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Operation and reoperation rates for Crohn’s disease remain unacceptably high. This is despite intensive scientific and clinical investigation for several decades. Recent clinical findings indicate that inclusion of the mesentery during surgery for Crohn’s disease, may be associated with reduced requirement for re-operation. At the least, the findings indicate that resection of the mesentery is associated with slowing of disease progression. Several clinical trials have commenced aimed at further determining the effects of inclusion of the mesentery during resection. In tandem with these, several groups have identified pathobiologic links between mesenteric cellular/molecular events, and intestinal manifestations of Crohn’s disease. Collectively the findings indicate the mesentery plays a pathobiologic role in Cohn’s disease and that alterations of mesenteric inputs (whether these by surgical or pharmaco-therapeutic means) will provide novel and beneficial therapeutic strategies.

Cardiovascular magnetic resonance (CMR) and coronary computed tomography (CCT) are established cardiovascular image diagnosis methods and becoming routine in the clinical investigation of cardiomyopathies.

This chapter is dedicated to describing the background that makes the examination of human semen much different from many other clinical laboratory investigations. Many of these aspects are due to the very specific physiology of ejaculate production. Still, basic principles for clinical laboratory science are valid, although not always complied in real-life laboratory work. Since 1980, the World Health Organization (WHO) has provided a series of manuals with recommendations for the standard operating procedures for the examination of human semen. Presently, a formal International Standards Organization (ISO) based on the best available science is under development. The aim of this chapter is to give an outline of these attempts for standardization and how it is expected to contribute to improvement of clinical investigation and treatment of men and to enhanced scientific development of the understanding of male reproductive organ function.

This unusual history of how a small team transformed the global system composed of Army and then DoD medical research processes has been unrecorded until now. It offers guidance to others attempting to transform similarly large systems. It begins with an evaluation of the Department of Clinical Investigation (DCI) at the US Army Medical Center (MEDCEN) in 2005, the formation of a collaboration team in 2006, and the team’s vision of an electronic records management tool (ERMT) for its documents in 2007. From this small beginning, these disparate efforts combined to transform the management of research protocol submission, review, and approval processes as well as research protocols and supporting documents at all DoD MEDCENs. Before this history began, the Army’s MEDCENs used a paper-based research protocol submission and review process by the Institutional Review Board (IRB) for the approval of medical research on human subjects (and animals). The team’s evaluation of the existing processes added metrics that enabled the design of an electronic system to measure the performance of the Army’s medical research mission. Merging the evaluation and the team’s vision to replace the Army’s paper-based IRB occurred with the purchase of a commercial electronic IRB system. It took until 2008 for the eIRB to become funded and another year to begin operations, but within 2 years of start-up, it was rapidly adopted across DoD’s global research community to become the largest enterprise eIRB in the world. In 2011, a formal evaluation project was proposed to measure the impact of the eIRB’s unexpected success across DoD; the impact study was funded in 2012, begun in 2013 and finished in 2014 when we end this history; subsequently, the team was disbanded. Although not a part of this history, we briefly address a few of the statistical results of the eIRB’s impact now and more fully at a later time. We close with a postscript to update readers on the unexpected closure of the eIRB and its reincarnation.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a treatment related toxicity that burdens the quality of life of cancer survivors. Unfortunately, no efficacious treatment (symptomatic or preventive) is available for this condition for many reasons. First, a still incomplete pathogenetic knowledge hampers the recognition of a strong biological rationale for clinical trials. Second, there are some methodological issues in clinical trial design that still need to be addressed. In this chapter we will present an overview of strategies that were undertaken in the past and some that are now undergoing clinical investigation for prevention of CIPN. This is a complex challenge that will require multidisciplinary collaborative research between basic scientists, health care professionals, and patient representatives.

While patch test is the main tool for clinical investigation in the field of contact dermatitis, other methods may represent a useful, often essential complement. Additional in vivo and laboratory tests may be used to explore non-type IV immune responses (mainly IgE-mediated hypersensitivity), to assess the irritant and/or sensitizing potential of products or materials of unknown composition, or to verify the actual relevance of a positive reaction to patch test in doubtful cases. Spot tests and other chemical or physical tests on materials help to define the components (and possible sensitizers) of objects and substances suspected to be the cause of contact dermatitis. Last but not least, noninvasive diagnostic techniques allow to observe and objectively measure parameters invisible or only indirectly visible to clinical observation, improving our knowledge of the pathophysiological mechanisms of contact dermatitis and, in some cases, diagnostic precision.

