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Manufacturers of pathology imaging devices and associated software engage regulatory affairs and clinical affairs (RACA) throughout the Total Product Life Cycle (TPLC) of regulated products. A number of manufacturers, pathologists, and end users are not familiar with how RACA involvement benefits each stage of the TPLC. RACA professionals are important contributors to product development and deployment strategies because these professionals maintain an understanding of the scientific, technical, and clinical aspects of biomedical product regulation, as well as the relevant knowledge of regulatory requirements, policies, and market trends for both local and global regulations and standards. Defining a regulatory and clinical strategy at the beginning of product design enables early evaluation of risks and provides assurance that the collected evidence supports the product's clinical claims (e.g., in a marketing application), its safe and effective use, and potential reimbursement strategies. It is recommended to involve RACA early and throughout the TPLC to assist with navigating changes in the regulatory environment and dynamic diagnostic market. Here we outline how various stakeholders can utilize RACA to navigate the nuanced landscape behind the development and use of clinical diagnostic products. Collectively, this work emphasizes the critical importance of RACA as an integral part of product development and, thereby, sustained innovation.

Background Opioids have narrow therapeutic windows, and errors in ordering or administration can be fatal. The purpose of this study was to describe deaths involving hydromorphone and morphine, which have similar-sounding names, but different potencies. Methods In this case series, we describe deaths of patients admitted to hospital or residents of long-term care facilities that involved hydromorphone and morphine. We searched for deaths referred to the Patient Safety Review Committee of the Office of the Chief Coroner for Ontario between 2007 and 2012, and subsequently reviewed by 2014. We reviewed each case to identify intervention points where errors could have been prevented. Results We identified 8 cases involving decedents aged 19 to 91 years. The cases involved errors in prescribing, order processing and transcription, dispensing, administration and monitoring. For 7 of the 8 cases, there were multiple (2 or more) possible intervention points. Six cases may have been prevented by additional patient monitoring, and 5 cases involved dispensing errors. Interpretation Opioid toxicity deaths in patients living in institutions can be prevented at multiple points in the prescribing and dispensing processes. Interventions aimed at preventing errors in hydromorphone and morphine prescribing, administration and patient monitoring should be implemented and rigorously evaluated.

Unlocking the full potential of pathology data by gaining computational access to histological pixel data and metadata (digital pathology) is one of the key promises of computational pathology. Despite scientific progress and several regulatory approvals for primary diagnosis using whole-slide imaging, true clinical adoption at scale is slower than anticipated. In the U.S., advances in digital pathology are often siloed pursuits by individual stakeholders, and to our knowledge, there has not been a systematic approach to advance the field through a regulatory science initiative. The Alliance for Digital Pathology ( the Alliance) is a recently established, volunteer, collaborative, regulatory science initiative to standardize digital pathology processes to speed up innovation to patients. The purpose is: (1) to account for the patient perspective by including patient advocacy; (2) to investigate and develop methods and tools for the evaluation of effectiveness, safety, and quality to specify risks and benefits in the precompetitive phase; (3) to help strategize the sequence of clinically meaningful deliverables; (4) to encourage and streamline the development of ground-truth data sets for machine learning model development and validation; and (5) to clarify regulatory pathways by investigating relevant regulatory science questions. The Alliance accepts participation from all stakeholders, and we solicit clinically relevant proposals that will benefit the field at large. The initiative will dissolve once a clinical, interoperable, modularized, integrated solution (from tissue acquisition to diagnostic algorithm) has been implemented. In times of rapidly evolving discoveries, scientific input from subject-matter experts is one essential element to inform regulatory guidance and decision-making. The Alliance aims to establish and promote synergistic regulatory science efforts that will leverage diverse inputs to move digital pathology forward and ultimately improve patient care.

The rise in antibiotic-resistant bacteria has led to an active search for new and more effective antimicrobial drugs. A hexapeptide (LfB6: RRWQWR-NH2) derived from the iron-binding protein lactoferrin exhibits antimicrobial activity (Tomita, Acta Paediatr Jpn, 1994, 36:585). A related heptapeptide produced in our lab, with 4 positively charged arginines and 2 methylated tryptophans (RRMeWQMeWRR-NH2; MeTrp-LfB7), exhibits enhanced activity against gram negative and gram positive bacteria. Substitutions of the central glutamine (Gln4;Q) residue that may alter peptide conformational flexibility are now being investigated. When Gln4 was changed to glycine (Gly;G) or proline (Pro;P), significant changes in peptide-membrane interactions were observed, although the antimicrobial activity was not increased. We now examine the effects of replacing Gln4 with gamma amino butyric acid (GABA), to introduce more flexibility; or D-Pro-Gly, to constrain the backbone into a β-hairpin turn (Stanger and Gellman, J. Am. Chem. Soc. 1998, 120:4236). The increased positive ellipticity at ∼230 nm observed in the CD spectrum of the D-Pro-Gly peptide in anionic membranes suggests significant Trp-Trp interactions. Tryptophan fluorescence emission spectra indicate that peptides with either GABA or D-Pro-Gly substitutions are more deeply buried in anionic membranes. Although the GABA and D-Pro-Gly peptides were both more active against gram negative (E. coli), compared to gram positive (S. aureus) bacteria, they were not as active as the Gln4 peptide. Investigations of the peptide-lipid interactions are being continued by means of solid-state 2H and 31P NMR spectra.

