The management of pediatric hidradenitis suppurativa differs between dermatologic and non-dermatologic providers: A retrospective review.

BACKGROUND/OBJECTIVES: There is a paucity of pediatric hidradenitis suppurativa (HS) literature. The objective of this study was to characterize differences in management of pediatric HS patients by dermatology versus non-dermatology clinicians. METHODS: We examined a retrospective cohort of 195 pediatric patients with HS seen at our institution (3/1/19-3/1/20). Two-sample t-tests and two-proportion z-tests were performed. RESULTS: A total of 76.1% of subjects were seen by dermatology at least once, and of these, 79.1% were referred. HS diagnosis was most often made by dermatology (36.6%), followed by pediatrics (21.6%). Patients managed by dermatology were significantly more likely to have used standard of care therapies (p < .001). Of dermatology-managed patients, 19.7% were currently prescribed a biologic, as compared with zero patients not managed by dermatology. Those managed by dermatology were less likely to undergo surgical excision (13.3% vs. 25.5%, p = .04). CONCLUSIONS: Our results support increased likelihood of treatment escalation with medical management by dermatologists. Relatively high utilization of referral to dermatology exists, but with only moderate patient adherence. There is a need for improved access to dermatologic care and prospective studies to determine whether differences in specialty management translate to improved patient outcomes.

Re-evaluating the need for chronic toxicity studies with therapeutic monoclonal antibodies, using a weight of evidence approach.

To support registration of monoclonal antibodies (mAbs) for chronic indications, 6-month toxicity studies have historically been conducted. Experience with mAb development has shown a relatively benign and well-understood safety profile for this class, with most toxicity findings anticipated based on pharmacology. We evaluated whether a 6-month toxicity study is necessary to assess the long-term safety of mAbs. Data on First-in-Human (FIH)-enabling and chronic toxicity studies were shared for 142 mAbs submitted by 11 companies. Opportunities to further optimize study designs to reduce animal usage were identified. For 71% of mAbs, no toxicities or no new toxicities were noted in chronic studies compared to FIH-enabling study findings. New toxicities of potential concern for human safety or that changed trial design were identified in 13.5% of cases, with 7% being considered critical and 2% leading to program termination. An iterative, weight-of-evidence model which considers factors that influence the overall risk for a mAb to cause toxicity was developed. This model enables an evidence-based justification, suggesting when 3-month toxicity studies are likely sufficient to support late-stage clinical development and registration for some mAbs.

The use of recovery animals in nonclinical safety assessment studies with monoclonal antibodies: further 3Rs opportunities remain.

Assessment of reversibility from nonclinical toxicity findings in animals with potential adverse clinical impact is required during pharmaceutical development, but there is flexibility around how and when this is performed and if recovery animals are necessary. For monoclonal antibodies (mAbs) and in accordance with ICH S6(R1) if inclusion of recovery animals is warranted, this need only occur in one study. Data on study designs for first-in-human (FIH)-enabling and later-development toxicity studies were shared from a recent collaboration between the NC3Rs, EPAA, Netherlands Medicines Evaluation Board (MEB) and 14 pharmaceutical companies. This enabled a review of practices on recovery animal use during mAb development and identification of opportunities to reduce research animal use. Recovery animals were included in 68% of FIH-enabling and 69% of later-development studies, often in multiple studies in the same program. Recovery groups were commonly in control plus one test article-dosed group or in all dose groups (45% of studies, each design). Based on the shared data review and conclusions, limiting inclusion of recovery to a single nonclinical toxicology study and species, study design optimisation and use of existing knowledge instead of additional recovery groups provide opportunities to further reduce animal use within mAb development programs.

The far-reaching burden of Hyperemesis Gravidarum - an exploration of women's experiences and perceptions of healthcare support.

