open question about the BV is which of the hundreds of bacteria found in the human vaginal microbiome (HVM) are the major force driving the vaginal microbiota dysbiosis. Here, we recast the question of microbial causality of BV by asking if there are any prevalent ‘signatures’ (network motifs) in the vaginal microbiome networks associated with it? We apply a new framework [species dominance network analysis by Ma & Ellison (2019): Ecological Monographs) to detect critical structures in HVM networks associated with BV risks and etiology. We reanalyzed the 16 s-rRNA gene sequencing datasets of a mixed-cohort of 25 BV patients and healthy women. In these datasets, we detected 15 trio-motifs that occurred exclusively in BV patients. We failed to find any of these 15 trio-motifs in three additional cohorts of 1535 healthy women. Most member-species of the 15 trio motifs are BV-associated anaerobic bacteria (BVAB), Ravel’s community-state type indicators, or the most dominant species; virtually all species interactions in these trios are high-salience skeletons, suggesting that those trios are strongly connected ‘cults’ associated with the occurrence of BV. The presence of the trio motifs unique to BV may act as indicators for its personalized diagnosis and could help elucidate a more mechanistic interpretation of its risks and etiology. We caution that scarcity of large longitudinal datasets of HVM also limited further verifications of our findings, and these findings require further clinical tests to launch their applications.

Dry eye disease (DED) has a prevalence of between 5 and 50%, depending on the diagnostic criteria used and population under study. However, it remains one of the most underdiagnosed and undertreated conditions in ophthalmology. Many tests used in the diagnosis of DED rely on an experienced observer for image interpretation, which may be considered subjective and result in variation in diagnosis. Since artificial intelligence (AI) systems are capable of advanced problem solving, use of such techniques could lead to more objective diagnosis. Although the term 'AI' is commonly used, recent success in its applications to medicine is mainly due to advancements in the sub-field of machine learning, which has been used to automatically classify images and predict medical outcomes. Powerful machine learning techniques have been harnessed to understand nuances in patient data and medical images, aiming for consistent diagnosis and stratification of disease severity. This is the first literature review on the use of AI in DED. We provide a brief introduction to AI, report its current use in DED research and its potential for application in the clinic. Our review found that AI has been employed in a wide range of DED clinical tests and research applications, primarily for interpretation of interferometry, slit-lamp and meibography images. While initial results are promising, much work is still needed on model development, clinical testing and standardisation.

Introduction Fatigue is a prevalent and potentially debilitating symptom that impacts the health-related quality-of-life of individuals diagnosed with acute and chronic medical conditions. Yet, its etiologic mechanism is not fully understood. Additionally, the assessment and determination of the clinical meaning of fatigue and its multidimensionality may vary by medical condition. Methods A scoping literature review was conducted to investigate how fatigue is defined and measured, including its dimensions, in non-oncologic medical conditions. The PubMed database was searched using keywords. Results Overall, 8376 articles were screened at the title/abstract levels, where 293 articles were chosen for full-text review that mentioned fatigue or included fatigue measures. The review of the full text excluded 246 articles that did not assess at least one fatigue dimension using validated questionnaires and clinical tests. The final set included 47 articles. Physical fatigue was the most assessed fatigue dimension and the Multidimensional Fatigue Inventory was the most widely used questionnaire to assess fatigue in this review. Limitations This review was limited by including only English-language publications and using PubMed as the sole database for the search. Conclusions This review affirms that fatigue is a multidimensional construct, agnostic of medical condition, and that individual fatigue dimensions can be measured by validated clinical measures. Future research should focus on expanding the repertoire of clinical measures to assess specific fatigue dimensions., Highlights • The 27 different validated clinical measures used to assess fatigue and its dimensions; 20 instruments assessed the physical, 8 for mental, 7 cognitive, 5 for motivational, 2 for emotional, 1 peripheral, 1 for central, 1 psychosocial. • Physical was the most measured dimension, as assessed in 42 of 47 included articles. • This review affirms that fatigue is a multidimensional construct, agnostic of medical condition, and that individual fatigue dimensions can be measured by validate clinical measures.

