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Recent reports related to in utero exposure of marketed immunosuppressive biologics led to clinical recommendations to delay live vaccinations for infants due to the concern of reduced vaccine effectiveness and/or increased risk of vaccine‐related disease. These delays can increase the risk of children contracting vaccine preventable diseases, yet the alternative cessation of biologics during pregnancy may result in increased autoimmune disease activity for the pregnant person, raising complex benefit–risk (B‐R) considerations and trade‐offs. Our goal is to develop a conceptual framework for B‐R assessment based on the key benefits and risks pregnant people would consider for themselves and their children when continuing (vs. discontinuing) a biologic during pregnancy. The proposed framework defines the decision contexts, key domains and attributes for potential benefits, and risks of biologic use during pregnancy, informed by a literature review of indications for biologics and refined with key clinical stakeholders. The framework includes both the pregnant person taking the biologic and the infant potentially exposed to the biologic in utero, with potential benefit and risk domains and attributes for each participant. To advance this conceptual framework, there are considerations of potential biases and uncertainty of available data that will be imperative to address when quantifying the B‐R framework. For these reasons, we recommend the formation of a consortium to ensure development of a robust, validated framework that can be adopted in the healthcare setting. [ABSTRACT FROM AUTHOR]

Leslie Marmon Silko’s Ceremony is a novel about a young man named Tayo who returns to the Laguna Reservation, probably in 1948, after horrifying experiences on the Pacific front in World War II and an unspecified period of time in a Veteran’s Administration hospital in California. He comes home a psychological mess after being released from a prisoner of war camp, probably in the Philippines. In one sense, Tayo’s story is straightforward enough. A man grows from confusion to clarity, from being lost to being found, from being muddleheaded to being clearheaded, from being alone to getting connected, from feeling afraid to feeling confident, from thinking of himself as a villain to realizing that he may just be a hero. Why, then, do so many first-time readers of Ceremony get so confused by this narrative? The central reason is that most of the novel takes place in the consciousness of Tayo, who, for the first hundred or so pages, has no idea who he is or where he is going.Part of Tayo’s problem is that he cannot sort things out properly; part of his madness is that he cannot distinguish past from present. And just as his mind is a jumble of events, the opening of the novel portrays unsorted, jumbled events. On the second page of the novel Tayo speaks of the tangle of events and memories in his mind:The memories were tangled with the present, tangled up like colored threads from old Grandma’s wicker sewing basket when he was a child, and he had carried them outside to play and they had spilled out of his arms into the summer weeds and rolled away in all directions, and then he had hurried to pick them up before Auntie found him. He could feel it inside his skull, the tension of little threads being pulled and how it was with tangled things, things tied together, and as he tried to pull them apart and rewind them into their places, they snagged and tangled even more.

One important symptom of the disease that the ceremony of Ceremony is designed to cure is flawed vision, physiological as well as psychological. At the beginning of the novel, Tayo does indeed suffer from physiological eyestrain—sunlight hurts his eyes so much that he vomits, and we are told that “he had to keep moving so that the sinews connected behind his eyes did not slip loose and spin his eyes to the interior of his skull where the scenes [World War II flashbacks] waited for him.” This early in the novel Tayo is desperate for a vision of biomechanics that aligns with the felt reality of his condition. Tayo also suffers from flawed psychological vision, mainly as a result of being contaminated by certain preconceptions that he, like most Americans, has acquired from the social environment. Tayo’s doctor Betonie later tells him that the Ck’o’yo witchery has created these preconceptions and put them into circulation to blind Indians into believing that the land is a dead thing and that, to put it in mid-twentieth century terminology, White is Right. In one important sense, then, the measure of Tayo’s recovery is change, or improvement, in his vision—physiological and psychological, and vision in the sense of perception as well as in the sense of conception or ideation.As I and others have argued elsewhere, Silko works to align the prose narrative story of Tayo’s transformation with the poetic-looking body of traditional Laguna narrative embedded in the text and functioning as the novel’s formal and thematic backbone. Two of these embedded texts are particularly germane to the theme of transformed—and transforming—vision. One of these is the Kaupata story that functions as a prologue and preview of the Mount Taylor episode; the other is the brief Arrowboy fragment that serves the same function for the Jackpile Mine episode. These two backbone stories treat the phenomenon of vision rather differently, one picking up the possibilities of development of vision where the other leaves off; like two of Betonie’s colored mountains, they represent successive phases of the overall process of moving from lack or loss of vision to recovery of it. In the accompanying phases of the prose narrative, Tayo must understand, and then use, the modes of vision modeled in these two stories of departure and recovery in order to become the one who can tell the story of Our Mother’s return to the Fifth World and to the People who are her children.