Hyperemesis Gravidarum (HG) is a rare condition of pregnancy that exerts a profound effect on a woman's physical and psychological health, but limited research regarding women's perceptions of healthcare for this condition exists. The aim of this study was to gain insight into the personal and healthcare experiences of women with HG. Eligible participants included women who had experienced HG in a current or recent pregnancy and were referred to the dietitian at the National Maternity Hospital, Dublin, Ireland. Suitable women were invited to participate by letter, with a follow-up phone call to confirm eligibility. Four semi-structured focus groups were conducted (n = 11). Audio recordings were transcribed and data was thematically analyzed using an inductive, data-driven approach. Participants emphasized the psychological hardship of HG, which manifested in many different ways, and unveiled the far-reaching burden of HG. Women advocated for a dedicated service for HG and the need for increased knowledge, understanding and support for HG, in order to ensure optimal HG management and woman-centered care. Women also highlighted the need for obvious clinical leadership of HG and a continuum of care throughout pregnancy and post-partum. Improvements to the day ward setting and access to HG-specific mental health support would be welcomed. At a government level, timely resolution of the financial assistance for first-line anti-emetics is needed. Overall, greater awareness and understanding of the condition is needed to improve support from family, friends and colleagues. Further research is warranted to determine whether these recommendations would result in improved pregnancy outcomes.

Reducing Nonemergent Visits to the Emergency Department in a Veterans Affairs Multistate System.

STUDY OBJECTIVE: The purpose of this quality improvement study was to reduce nonemergent visits to the emergency department attendance within a multistate Veterans Health Affairs network. METHODS: Telephone triage protocols were developed and implemented for registered nurse staff to triage selected calls to a same-day telephonic or video virtual visit with a provider (physician or nurse practitioner). Calls, registered nurse triage dispositions, and provider visit dispositions were tracked for 3 months. RESULTS: There were 1606 calls referred by registered nurses for provider visits. Of these, 192 were initially triaged as emergency department dispositions. Of these, 57.3% of calls that would have been referred to the emergency department were resolved via the virtual visit. Thirty-eight percent fewer calls were referred to the emergency department following licensed independent provider visit compared to the registered nurse triage. CONCLUSION: Telephone triage services augmented by virtual provider visits may reduce emergency department disposition rates, resulting in fewer nonemergent patient presentations to the emergency department and reducing unnecessary emergency department overcrowding. Reducing nonemergent attendance to emergency departments can improve outcomes for patients with emergent dispositions.

An unbelievable ordeal: The experiences of adult survivors treated with extracorporeal membrane oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a rescue treatment option for adult patients with severe cardiac dysfunction or respiratory failure. While short-term patient outcomes, such as in-hospital mortality and complications, have been widely described, little is known about the illness or recovery experience from the perspectives of survivors. Subjective reports of health are important indicators of the full, long-term impact of critical illness and treatment with ECMO on survivors' lives. OBJECTIVE: The objective of this study was to describe the experiences and needs of adults treated with ECMO, from onset of illness symptoms through the process of survivorship. METHODS: This study was guided by the qualitative method of interpretive description. We conducted in-depth, semistructured interviews with 16 adult survivors of ECMO who were treated at two participating regional ECMO centres in the northeast United States. Additional data were collected from demographic questionnaires, field notes, memos, and medical record review. Development of interview guides and data analysis were informed by the Family Management Style Framework. Qualitative data were analysed using thematic analysis techniques. RESULTS: The sample (n = 16) included 75% male participants; ages ranged from 23 to 65 years. Duration from hospital discharge to interviews ranged from 11 to 90 (M = 54; standard deviation = 28) months. Survivors progressed through three stages: Trauma and Vulnerability, Resiliency and Recovery, and Survivorship. Participants described short- and long-term impacts of the ECMO experience: all experienced physical challenges, two-thirds had at least one psychological or cognitive difficulty, and 25% were unable to return to work. All were deeply influenced by their own specific contexts, family support, and interactions with healthcare providers. CONCLUSIONS: The ECMO experience is traumatic and complex. Recovery requires considerable time, perseverance, and support. Long-term sequelae include impairments in cognitive, mental, emotional, physical, and social health. Survivors could likely benefit from specialised posthospital health services that include integrated, comprehensive follow-up care.

Industry experiences with immune-mediated findings in biotherapeutic nonclinical toxicology studies.