The expanding CRISPR-Cas9 technology is an easily accessible, programmable, and precise gene-editing tool with numerous applications, most notably in biomedical research. Together with advancements in genome and transcriptome sequencing in the era of metadata, genomic engineering with CRISPR-Cas9 meets the developmental requirements of precision medicine, and clinical tests using CRISPR-Cas9 are now possible. This review summarizes developments and established preclinical applications of CRISPR-Cas9 technology, along with its current challenges, and highlights future applications in translational research. Keywords: CRISPR-Cas9, gene editing, off-target, gene therapy, tumor immunotherapy

Medical imaging has undergone tremendous growth over the last few decades and now plays a central role in clinical oncology. The future of imaging in the management of oncology patients is molecular imaging with specific targeted agents. Molecular imaging differs from conventional anatomical imaging as we visualize the target molecules-of-interest with the help of imaging probes. It is certain that molecular imaging will have a major impact on oncology and personalized medicine in near future by allowing earlier diagnosis, assessing early response to treatment, and predicting treatment response. It will, hopefully, also have an impact on drug development by streamlining preclinical and clinical tests for new drug candidates. This field of medical imaging had emerged from the field of radiology in the mid-20th century. It focuses on visualization, characterization, and quantification of biologic processes of medical interest at the cellular and molecular levels in living organisms. This enables us to image and study disease mechanisms in their own physiologic environment. Molecules of interest may be either ones produced naturally by the body, or synthetic molecules produced in the laboratory and injected into a patient by the doctor called as biomarkers. Their interaction with the tissue surroundings alters the image according to molecular changes occurring within the area of interest. Cancer is a multifactorial genetic disease that is a result of aberrations of mechanisms at the cellular level. To target the key areas with the help of imaging modalities, we need to address these molecular events. The oncogenic process is a complex outcome of mutations and deletions occurring at the molecular level. Thus, it is impelling that treatment strategies should not only be directed at the tumor cells but also at the microenvironment of tumor cells.

Posterolateral rotatory instability (PLRI) is the most common form of symptomatic acute and chronic elbow instability. Diagnosis is usually made using a combination of clinical tests and imaging modalities; however, in more subtle forms of instability, these measures may be equivocal. Arthroscopy is a valuable adjunct for diagnosis and treatment of PLRI. It allows direct appreciation of the instability process, quantification of the degree of instability, and identification of concurrent associated pathology. The aim of this technique article is to report a series of reproducible arthroscopic tests used for diagnosis of PLRI with examples of normal and pathologic arthroscopic findings.

Nanotechnology-based therapies are intended to significantly improve drug delivery, therefore enabling the creation of more efficient devices to prevent, diagnose, and/or cure disease. These drug delivery systems, designed at the smallest scale possible, are meant for maximal distribution, specific target internalization, and intracellular agent activity while preserving the integrity of healthy tissues or organs. In this chapter, we will discuss (i) the key properties of currently available formulations; (ii) the challenges posed by the most common routes of administration, namely, oral, ocular, intranasal, intra-/transdermal, intramuscular, intravenous, and intrathecal; highlighting (iii) the physiological barriers faced by nanoformulations; and (iv) the strategies devised to evade these endogenous clearance mechanisms and to reduce off-target toxicity. These challenges require initially the fine-tuning of features like the mode of transportation (covalent bound, adsorption, and entrapment); charge; ligand expression for functionalization purposes; and size, shape, and composition of the formulation. Then the next steps consist of pharmacokinetic and toxicity studies in in vitro and/or in vivo models before proceeding to clinical tests. Considering the time-consuming and costly hurdles inherent to the discovery and development of new formulations, only a reduced number of nanotechnology-based pharmaceuticals eventually reach the patient. Nevertheless, continuous advances in the field of nanomedicine are bolstering our knowledge on safer and more efficient tools for optimal intracellular delivery and targeting.

