International Retrospective Chart Review of Treatment Patterns in Severe Familial Mediterranean Fever, Tumor Necrosis Factor Receptor–Associated Periodic Syndrome, and Mevalonate Kinase Deficiency/Hyperimmunoglobulinemia D Syndrome

Objective: Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor–associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS). Methods: PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de‐identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment. Results: A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute‐phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8‐year delay in FMF patients. An equal proportion of TRAPS patients first received anti–interleukin‐1 (anti‐IL‐1) and anti–tumor necrosis factor (anti‐TNF) biologic agents, whereas IL‐1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti‐TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P < 0.01, respectively). No significant differences in responses were observed between biologic agents among other cohorts. Conclusion: Referral patterns and diagnostic delays highlight the need for greater awareness and improved diagnostics for PFS. This real‐world treatment assessment supports the need for further refinement of treatment practices

Noncanonical DNA Motifs as Transactivation Targets by Wild Type and Mutant p53

Sequence-specific binding by the human p53 master regulator is critical to its tumor suppressor activity in response to environmental stresses. p53 binds as a tetramer to two decameric half-sites separated by 0–13 nucleotides (nt), originally defined by the consensus RRRCWWGYYY (n = 0–13) RRRCWWGYYY. To better understand the role of sequence, organization, and level of p53 on transactivation at target response elements (REs) by wild type (WT) and mutant p53, we deconstructed the functional p53 canonical consensus sequence using budding yeast and human cell systems. Contrary to early reports on binding in vitro, small increases in distance between decamer half-sites greatly reduces p53 transactivation, as demonstrated for the natural TIGER RE. This was confirmed with human cell extracts using a newly developed, semi–in vitro microsphere binding assay. These results contrast with the synergistic increase in transactivation from a pair of weak, full-site REs in the MDM2 promoter that are separated by an evolutionary conserved 17 bp spacer. Surprisingly, there can be substantial transactivation at noncanonical ½-(a single decamer) and ¾-sites, some of which were originally classified as biologically relevant canonical consensus sequences including PIDD and Apaf-1. p53 family members p63 and p73 yielded similar results. Efficient transactivation from noncanonical elements requires tetrameric p53, and the presence of the carboxy terminal, non-specific DNA binding domain enhanced transactivation from noncanonical sequences. Our findings demonstrate that RE sequence, organization, and level of p53 can strongly impact p53-mediated transactivation, thereby changing the view of what constitutes a functional p53 target. Importantly, inclusion of ½- and ¾-site REs greatly expands the p53 master regulatory network

Cotranslational protein assembly imposes evolutionary constraints on homomeric proteins

Cotranslational protein folding can facilitate rapid formation of functional structures. However, it might also cause premature assembly of protein complexes, if two interacting nascent chains are in close proximity. By analyzing known protein structures, we show that homomeric protein contacts are enriched towards the C-termini of polypeptide chains across diverse proteomes. We hypothesize that this is the result of evolutionary constraints for folding to occur prior to assembly. Using high-throughput imaging of protein homomers in vivo in E. coli and engineered protein constructs with N- and C-terminal oligomerization domains, we show that, indeed, proteins with C-terminal homomeric interface residues consistently assemble more efficiently than those with N-terminal interface residues. Using in vivo, in vitro and in silico experiments, we identify features that govern successful assembly of homomers, which have implications for protein design and expression optimization

Impact of systemic juvenile idiopathic arthritis/Still&rsquo;s disease on adolescents as evidenced through social media posts