With the growth of monoclonal antibodies and other proteins as major modalities in the pharmaceutical industry, there has been an increase in pharmacology and toxicity testing of biotherapeutics in animals. Animals frequently mount an immune response to human therapeutic proteins. This can result in asymptomatic anti-drug antibody formation, immune complexes that affect drug disposition and/or organ function such as kidney, cytokine release responses, fatal hypersensitivity, or a range of reactions in between. In addition, an increasing number of oncology therapeutics are being developed that enhance or directly stimulate immune responses by a variety of mechanisms, which could increase the risk of autoreactivity and an autoimmune-like syndrome in animals and humans. When evaluating the risk of biotherapeutics prior to entering the clinic, the nonclinical safety data may include any of these responses and it is critical to understand whether they represent a safety liability for humans. The DruSafe Leadership group of the IQ Consortium conducted a survey of industry to understand sponsors' experiences with these immune reactions in nonclinical studies related to both immunogenicity and pharmacologically-mediated immune perturbations. The survey covered what pathways were affected, how the immune responses were presented, how the company and health authorities interpreted the data and whether the immune responses were observed in the clinic. Additionally, the survey gathered information on association of these findings with anti-drug antibodies as well as sponsor's use of immunogenicity predictive tools. The data suggests that the ability of a biotherapeutic to activate the immune system, intended or not, plays a significant role on characteristics of the response and whether theys are translatable.

Classic and evolving approaches to evaluating cross reactivity of mAb and mAb-like molecules - A survey of industry 2008-2019.

Monoclonal antibodies (mAbs) and mAb derivatives have become mainstay pharmaceutical modalites. A critical assessment is to ascertain the specificity of these molecules prior to human clinical trials. The primary technique for determining specificity has been the immunohistochemistry (IHC)-based "Tissue Cross-Reactivity" (TCR) assay, where the candidate molecule is applied to > 30 tissues to look for unexpected staining. In the last few years, however, non-IHC array-based platforms have emerged that allow for screening 75-80% of the human membrane proteome, indicating a viable alternative and/or addition to the IHC methods. The preclinical sciences subcommittee of the Biotechnology Innovation Organization (BIO), "BioSafe", conducted a survey of 26 BIO member companies to understand current sponsor experience with the IHC and array techniques. In the last ten years, respondents noted they have conducted more than 650 IHC TCR assays, largely on full length mAbs, with varying impacts on programs. Protein/cell arrays have been utilized by almost half of the companies and sponsors are gaining familiarity and comfort with the platform. Initial experience with recent versions of these arrays has been largely positive. While most sponsors are not prepared to eliminate the IHC TCR assay, growing experience with these alternatives allows them to confidently choose other approaches with or without TCR assays.

Implementation of a Pooled Surveillance Testing Program for Asymptomatic SARS-CoV-2 Infections on a College Campus - Duke University, Durham, North Carolina, August 2-October 11, 2020.

On university campuses and in similar congregate environments, surveillance testing of asymptomatic persons is a critical strategy (1,2) for preventing transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). All students at Duke University, a private research university in Durham, North Carolina, signed the Duke Compact (3), agreeing to observe mandatory masking, social distancing, and participation in entry and surveillance testing. The university implemented a five-to-one pooled testing program for SARS-CoV-2 using a quantitative, in-house, laboratory-developed, real-time reverse transcription-polymerase chain reaction (RT-PCR) test (4,5). Pooling of specimens to enable large-scale testing while minimizing use of reagents was pioneered during the human immunodeficiency virus pandemic (6). A similar methodology was adapted for Duke University's asymptomatic testing program. The baseline SARS-CoV-2 testing plan was to distribute tests geospatially and temporally across on- and off-campus student populations. By September 20, 2020, asymptomatic testing was scaled up to testing targets, which include testing for residential undergraduates twice weekly, off-campus undergraduates one to two times per week, and graduate students approximately once weekly. In addition, in response to newly identified positive test results, testing was focused in locations or within cohorts where data suggested an increased risk for transmission. Scale-up over 4 weeks entailed redeploying staff members to prepare 15 campus testing sites for specimen collection, developing information management tools, and repurposing laboratory automation to establish an asymptomatic surveillance system. During August 2-October 11, 68,913 specimens from 10,265 graduate and undergraduate students were tested. Eighty-four specimens were positive for SARS-CoV-2, and 51% were among persons with no symptoms. Testing as a result of contact tracing identified 27.4% of infections. A combination of risk-reduction strategies and frequent surveillance testing likely contributed to a prolonged period of low transmission on campus. These findings highlight the importance of combined testing and contact tracing strategies beyond symptomatic testing, in association with other preventive measures. Pooled testing balances resource availability with supply-chain disruptions, high throughput with high sensitivity, and rapid turnaround with an acceptable workload.