Advances in cell and molecular biology studies have revolutionized the diagnosis and treatment of many different diseases. Cell and molecular diagnostics (CMD) have become an essential part of investigations required in providing optimal care and has become an important tool for the health care providers for better treatment. CMD gives insights into the pathogenesis and prognosis of various diseases. Rapid technological advances have helped to increase the speed and performance of various molecular assays thereby reducing turnaround time, in turn translating to providing better clinical services. With the increase in CMD applications to clinical services, entire world has seen a sudden spurt of cellular and molecular labs. However, this has highlighted an acute shortage of trained laboratory personnel who can carry out cellular or molecular assays in a diagnostic mode. Understanding the mechanisms of disease at the molecular and genetic levels can now be translated into diagnostic, prognostic, and therapeutic applications in modern medicine. Molecules at abnormal levels (quantitative or qualitative) provide not only a signature for the presence of a disease, but also the indication for a drug targeting the specific abnormal function. Concurrently, the role of CMD has expanded from mere study observations to constantly translating new discoveries and novel technologies into useful clinical tests that provide a molecular fingerprint of diseases and that are predictive of the response. In the introductory chapter we will cover the importance of biological sample collection from different methods; cell-based diagnostic methods, cellular pathway diagnostic targets, and molecular-based methods.

Proteins are the functional output of genes. The proteome is defined as the expressed protein and peptide complement of a cell, organ, or organism, including all isoforms and posttranslational variants. While an organism possesses a single genome, it possesses multiple proteomes depending on the cell compartment, the type of cell, type of tissue, and organ which undergo constant temporal changes. The term proteomics summarizes all of the procedures required for analysis of a proteome. Clinical proteomics in nephrology aims at providing the clinician with tools to accurately diagnose and monitor patients as well as predict treatment effects, thus, enabling individualized patient management. Protein-marker based strategies hold the promise of being sensitive, specific, predictive, and able to outperform the currently established clinical diagnostic tests overall. Proteomics research in nephrology has primarily focused on kidney tissues and urine. Urine is attractive since it is considered a “proximal” matrix, meaning it is a biofluid that is in direct contact with the site of disease. Proximal matrices are local sinks for metabolites, proteins, or peptides secreted, shed or leaked from the tissue of interest. Thus urine protein patterns often reflect disease processes of and drug effects on the kidney. Proteomics commonly involves sample fractionation, separation, mass spectrometry, and biostatistical analysis. The technologies required to enable implementation of truly nonbiased proteome analysis in clinical practice are not available yet. Proteomics is a hypothesis-generating technology that plays an important role in nephrology research today regarding molecular marker discovery and qualification of molecular markers during their development into potential clinical diagnostic tools. As evidenced by the regulatory approval of protein kidney injury markers in rats for preclinical drug toxicity studies, proteins in urine as diagnostic markers are starting to have an impact in clinical medicine. It is reasonable, therefore, to expect that proteins and the analysis of combinatorial protein patterns, especially in urine, will play an increasingly important role as clinical diagnostic tools in nephrology in the near future.

While mass spectrometry (MS) has been available as an analytical tool for more than 100 years and analytical methods based on MS have been used by both scientific researchers and industrial application scientists for quantitative and qualitative analyses routinely, the use of this technology in clinical laboratories is a relatively new development. Based on emerging needs for patient care, the importance of MS in the clinical laboratory is increasing, and doesn’t appear to be slowing down any time soon. Emerging unmet needs for testing often occur because vendors of in vitro diagnostic devices wait until the clinical utility of a particular assay is established and widely accepted prior to the development of a commercial assay. As a result, improvements in patient care from these new clinical tests can be delayed until a commercial assay is available. For laboratories with the capability to develop and implement laboratory-developed tests, MS provides an attractive alternative solution based on the ability to rapidly develop an analytically robust assay with excellent analytical sensitivity and specificity. In some cases, it offers an attractive alternative to commercially available assays that have already been developed, but do not offer acceptable performance relative to the clinical decision point. Liquid chromatography (LC)-MS technology shows significant potential as a tool to rapidly develop clinical assays for emerging biomarkers, and advances in instrumentation are likely to enable application of LC-MS technology in routine clinical diagnostic testing.

Dentine hypersensitivity is a significant burden for patients and practitioners. Knowing its prevalence and methods for accurate diagnosis is imperative to guide treatment decisions and develop new treatments. In this chapter, we describe the methods commonly used to diagnose dentine hypersensitivity including self-reports, clinical tests to elicit pain, and clinical examination to exclude other causes of tooth pain. The prevalence of dentine hypersensitivity is presented through a systematic review of the studies published since 1964. A wide range of estimates of prevalence of dentine hypersensitivity was observed in 56 studies, from as low as 1.8% to as high as 84%, and this heterogeneity could not be completely explained by study characteristics. The meta-analysis revealed that the average prevalence of all studies was 33% and the best estimate was approximately 10%.