The current landscape of multiple myeloma treatment has greatly improved outcomes for the majority of patients and includes proteasome inhibitors, immunomodulatory imide drugs, and more recently, a number of monoclonal antibodies. However, there remains a proportion of patients that possess inherent resistance and fail to achieve optimal responses to these treatments. To overcome this problem, the continued research into and development of novel therapies is needed with the hope of further improving outcomes for all MM patients. This chapter will discuss novel targeted therapies currently being evaluated for the treatment of MM including antibody therapies, cellular therapies, and small-molecule inhibitors.

Craniofacial malformations (CM) comprise diverse diagnoses, implying a wide range of morbidity and disability; therefore, a thorough clinical investigation is indispensable. This chapter presents the clinical features of the most common CM. Clinical examination with a focus on maxillofacial investigation is presented. Maxillofacial and craniofacial assessment covers the whole region of the skull (neurocranium and viscerocranium) with special respect to the jaws, the oral cavity, and the occlusion.

In the previous chapters, the complexities of sexual problems accompanying different mental disorders have been comprehensively described. This chapter deals with the impact of psychotropic medications on sexual functioning. It encompasses biochemical mechanisms that modulate both mental state and sexual response through neurotransmitters and neurohormones, as well as indirect influences through their impact on psychomotor and cardiometabolic profile. Treatment-emergent changes in body image and sexual functioning can have a profound effect on self-esteem and intimate relationships. Treatment-related sexual side effects are underreported and poorly recognized in clinical practice of mental health professionals; although, they have a great impact on poor adherence to medication and related clinical outcomes. As sexual satisfaction is one of the most important determinants influencing well-being and quality of life, clinicians should give more attention to it and actively ask their patients about sexual functioning and adapt the medication accordingly. A comprehensive overview and practical recommendations on clinical investigation and management of psychotropic medication-related sexual side effects are presented in the second part of the chapter.

Currently available targeted therapeutic agents may lead to prolongation of overall survival, but no cure of MDS. Therefore, HCT remains the only potential curative therapy for MDS patients, but the decision for the right candidates and the optimal moment for transplant is still a challenge. The clinical basis to recommend MDS patients for transplantation besides considering only disease-specific factors is currently provided by IPSS. Fit patients with IPSS intermediate 2 or high-risk MDS should be transplanted early in their disease course. In patients with lower-risk IPSS and without poor-risk features, HCT is usually postponed until disease progression to higher-risk disease. The introduction of reduced-intensity conditioning (RIC) regimens have extended the indication for HCT to patients with comorbidities or reduced fitness. Less toxic but intensive regimens prior HCT and further prophylactic strategies to prevent relapse are currently under clinical investigation.

Many exciting food allergy therapies, including allergen-specific and non-specific treatment techniques, are currently under clinical investigation. The most well-studied treatment modality is food immunotherapy, which comes in several types including oral (OIT), epicutaneous (EPIT), and sublingual (SLIT). As a follow-up to the prior discussions on OIT and EPIT, this chapter focuses on emerging therapies that are earlier in development. With its growing body of evidence, this chapter begins with a general overview of SLIT, including its proposed mechanism of action, efficacy, and side effects. Advantages and disadvantages of SLIT when compared to OIT and EPIT are also highlighted. Other food-specific therapies reviewed in this chapter include peptide-based vaccines, recombinant allergen vaccines, allergen DNA vaccinations, and transgenic plants, which have less supportive clinical study data available but which present exciting possible treatment modalities. Studies evaluating the use of non-allergen-specific therapies in the treatment of food allergy, including anti-IgE treatment (used as monotherapy or as an adjunct to food-specific therapies), traditional Chinese medicine, and probiotics are also reviewed. Finally, understanding that food immunotherapy may become a standard part of clinical practice in the very near future, this chapter concludes with a discussion about patient-specific factors and preferences for the clinician to consider when deciding on the optimal treatment modality for an individual patient.