Objective: Stakeholders met to address persistent challenges facing the development of therapeutics for polyarticular juvenile idiopathic arthritis (pJIA), which result in fewer approved therapies for children with pJIA than adults with rheumatoid arthritis (RA) and long lag times from adult RA approval to pediatric labeling. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critically important to multiple stakeholders. Methods: The Food and Drug Administration in collaboration with the University of Maryland Center for Regulatory Science and Innovation held a public workshop entitled "Accelerating Drug Development for pJIA" on October 2, 2019, to address challenges surrounding access to new medications for children and adolescents with pJIA. Regulatory, academic, and industry stakeholders, as well as patient representatives, participated in the workshop, which consisted of 4 sessions, including panel discussions. Results: The workshop facilitated broad public discussion of challenges facing the development of pJIA therapeutics, highlighting areas of need and outlining opportunities to expedite development, while underscoring the necessity of close collaboration between all stakeholders, including patients and families. Conclusion: This report summarizes key aspects of the workshop, including the appropriate application of innovative approaches to the development of pJIA therapeutics, including extrapolation, to address current challenges and provide timely access to newer safe and effective treatments. Long‐term safety assessment is of pressing concern to stakeholders and cannot be fully extrapolated from adult studies but requires consistent postmarketing long‐term follow‐up. [ABSTRACT FROM AUTHOR]

Background: Historically, pediatric medicines are developed after adult trials are completed, even when identical drug targets and disease similarities exist across the populations. This has resulted in significant delays in the authorization of medicines for adolescent use, limiting access to beneficial drugs. This study sought to understand how adolescent inclusion in adult trials is positioned in regulatory guidance documents as they set critical expectations for trial design and regulatory decision-making. Methods: This study utilized a qualitative analysis approach. Guidance documents were identified via Food and Drug Administration and European Medicines Agency websites. Utilizing a blinded adjudication process, the documents were classified as permissive, exclusionary, or silent regarding recommendations about adolescent inclusion in adult clinical trials. A post hoc analysis of similarities and differences between the Food and Drug Administration and European Medicines Agency guidance documents was conducted to assess the possible role of regional pediatric research laws on age-inclusive trial methodologies as well as emergent themes by therapeutic area. Results: In total, 96 Food and Drug Administration (1977 to 2019) and 106 European Medicines Agency (1987 to 2019) guidance documents were identified for analysis. The guidance contained explicit or implicit recommendations supporting adolescent inclusion in adult trials in 32% of Food and Drug Administration and 15% of European Medicines Agency documents, while 14% and 21%, respectively, were found to be exclusionary. A large number of guidance documents were silent regarding the applicability of adolescent-inclusive trial designs (53% and 64%, Food and Drug Administration and European Medicines Agency, respectively). Analysis by therapeutic area revealed the most permissive of adolescent inclusion in Food and Drug Administration guidance for infectious diseases and conditions requiring blood products in European Medicines Agency guidance. A more holistic approach to age-inclusive trial design was identified in disease guidance published by the Food and Drug Administration Oncology Center of Excellence. Discussion: There are many influences on the development and/or revision of regulatory guidance documents. Substantial scientific knowledge and regulatory precedence for the inclusion of adolescents within adult trials are available to inform research approaches. Our study has identified important opportunities for the enhancement of guidance. For example, contextualization of developmental factors influencing adolescent disease progression provides insights into the role of adolescent inclusion. If addressed, guidance documents can facilitate broader acceptance of age-inclusive trial methodologies and accelerate adolescent access to medicines. [ABSTRACT FROM AUTHOR]