Platelet function tests are traditionally utilized to aid in the diagnosis and management of patients with platelet and haemostatic disorders. A number of dedicated platelet function instruments have now become available that are much simpler to use and are beginning to be utilized as point of care instruments. These can now provide measurement of platelet function within whole blood without the requirement of sample processing. Some are also beginning to be incorporated into routine clinical use and can be utilized as not only as general screening tests of platelet function but to monitor anti-platelet therapy and to potentially assess both risk of bleeding and/or thrombosis. This chapter will discuss the potential utility of tests/instruments that are currently available.

The search for new and more predictive biomarkers in toxicology is an important pursuit across many discovery technologies (particularly ‘omics’ technologies) including, genotyping, transcriptomics, proteomics, and metabolomics. In fact, many future personalized health interventions or products rest squarely on the ability to discover and validate new biomarkers and on the healthcare industry's ability to commercialize these new clinical tests. The biomarkers themselves can be nearly anything that distinguishes one individual from another. Unfortunately, likely due to technical isssues associated with ‘omics’ technologies (such as lack of annotation of detected analytes, lack of sensitivity, and difficulties in data analysis and interpretation), these general screening methods for the discovery of new biomarkers have been very challenging with relatively few success stories. Many FDA approved companion diagnostics come from a deep understanding of the drug metabolism or function and were not discovered through profiling ‘omics’ technologies. In addition, many diseases involve multiple molecular pathway disturbances and validating any one change in a large set of biomarker data is hugely challenging. One recent promising technology with the potential to overcome a number of these issues is metabolomics, or in the case of applying metabolomics to toxicology – toxicometabolomics. The focus of this chapter will be to explore biochemical biomarkers in toxicology research and ways in which toxicometabolomics is an ideal technology for gaining these new insights.

The search for new and more predictive biomarkers in toxicology is an important pursuit across many discovery technologies (particularly “omics” technologies) including, genotyping, transcriptomics, proteomics, and metabolomics. In fact, many future personalized health interventions or products rest squarely on the ability to discover and validate new biomarkers and on the healthcare industry's ability to commercialize these new clinical tests. The biomarkers themselves can be nearly anything that distinguishes one individual from another. Unfortunately, likely due to technical isssues associated with “omics” technologies (such as lack of annotation of detected analytes, lack of sensitivity, and difficulties in data analysis and interpretation), these general screening methods for the discovery of new biomarkers have been very challenging with relatively few success stories. Many FDA approved companion diagnostics come from a deep understanding of the drug metabolism or function and were not discovered through profiling “omics” technologies. In addition, many diseases involve multiple molecular pathway disturbances and validating any one change in a large set of biomarker data is hugely challenging. One recent promising technology with the potential to overcome a number of these issues is metabolomics, or in the case of applying metabolomics to toxicology – toxicometabolomics. The focus of this chapter will be to explore biochemical biomarkers in toxicology research and ways in which toxicometabolomics is an ideal technology for gaining these new insights.

A disease causes specific changes in the profiles (chemical and biochemical) of biological fluids and tissues before the development of clinical symptoms. Proteomic and metabolomic analysis of biological samples can reveal changes in abundance levels of proteins and metabolites, with these changes potentially functioning as useful diagnostic and prognostic clinical tests. To become a clinically approved test, a potential biomarker needs to be confirmed and validated. Confirmation and validation apply to the analytical methodology as well as the candidate biomarker. A search of the scientific and medical literature indicates that many studies reported the discovery of potential biomarkers without proper validation. In this chapter, the discussion centers on biomarker study design and execution and details the steps needed for a successful biomarker discovery.

Publisher Summary This chapter reviews that dizziness is common in older people and the number of patients presenting with it will only continue to increase. The common forms of dizziness can be identified and treated, but for some patients a specific diagnosis cannot be made even after a thorough history and examination. It discusses that testing may help identify or quantify abnormalities but should be interpreted with caution in older patients, because abnormalities are common even among healthy older people without complaints of dizziness, thus lowering the diagnostic accuracy. The chapter also reviews that when developing new clinical tests or improving upon old ones, care should be taken to properly design the studies and report the results in a manner allowing the readers to assess the potential value of the test. The most important clinical issues in older patients are to identify the treatable causes of dizziness early, address any possible contributing factors, and take measures to prevent falls. The elderly person who falls is at high risk for a hip fracture, other disabling injury, and even death.