Effects of Cognitive Behavioral Therapy for Insomnia on Sleep, Symptoms, Stress, and Autonomic Function Among Patients With Heart Failure.

Background: Insomnia is common among patients with stable heart failure (HF) and associated with inflammation and altered autonomic function. Purpose: The purposes of this study were to examine the effects of cognitive behavioral therapy for insomnia (CBT-I) on the Hypothalamic Pituitary (HPA) Axis, autonomic function, inflammation, and circadian rhythmicity and the associations between these biomarkers and insomnia, sleep characteristics, symptoms, functional performance, and sleep-related cognitions. Methods: We conducted a subanalysis of a pilot randomized controlled trial (RCT, NCT02827799) whose primary aim was to test the effects of CBT-I on insomnia. We randomized 51 patients with stable Class II-IV HF to CBT-I (n = 30) or attention control (n = 21). Participants completed wrist actigraphy and self-reported insomnia severity, sleep characteristics, sleep-related cognitions, daytime symptoms, and functional performance. We measured day and nighttime urinary free cortisol, melatonin sulfate, epinephrine, and norepinephrine at baseline, and two weeks after CBT-I and computed general linear models and partial correlations. Results: CBT-I had no effects on the biomarkers, but there were statistically significant negative cross-sectional correlations between the ratio of day and night urinary free cortisol and sleep disturbance, anxiety, fatigue, depression, and negative sleep cognitions. Increases in the ratio between day and night cortisol were associated with statistically significant improvements in fatigue, depression, sleep duration, and sleep-related cognitions. Conclusions: Biomarkers of stress and autonomic function are associated with sleep, sleep-related symptoms, and cognitions among people with chronic HF. Future studies are needed to identify potential causal relationships and the impact of sleep interventions.

Special care dentistry trainee views on the medical and oral medicine elements of the specialist training curriculum.

INTRODUCTION: Specialty training curricula are subject to periodic update, and trainee views are an important element in identifying which areas need particular focus. In this study, we wished to examine specialty trainee opinions on two areas of a curriculum for special care dentistry, in particular oral medicine, and the component elements of related systemic disease and therapies (RSDT), namely pathology, pharmacology and therapeutics, and human systemic disease. MATERIALS AND METHODS: Following ethical approval, we identified 35 specialty registrars in special care dentistry in the UK and Ireland who were invited to use an online survey tool to gather demographic data and then to ask their views on the delivery of training in oral medicine and RSDT. Respondents were also asked whether sufficient importance was placed on these topics and whether they could be accessed and delivered appropriately. RESULTS: The 23 registrars surveyed comprised a representative group from all parts of the UK and Ireland and were at different stages of specialty training. The majority thought oral medicine and RSDT were key elements of the curriculum and could be given more prominence, especially in the context of an increasingly ageing population with associated oral manifestations of chronic disease, multiple drugs and disabilities. DISCUSSION AND CONCLUSION: The registrars surveyed felt that oral medicine and RSDT and were integral to training and that emphasis and opportunities for training in these areas could be improved, especially for those trainees based outside of a dental hospital setting.

Nano-lipospheres as acoustically active ultrasound contrast agents: evolving tumor imaging and therapy technique.