Renee F Modica,1 Kathleen G Lomax,2 Pamela Batzel,3 Armelle Cassanas3 1Department of Pediatrics, University of Florida, Gainesville, FL, USA; 2Immunology, Hepatology and Dermatology Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 3Treato, Princeton, NJ, USA Purpose: To understand the experience of adolescent systemic juvenile idiopathic arthritis (SJIA) patients and those of their parents based on their social media posts.Methods: English language posts related to SJIA, Still&rsquo;s disease, or juvenile arthritis were collected and analyzed.Results: In total, 71 posts created between 2009 and 2015 on 15 websites were identified in November 2015. Of the 32 unique authors, 17 were SJIA patients aged 13&ndash;20 years (40 posts), 7 were mothers of SJIA patients (12 posts), and 8 patients had unspecified forms of juvenile arthritis (19 posts). Many patients posted about similar diagnostic experiences marked by 5 phases: 1) early prediagnosis: pain and fatigue overlooked until crisis occurred, 2) first misdiagnosis: doctors talked about &ldquo;growing pains&rdquo; and psychosocial problems (&ldquo;fake pains&rdquo; to avoid school), 3) second misdiagnosis: severity acknowledged, but diagnosed as leukemia or another cancer, 4) tests: tests leading to diagnosis and treatment conducted, and 5) cognitive identity: patient accepted the diagnosis and its implications. Many adolescent patients, looking back at disease onset in their childhood, described themselves as a &ldquo;sleeping child&rdquo; rather than the typical active child. Several patients tried to hide their illness from friends, but expressed concerns openly online. Many patients described SJIA as a powerful external enemy, using terms like &ldquo;bulldozer,&rdquo; &ldquo;dragon,&rdquo; and &ldquo;monster.&rdquo; Many posts from patients and their mothers used superhero language/imagery to help &ldquo;fight&rdquo; SJIA. Some patients also posted about the risk of death.Conclusion: Although most adolescent SJIA patients openly posted about the difficulties of their disease online, they made efforts to hide their disease in the real world. They frequently used superhero words and images in describing their fight for better health. Physicians can use these insights when counseling SJIA patients to provide a narrative that meshes with the patients&rsquo; worldview and perhaps to improve physician&ndash;patient communication to increase treatment adherence. Keywords: adolescents, juvenile arthritis, SJIA, social media, Still&rsquo;s disease, superheroe

Patient perspectives on the impact of acromegaly: results from individual and group interviews

Michelle H Gurel,1 Paul R Bruening,2 Christine Rhodes,2 Kathleen G Lomax31Neuroendocrine Clinical Center, Massachusetts General Hospital, Boston, MA, USA; 2Nicholas Research Associates International, New York, NY, USA; 3Medical Affairs, Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ, USAPurpose: Acromegaly is a chronic condition resulting from a growth hormone-secreting pituitary tumor that can substantially impact patients&#39; physical and emotional well-being. We sought to understand the impact of acromegaly on disease-related concerns and treatment choices from the patient perspective. The path to diagnosis, current disease management, interactions with the treating health care providers (HCPs), and support networks were also assessed.Methods: Acromegaly patients were recruited primarily from a patient support group (Acromegaly Community). In Phase I, ten patients participated over the course of 5 days in a moderated online discussion board and they answered questions about their disease. In Phase II, a separate nine-patient cohort participated in face-to-face interviews conducted during an acromegaly patient conference. Data were summarized qualitatively by grouping similar answers and quotations.Results: Nineteen acromegaly patients were recruited across the two cohorts, and both groups shared similar concerns. They demonstrated a notable interest in understanding their disease and its treatment. Patients were focused on the impact of the disease on their life, and they expressed a desire to get beyond reminders of their disease. The patients described long journeys to a correct diagnosis and relief at having a name for their condition. Many shared a sense of shock at needing pituitary surgery and felt unsatisfied by the treatment decision process, motivating them to discuss it with other patients. Patients not connected to a patient support group reported feeling helpless and lonely. Most patients shared a desire to improve their general knowledge about acromegaly to spare others their protracted diagnostic period. Patients also reported hesitancy in asking questions or sharing details about the disease&#39;s impact on their lives with their HCPs.Conclusion: Acromegaly can be a life-changing diagnosis with profound, ongoing effects on patients&#39; lives. Patients struggle with many issues they fail to openly share with their HCPs, but may discuss these issues more easily with other acromegaly patients. Better collaboration between patients and care providers could lead to increased patient satisfaction.Keywords: acromegaly, impact on patients&#39; lives, patient perspective, somatostatin analog

Patient perspectives on the impact of Crohn&amp;rsquo;s disease: results from group interviews

Beth-Ann Norton,1 Rosemarie Thomas,2 Kathleen G Lomax,2 Sharon Dudley-Brown31Massachusetts General Hospital, Boston, MA, USA; 2Abbott Laboratories, Abbott Park, IL, USA; 3Johns Hopkins University, Schools of Medicine and Nursing, Baltimore, MD, USAAim: To understand the impact of Crohn&amp;rsquo;s disease (CD) on various aspects of daily life from the perspective of patients living with CD. Awareness of the disease and biologic therapies, patient satisfaction and adherence, and physician (provider) relationships were also assessed.Background: CD is a chronic, inflammatory, autoimmune disorder of the gastrointestinal tract that substantially impacts patients&amp;rsquo; physical and emotional well-being. For patients eligible for biologic therapy, anti-tumor necrosis factor agents represent an important addition to the available therapies for CD.Methods: The study sample included biologic-na&amp;iuml;ve and biologic-experienced patients who had self-reported moderate to severe CD, were under the care of a specialist, and agreed to film a video diary and participate in a focus group. Data from the videos and group interviews were collected from May to June of 2009 and summarized qualitatively by grouping similar answers and quotations.Results: Of the 44 participants who submitted video diaries, 23 were biologic-experienced and 21 were biologic-na&amp;iuml;ve. Participants stated that CD caused fear and embarrassment, that they were reluctant to share the full impact of CD with family and providers, and that they relied on their provider for treatment decisions. Many participants accepted a new state of normalcy if their current medication helped their most bothersome symptoms without providing sustained remission. Participants receiving biologic therapy generally were more informed, more satisfied, and more likely to adhere to treatment regimens.Conclusion: Participants&amp;rsquo; responses suggest a need for more patient education and more collaborative relationships between patients and providers (physicians) regarding treatment decisions.Keywords: Crohn&amp;rsquo;s disease, patient perspective, quality of lif