A model-based experiment design techniques is used to design improved test protocols for the identification of the parameters of a detailed physiological models of diabetes specific to single subjects. This paper considers the problem of parameter identification focusing on the impact of some decision variables such as sampling frequency and test duration on both the design effectiveness and the ability to meet safety critical constraints on the subject response. The proposed methodology permits to establish the minimal experimental budget required to achieve a satisfactory parameter estimation from the planned test without upsetting the subject excessively.

Publisher Summary This chapter introduces an anatomical schema of cognitive failures and then proposes ways to test mental functions. The testing of mental functions through concise clinical tests or extensive neuropsychological batteries has long been an important instrument for localizing brain lesions. Mental testing performed by most behavioral neurologists, continues to be guided by anatomical consideration. The approach described in the chapter is based on the observation that most mental failures have a clear anatomical significance. A simple schema of cognitive disorders and their association with damage of specific regions of the brain is presented in the chapter. This schema serves as a guideline for the mental status testing. The chapter describes some techniques to test mental functions. The bedside tests described in the chapter are but suggestions that should be adapted to the clinical practice. Although it is wise to test all mentioned cognitive domains, the examiner should feel free to replace proposed tests by more difficult or easy items, according to the clinical situation. It may also be useful to include extracts from or complete standardized tests or to have a series of questions prepared to explore behavioral disorders.

Publisher Summary Medical image data are acquired for different purposes, such as diagnosis, therapy planning, intraoperative navigation, and postoperative monitoring. The most important and widespread use of medical image data is for diagnostics. The acquisition of medical image data is usually not the first step in a diagnostic process; exceptions are urgent cases or severe accidents with unconscious patients. Simple diagnostic procedures such as palpation, auscultation with a stethoscope, and blood pressure measurements are carried out. As a further building block of diagnosis, clinical tests are performed in which liquids of the body, such as blood and urine, are analyzed. Many diagnostic procedures can be completed with these examinations. The chapter also discusses medical image data acquired primarily when the previously described diagnostic steps raised the suspicion for a severe disease, such as a malignancy or heart disease. From a computer science perspective, this situation is the motivation for developing electronic patient records and hospital information systems, which contain this information and share it among all doctors involved in the diagnosis and treatment of the patient.

Platelets play a pivotal role in both normal hemostasis and pathological bleeding and thrombosis.1 Most platelet function tests have been traditionally utilized for the diagnosis and management of patients presenting with bleeding problems rather than thrombosis.2 However, as platelets are now implicated in the development of atherothrombosis, which is the leading cause of mortality in the Western world,3,4 new and existing platelet function tests are increasingly being used for monitoring the efficacy of antiplatelet drugs to treat these conditions and/or to try to identify patients at risk of arterial disease. Conversely, as increasing numbers of patients are being treated with antiplatelet drugs, there is an associated increased risk of bleeding, especially during trauma and surgical procedures. Platelet function tests are therefore also being increasingly proposed as presurgical/ perioperative tools to aid in the prediction of bleeding and for monitoring the efficacy of various types of prohemostatic therapies. This, coupled with the development of new, simpler tests and point-of-care (POC) instruments, has resulted in the increasing tendency of platelet function testing to be performed away from specialized hemostasis clinical or research laboratories, where the more traditional and complex tests are still performed. 5,6

Publisher Summary This chapter discusses a variety of available approaches for testing the autonomic nervous system and their technical and methodological limitations. The discussion is complete but not exhaustive, and the focus is on techniques that have been used in clinical contexts or show particular promise for clinical use. The current understanding of the clinical relevance of autonomic dysfunction followed the development of autonomic testing and its application to clinical populations. It is now apparent that autonomic testing predicts prognosis in patients with diabetes, identifies some patients with asymptomatic myocardial ischemia, and correlates with fatigue and impaired exertional capacity in a variety of medical and neurological disorders. Several simple clinical tests can also be performed in the EMG laboratory. Simply measuring the blood pressure response to sitting and standing is perhaps the most informative clinical test of autonomic function. Skin wrinkling and pressor response to ice water immersion or handgrip are other simple tests that can provide a rapid screening of autonomic function as well.