Clinical investigation of New Molecular Entities (NME) in oncology is changing. Drivers of this transformation are advances in pharmacological platforms, such as antibody technology, changes in the regulatory framework to accelerate approval of new treatments, and rapid scientific discovery. As a result of this transformation the established drug development process is being modified and continues to adapt. Today significant resources are being moved towards early clinical development and NME have to show early promise of therapeutic activity. The ideal NME targets specific pathways, for which diagnostic tools can be developed to select or enrich patients for the treatment with NME. This chapter reviews the critical steps enabling the early phase clinical development from the perspective of a pharmaceutical drug developer. The required steps include non-clinical pharmacokinetic (PK) studies, pharmacokinetic/pharmacodynamic (PK/PD) models, pharmacology and toxicology studies, and biomarker development plans.

New carbon nanostructured material is an ideal candidate for bone defects substitution and development of fundamental approaches for conventional orthopaedic surgery. Experiment on rats has been performed, which demonstrated biological compatibility with bone. Some characteristics of biocomposite at the bone-to-implant interface have been described. Mechanical properties of a wedge-shaped implant were tested under static and cyclic loading conditions. The need incompression between bone and implant has been shown. Clinical application of some special-shaped implants for substituting large bone defects and axial bone disorders has been performed. The excellent clinical and economic prospects of new carbon nanostructural implants have been demonstrated.

Though many agents have been identified as potential chemoprevention strategies against oral cancer, the availability of high-quality evidence supporting their use in clinical practice remains limited. In this chapter, we discuss the concept of chemoprevention of oral cancer, review the evidence of several chemoprevention agents that have undergone clinical studies, and conclude with the challenges that prevent the use of these agents in general clinical practice. We suggest that molecular identification of markers that can be measured and can correlate with disease risk and progression may aid in selecting high-risk populations and therapeutics suitable for future clinical investigation.

The elder with mild or moderate cognitive impairment (MMCI) suffers from progressive cognitive decline with increasing difficulties in performing activities of daily living. Information and Communication Technology (ICT) for Healthcare can provide solutions to relief the caregivers’ burden and to support the elder in maintaining dignity and independence. The UNCAP European project aimed at developing and testing a bundle of hardware and software technologies able to fit the individual needs of the elder with MMCI and his/her formal and informal caregivers. A multicenter clinical investigation was designed for assessing improvements in the quality of life of all users (elderly with MMCI and their caregivers) and the impact on the use of resources for care. Six pilot sites in Italy were involved in this clinical investigation. A complex set of assessment tools allowed exploring a wide range of dimensions and to extract common indicators and outcomes in accordance to the assessment dimensions required by the Health Technology Assessment approach.

The prognosis of acute promyelocytic leukemia (APL) has significantly improved since the introduction of anthracyclines, but especially after the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The identification of prognostic factors is a key process in clinical investigation, since their recognition allows the stratification of disease risks and promotes refined therapeutic adjustments. In fact, most treatments are now designed following risk-adapted strategies in order to optimize the therapeutic efficacy and minimizing side effects. The efficacy of treatment is one major determinant in prognosis. Therefore, the impact of a number of disease and patient characteristics on outcome should be analyzed according to their predictive value with the two main therapeutic approaches currently used for APL, i.e., ATRA plus chemotherapy-based and ATRA plus ATO-based therapy. The prognostic impact of WBC counts on induction response and the risk of relapse are universally accepted, regardless of the type of treatment used. A score defined by the GIMEMA and PETHEMA groups, based on the presenting WBC and platelet counts, is the most widely used for risk stratification in clinical trials and routine practice, because of its simplicity and accuracy. Other prognostic factors, including clinical and molecular markers, have been associated with outcome in some studies, but in general they have not been incorporated into decision-making algorithms, with the exception of age. This chapter includes a comprehensive review of patient- and disease-related prognostic factors, with special emphasis on those reported with state-of-the-art treatments.

The measurement of eye and head movement remains central to the investigation of the vestibular and oculomotor systems. This applies equally to clinical investigation and experimental studies. Around 80 years ago, the first reports of the employment of image-based techniques for oculometric measurement were published. These involved photographic and cinematographic recording of the eye for pupillometric analysis (Machemer 1933; Lowenstein and Friedman 1942). Some 25 years later, Lowenstein and Lowenfeld (1958) reported the use of mechano-optical image scanning, as adapted from classic television camera principles. This seminal report was succeeded by a number of refinements. For example, Stark and Sandberg (1961) employed electronic techniques based on the television image-scanning principle. Subsequent developments by Green and Maaseidvaag (1967) and O’Neill and Stark (1968) employed more sophisticated exploitation of vidicon imaging tubes. In the meantime a wide range of image-based video eye trackers have been developed.