Applying nanobubbles (NBs) for contrast-enhanced ultrasound imaging has received increased attention. NBs are biocompatible, multifunctional, theranostic agents. Their properties of high echogenicity and stability create an agent suitable for ultrasonography diagnosis. Their favorable properties of size, in vivo stability, and ease of modification are being exploited to implement a theranostic platform for cancer treatment. The considerable development offers the potential to overcome drug resistance and adverse side effects that are associated with traditional chemotherapy. This review outlines the principles of ultrasonography and angiogenesis. Microbubbles and micelles are also discussed to underline the superior capabilities of NBs for the application. NBs could passively accumulate to tumor tissue by enhanced permeability and retention effect. In addition, it can also achieve the active transportation by surface modification. Active targeting modalities and stimuli-responsive drug delivery modifications generate a therapeutic vehicle. The cytotoxicity of NBs formulations, multimodal imaging capability, active targeting mechanisms, and drug delivery methods are highlighted to confirm the NB as a vehicle for targeted treatment and enhanced ultrasound imaging.

Effects of Cognitive Behavioral Therapy for Insomnia on Sleep-Related Cognitions Among Patients With Stable Heart Failure.

OBJECTIVE/BACKGROUND: Cognitive behavioral therapy for insomnia (CBT-I) improves insomnia and fatigue among chronic heart failure (HF) patients, but the extent to which sleep-related cognitions explain CBT-I outcomes in these patients is unknown. We examined the effects of CBT-I on sleep-related cognitions, associations between changes in sleep-related cognitions and changes in sleep and symptoms after CBT-I, and the extent to which cognitions mediated the effects of CBT-I. PARTICIPANTS: Stable New York Heart Association Class II-III HF patients (total n = 51; n = 26 or 51.0% women; M age = 59.1 ± 15.1 years). METHODS: HF patients were randomized in groups to group CBT-I (n = 30) or attention control (HF self-management education, n = 21) and completed actigraphy, the Insomnia Severity Index, Pittsburgh Sleep Quality Index, Dysfunctional Beliefs and Attitudes about Sleep (DBAS) and Sleep Disturbance Questionnaires (SDQ), and self-reported fatigue, depression, anxiety, and sleepiness (baseline, immediately after treatment, six months). We used mixed-effects modeling, mediation analysis with a bootstrapping approach, and Pearson correlations. RESULTS: There was a statistically significant group × mult time effect on DBAS. DBAS mediated the effects of CBT-I on insomnia severity and partially mediated CBT-I effects on fatigue. Improvements in dysfunctional cognitions were associated with improved sleep quality, insomnia severity, sleep latency and decreased fatigue, depression, and anxiety, with sustained effects at six months. CONCLUSIONS: Improvement in dysfunctional sleep-related cognitions is an important mechanism for CBT-I effects among HF patients who are especially vulnerable to poor sleep and high symptom burden.

Current strategies in the non-clinical safety assessment of biologics: New targets, new molecules, new challenges.

Nonclinical safety testing of biopharmaceuticals can present significant challenges to human risk assessment with these innovative and often complex drugs. Emerging topics in this field were discussed recently at the 2016 Annual US BioSafe General Membership meeting. The presentations and subsequent discussions from the main sessions are summarized. The topics covered included: (i) specialty biologics (oncolytic virus, gene therapy, and gene editing-based technologies), (ii) the value of non-human primates (NHPs) for safety assessment, (iii) challenges in the safety assessment of immuno-oncology drugs (T cell-dependent bispecifics, checkpoint inhibitors, and costimulatory agonists), (iv) emerging therapeutic approaches and modalities focused on microbiome, oligonucleotide, messenger ribonucleic acid (mRNA) therapeutics, (v) first in human (FIH) dose selection and the minimum anticipated biological effect level (MABEL), (vi) an update on current regulatory guidelines, International Council for Harmonization (ICH) S1, S3a, S5, S9 and S11 and (vii) breakout sessions that focused on bioanalytical and PK/PD challenges with bispecific antibodies, cytokine release in nonclinical studies, determining adversity and NOAEL for biologics, the value of second species for toxicology assessment and what to do if there is no relevant toxicology species.