Brain death, the colloquial term for the determination of human death by showing the irreversible cessation of the clinical functions of the brain, has been practiced since the 1960s and is growing in acceptance throughout the world. Of the three concepts of brain death--the whole-brain formulation, the brain stem formulation, and the higher brain formulation--the whole-brain formulation is accepted and practiced most widely. There is a rigorous conceptual basis for regarding whole-brain death as human death based on the biophilosophical concept of the loss of the organism as a whole. The diagnosis of brain death is primarily a clinical determination but laboratory tests showing the cessation of intracranial blood flow can be used to confirm the clinical diagnosis in cases in which the clinical tests cannot be fully performed or correctly interpreted. Because of evidence that some physicians fail to perform or record brain death tests properly, it is desirable to require a confirmatory test when inadequately experienced physicians conduct brain death determinations. The world's principal religions accept brain death with a few exceptions. Several scholars continue to reject brain death on conceptual grounds and urge that human death determination be based on the irreversible cessation of circulation. But despite the force of their arguments they have neither persuaded any jurisdictions to abandon brain death statutes nor convinced medical groups to change clinical practice guidelines. Other scholars who, on more pragmatic grounds, have called for the abandonment of brain death as an anachronism or an unnecessary prerequisite for multi-organ procurement, similarly have not convinced public policy makers to withdraw the dead-donor rule. Despite a few residual areas of controversy, brain death is a durable concept that has been accepted well and has formed the basis of successful public policy in diverse societies throughout the world.

Publisher Summary This chapter describes the various clinical abnormalities identified in clones and provides clues on how to manage these abnormalities. In somatic-cell-cloned animals, placental abnormalities occur at a high incidence in early- and late-term cloned fetuses. First-trimester somatic-cell-cloned fetuses display a wide variety of placental morphologies, with a variable number and development of cotyledons, allantoic epithelium, and vascularization. In addition to underdeveloped placentas, overdevelopment has been reported in cloned mice, with placentas twice the normal weight. Fetuses recovered shortly after death are grossly normal; thus, it appears that the lack of normal placentation, rather than fetal abnormalities, is the likely cause of embryonic death. This can be attributed to inadequate placental development, which results in starvation due to inadequate maternal–fetal contact and poor transfer of nutrients. High-risk pregnancies can be identified by external examination and clinical observations in conjunction with ultrasonographic imaging and clinical tests. The presence of placental edema or excessive allantoic fluid often indicates a poor outlook for the fetus. Monitoring of body weight, feed intake, abdominal circumference, heart/respiratory rate, and body temperature can provide valuable data to assess the health of the recipient animal. Transabdominal ultrasonography can be used to monitor fetal viability and as an aid to detect increased allantoic fluid volumes. The most controlled method of delivery for the neonate is usually a cesarean section. The cesarean should ideally be performed at the beginning of second-stage labor, when the cervix is fully dilated. Waiting until second-stage labor gives the fetus maximum opportunity to be ready for birth.

SUMMARY. The aim of this preliminary study was to investigate the reliability of a selection of manual tests used for the examination of instability of the upper cervical region. Eleven children with Down's syndrome were examined by four independent examiners with different levels of experience in manual therapy. Three tests as described by Van der El (1992) were used: the lateral displacement test, the Sharp-Purser test, and the upper cervical flexion test. Scores of tests and retests were statistically analysed by calculating the percentage of agreement, and Brennan and Prediger's modified kappa, and with the binomial test. The results showed a significant agreement between test and retest for the upper cervical flexion test in three out of four investigators. Agreement between investigators was significant in four out of six combinations between two investigators, and near to significant for this test (P(bin) =.07) in the two remaining combinations. The other two investigated tests and the total score showed no tendancy towards a consistent level of significant intra- or interobserver reliability. Copyright 1997 Harcourt Publishers Ltd.