Numerous risk factors have been associated with the development of venous thromboembolism (VTE), and surgeons need to be aware of the risks and the various methods of prevention and treatment. Although considerable clinical investigation has been directed at developing protocols for VTE prophylaxis in hip and knee surgical patients, as well as general medical patients, specific guidelines pertaining to foot and ankle surgical patients have yet to be supported by high quality clinical evidence. Foot and ankle surgeons are encouraged to understand the pathophsyiology of VTE, risk stratification strategies, and the physical and pharmacologic options used to prevent and treat thrombose associated with foot and ankle surgery.

In recent years, the successful application of fenestrated and branched endograft technology in the visceral aortic segment has been expanded to include the aortic arch. A number of challenges exist specific to endovascular procedures in the aortic arch, including issues associated with the seal zone, device durability, the aortic valve, device alignment, stroke, and mortality. The arch branched endograft (a-Branch) from Cook Medical (Bloomington, IN) has been trialed in limited high-volume centers in Europe, the USA, and Canada. The device represents a third-generation arch branched endograft (ABE), which was designed to address specific challenges encountered with endovascular procedures in the aortic arch and lessons learned from earlier devices. A number of other devices are currently under clinical investigation. This chapter summarizes patient selection, technical aspects, and results of repair of aortic arch aneurysms.

Muscle and tendon injuries are extremely common in athletes. Appropriate diagnosis and management, including exact medical history and detailed clinical investigation, can optimize recovery and time to return to play. It is extremely important to maintain good physical conditions while the lesion heals. In addition, a positive attitude can hasten the recovery.

Paediatric inflammatory bowel disease (PIBD) represents several chronic idiopathic disorders of the gastrointestinal tract. Children and adolescents often present with a spectrum of overlapping clinical features making definitive diagnosis and therapy challenging. No single clinical investigation can accurately diagnose and phenotype all cases of PIBD. Despite recent advances in endoscopic technique, new faecal biomarkers, improved serological testing and refinements in the classification of PIBD, diagnostic imaging still plays a vital role in diagnosis and treatment evaluation. This chapter reviews the current clinical guidelines and role of diagnostic imaging techniques specifically related to paediatric Crohn’s disease.

Demographic trends, globalization, and advancing technology favor increasing demand for clinical research for the foreseeable future. Clinical investigation, though challenging, and requiring additional training, can provide a number of opportunities and benefits. Potential investigators can explore formal training programs or informal mentorship to help solidify their interest and begin taking steps toward independent research or consulting in academia, industry, government, or private practice.

Substantial efforts are currently invested in development of micro- and nanofluidics-based systems as front end technology for electrospray ionization (ESI) mass spectrometry (MS). Since its first introduction in biological MS chip-based ESI demonstrated a high potential to discover novel biopolymer species due to the efficient ionization properties, preferential formation of multiply charged ions and the elevated reproducibility and sensitivity. In combination with high-resolution mass spectrometers or instruments able to perform multistage fragmentation, chip-electrospray confirmed its unique ability to offer structural elucidation of minor species in complex mixtures, which often represent valuable biomarkers of severe diseases. This aspect is of particular importance for the applicability of chip MS in clinical investigation where only minute amounts of biological material are available. In view of these major advantages of nanofluidics in conjunction with modern MS, this chapter reviews the strategies, which allowed a successful application of chip technology for early diagnostic of lysosomal storage diseases. The first part is dedicated to the principles of ESI MS and to advanced nanochip systems for ESI MS. The second part highlights important achievements of nanochip ESI MS in biomarker discovery and diagnostic of LSDs such as Fabry and Schindler diseases. Finally, this chapter emphasizes that advanced chip ESI MS has real perspectives to become a routine method for early diagnosis and therapy of severe pathologies such as LSDs.

Cancer drug development is complex and associated with a high failure rate of new therapies in clinical trials. In particular, the history of cancer immunotherapy extends beyond a century with its most noteworthy successes having occurred just in the last 3 years. New drugs in this space – both approved and under investigation – demonstrate increased levels of benefit for patients, and their development is based on progress in basic science and investigational methods. Together these improvements created the environment for reproducible and biology-driven clinical investigation of new compounds and thus a higher success rate. This chapter summarizes the methodological improvements for immunotherapy drug development and their application.