The family journey-to-diagnosis with systemic juvenile idiopathic arthritis: a cross-sectional study of the changing social media presence

Renee F Modica,1 Kathleen Graham Lomax,2 Pamela Batzel,3 Leah Shapardanis,3 Kimberly Compton Katzer,3 Melissa E Elder1 1Division of Pediatric Rheumatology, Immunology and Infectious Diseases, University of Florida, Gainesville, FL, USA; 2Immunology and Dermatology Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, USA; 3Treato, Princeton, NJ, USA Background: Children with systemic juvenile idiopathic arthritis (SJIA) often encounter a delay between symptom onset and disease diagnosis, partly due to the broad differential of fever and lack of symptom recognition by providers. Families often seek multiple medical opinions and post on social media about their frustrations. This linguistic analysis observed the changing language patterns and social media posting behaviors of parents in the time leading to, during, and after SJIA diagnosis. Methods: Public social media sites were manually reviewed by a linguistic team to evaluate posts about SJIA from US-based parents. Results: A total of 3,979 posts between July 2001 and January 2015 were reviewed from 108 sites. Pre-SJIA diagnosis parents sought answers and shared status updates on social media, focusing primarily on the following three site types: alternative/natural lifestyle forums (39%), Facebook (27%), and disease-specific forums (17%). Posts during early prediagnosis phases were characterized by expressive language showing confidence in health care providers and trust in parental instincts. At later prediagnosis stages, parents continued to use social media, but the posts demonstrated increased frustration with delays in diagnosis and gaps in communication with providers. More objective symptom descriptions and a greatly reduced child-centered emotional focus were observed as parents shifted into caregiving roles. Once the diagnosis of SJIA was confirmed, parents used straightforward, less expressive language, and Facebook (47%) to make &quot;announcement&quot; posts and increased their use of SJIA websites (30%). With treatment initiation, the posts demonstrated a slow return of expressive language and an increased parental understanding of the &quot;new normal&quot;. Conclusion: Parents use different language styles, frames of reference, and websites before and after SJIA diagnosis. Gaps in parent&ndash;provider communication, especially before diagnosis, and their new roles as caregivers lead to parental use of social media to express frustration with the health care process. Providers should tailor their discussions with parents to address these issues. Keywords: systemic juvenile idiopathic arthritis, social media, linguistics, language frames, diagnostic proces

Prefazione

Si tratta della prefazione a un volume divulgativo dell’ANPO (Associazione Nazionale Prevenzione Oncologica) sulla prevenzione dei tumori professionali, opera che appare assai utile e tempestiva. Dopo avere inquadrato il complesso problema dell’oncogenesi occupazionale nel contesto legislativo e medico-legale italiano, lil volume riunisce in modo sintetico e comprensibile anche ai non medici le attuali conoscenze sulle malattie neoplastiche che possono insorgere a causa del lavoro. In particolare, sono descritti i compiti e le responsabilità delle figure professionali a vario titolo coinvolte nella tutela della salute dei lavoratori e cioè i lavoratori stessi, i loro rappresentanti, il datore di lavoro, i preposti, il responsabile del servizio di prevenzione e protezione, il medico competente. Delle più comuni forme neoplastiche sono illustrati l’eziologia (agenti coinvolti e comparti produttivi a rischio), le caratteristiche anatomo-patologiche (sede d’insorgenza, varianti istologiche), gli aspetti clinici (sintomatologia, prognosi, diagnosi, terapia, riabilitazione) e le possibilità di prevenzione (eliminazione/contenimento dei fattori di rischio, screening, sorveglianza sanitaria). È pertanto auspicabile che questa pubblicazione aumenti la consapevolezza e il senso di responsabilità di tutti nei confronti dei tumori sul lavoro e delle malattie neoplastiche in genere, intese non come eventi fatali e ineluttabili ma come patologie prevenibili, curabili e spesso guaribili