Publisher Summary The development process begins after the complete discovery of the product. This is a very lengthy, expensive, and tightly regulated process. Pharmaceutical companies spend much of the product development conducting clinical trials required to pass the safety, efficacy, and quality requirements of the drug, followed by the FDA review and approval. Product development also includes pharmaceutical development of dosage forms and formulations. In parallel with product development, process development is carried out. In microbial process biotechnology, it may start at the time of product discovery, when a new microbial product is available and when an appreciable amount of product is needed for chemical characterization. The technical development is expanded when a compound is more advanced and enters more extensive biological and preclinical test. Further process improvements and scale-up are needed for clinical tests and as the production decision is near. In addition, market development begins with the cost/benefit analysis, grows with product innovation, and peaks with capturing a substantial share of market.

Otoacoustic emissions can be used to study cochlear function in an objective, non-invasive and rapid manner. These and other desirable features of emissions have inspired a significant amount of investigation into the practicalities of utilizing evoked emissions as clinical tests of hearing. Variables which affect the measurement of emissions can be sorted into two major categories consisting of factors affecting either emission generation or expression. The present report consolidates and summarizes recent findings of a series of experiments in our laboratory which address both the generation and expression of transiently evoked and distortion-product otoacoustic emissions. Because these two emission types have the greatest promise of becoming clinically useful, a complete understanding of the factors responsible for their measured properties is particularly important.

Hydroxyapatite (HA), produced by chemical precipitation is normally used as a bone graft. Hydroxyapatite modified (HAM), allows the fabrication of granules of a different material with HA structure. The aqueous medium that involves HAM particles has higher pH than the particles of HA, improving the conditions of formation of new bone. In this work the chemical and physical properties of this new HAM granules were studied. A clinical test in dental alveolus in 10 patients, using plaster as binder was carried out. Microradiographic results and histological cuts, retrieved from experimental surgery in dogs, showed the useful behaviour of the association HAM/plaster.

This chapter reviews the basis of normal neuromuscular transmission, points out where abnormalities in transmission can develop, and discusses the various diseases in this category. The basic abnormalities and types of clinical tests of neuromuscular transmission are explained, with emphasis on their values and limitations. The most conventional way to assess neuromuscular transmission is to measure changes in amplitude of the maximum compound M-potential (MCMP) in response to supramaximal stimulation of the motor nerve. For such evaluations, surface electrodes are employed because they best reflect the activities of the whole muscle or group of muscles. The amplitude of the MCMP in such recordings depends most importantly on the number of MFs that generate action potentials in the underlying muscle(s), the temperature of the muscle, and the degree of temporal dispersion in the summation of the component action potentials. Repetitive stimulation of the motor nerve in healthy humans produces characteristic changes in the amplitude and duration of the MCP whose magnitude depends on frequency of stimulation. In the evaluation of changes in the M-potential in response to repetitive stimulation, it is vital to be aware of and to control technical errors. It is also important to ensure that the electrical stimulus remains supramaximal throughout the stimulus program and does not extend to other nearby motor nerves whose muscle responses can contribute significantly to the recorded potential.

Publisher Summary Insulin was the first substance to be administered as replacement therapy in a deficiency disorder—diabetes mellitus—the first peptide hormone to be sequenced, and among the first peptide hormones to be produced by recombinant technology. This chapter provides an overview of insulin, which is the first product of recombinant research to be studied extensively in clinical tests. It discusses the difficulties encountered in the radioimmunoassay (RIA) for human and pork insulin in the serum of volunteers who received these two types of insulin. The chapter also presents preliminary information on patients who never received insulin and were treated with biosynthetic human insulin (BHI) for six months. The BHI was all derived from human A and human β chain material produced by recombinant techniques combined and purified by chemical methods.

Publisher Summary This chapter discusses airborne contaminants. Many industrial processes produce airborne contaminants and their most common route of absorption is by inhalation. As world industry and the speed of production grow, the volume and variety of contaminants increase so that potential risks also increase. Most industrial processes involve known materials. Occasionally their composition is obscure or uncertain, perhaps through the use of proprietary formulations and trade names or the formation of unexpected by-products in chemical reactions. The identification of unknown air constituents occasionally calls for highly specialized tools, such as emission, x-ray, or mass spectroscopy. The identification of allergenic materials may require clinical tests of sensitization. In evaluating dusts or fumes of variable composition, it may be necessary to separately identify and assay one or several toxic components sampled under various working conditions. Both the physical and chemical properties of individual contaminants may be used in measurement techniques, selecting a property that is specific to the substance so as to minimize any interference from similar or unrelated compounds that may be present.