Digital Pathology Systems (DPS) are dynamic, image-based computer systems that enable the acquisition, management, and interpretation of pathology information generated from digitized glass slides. This article provides a roadmap for (1) qualification of a whole slide scanner (WSS) during a validation project, (2) validation of software required to generate the whole slide image (WSI), and (3) an introduction to visual digital image evaluation and image analysis. It describes a validation approach that can be utilized when validating a DPS. It is not the intent of this article to provide guidance on when validation of DPS is required. Rather, the article focuses on technical aspects of validation of the WSS system (WSS, IT infrastructure, and associated software) portion of a DPS and covers the processes of setting up the WSS for scanning a glass slide through saving a WSI on a server. Validation of a computerized system, such as a DPS, for use in a regulated nonclinical environment is governed by Code of Federal Regulations (CFR) Title 21 part 11: Electronic Records; Electronic Signature and predicate rules associated with Good Laboratory Practices documents including 21 CFR part 58. Similar regulation and predicate rules apply in the European Union and Japan.

A morphology-based assay such as immunohistochemistry (IHC) should be a highly effective means to define the expression of a target molecule of interest, especially if the target is a protein. However, over the past decade, IHC as a platform for biomarkers has been challenged by more quantitative molecular assays with reference standards but that lack morphologic context. For IHC to be considered a “top-tier” biomarker assay, it must provide truly quantitative data on par with non-morphologic assays, which means it needs to be run with reference standards. However, creating such standards for IHC will require optimizing all aspects of tissue collection, fixation, section thickness, morphologic criteria for assessment, staining processes, digitization of images, and image analysis. This will also require anatomic pathology to evolve from a discipline that is descriptive to one that is quantitative. A major step in this transformation will be replacing traditional ocular microscopes with computer monitors and whole slide images, for without digitization, there can be no accurate quantitation; without quantitation, there can be no standardization; and without standardization, the value of morphology-based IHC assays will not be realized.

Student health visitors led a Mini-MEND project for families with young children as part of their public health nursing course. The project gave a framework for the students and staff members from the children's centre to stimulate an awareness of health needs and facilitate health enhancing activities in terms of healthy eating and parenting. Reflection on the initiative identified application of the principles of health visiting and the domains of specialist community public health nursing, yet the pressures of current health visiting workloads mean that having developed public health skills to use with groups and communities, they may not be used by newly-qualified health visitors.

The term “telepathology” was introduced into the English language in 1986 by Weinstein,[1,2] and since then there have been many advances and publications.[3,4,5,6,7,8,9,10,11,12,13] The practice of telepathology involves obtaining macroscopic and/or microscopic images for transmission along telecommunication links for obtaining a remote interpretation (telediagnosis), second opinion or consultation (teleconsultation), quality assurance, education, teaching, self-study, and research (tele-education). A variety of terms has been used interchangeably to refer to telepathology including digital microscopy, remote robotic microscopy, teleconferencing, teleconsultation, telemicroscopy, video microscopy, virtual microscopy, and whole slide imaging (WSI).[9,11,14] With advances in technology and widespread access to the Internet, telepathology is increasingly being used around the world, improving rapid sharing of cases and access to expert pathologists. Telepathology can be used for remote-site interpretation of all types of pathology material including, but not limited to, H&E stained paraffin tissue sections, frozen sections, cytology or hematology slides, microbiology specimens, clinical fluids (e.g. urine), electron micrographs, electrophoresis gels, and cytogenetics images.[2,15,16,17,18,19,20,21,22,23,24] In practice, these digital images are typically linked to patient information including identification/medical record numbers, clinical history, and relevant laboratory and radiology data.[25] Table 1 summarizes milestones of the many technological advances in telepathology.[14] The primary modes of telepathology include static imaging, dynamic imaging, hybrid static/dynamic telepathology, and WSI. Tabel 1 Telepathology system classification[14]