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OBJECTIVE: The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance JDM Research Committee used case-based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM. RESULTS: Four bDMARD CTPs were proposed: tumor necrosis factor α (TNFα) inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67 of 72]) as well as for patient characteristics, assessments, outcome measures, and follow-up. By weighted average, respondents indicated that they would most likely administer rituximab, followed by abatacept, TNFα inhibitor, and tocilizumab. CONCLUSION: CTPs for the administration of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry-based prospective comparative effectiveness studies.

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Respiratory syncytial virus (RSV) infection and shingles are two viral diseases that affect older adults, and a combined vaccine to protect against both could be beneficial. RSV infection causes hospitalisations and significant morbidity in both children and adults and can be fatal in the elderly. The RSV fusion (F) envelope glycoprotein induces a strong RSV-neutralising antibody response and is the target of protective immunity in the first RSV vaccine for older adults, recently approved by the FDA. An initial childhood infection with the varicella zoster virus (VZV) results in chickenpox disease, but reactivation in older adults can cause shingles. This reactivation in sensory and autonomic neurons is characterized by a skin-blistering rash that can be accompanied by prolonged pain. The approved protein-in-adjuvant shingles vaccine induces VZV glycoprotein E (gE)-fspecific antibody and CD4+ T cell responses and is highly effective. Here we report the evaluation of RSV/shingles combination vaccine candidates based on non-replicating chimpanzee adenovirus (ChAd) vectors. We confirmed the cellular and humoral immunogenicity of the vaccine vectors in mice using T cell and antibody assays. We also carried out an RSV challenge study in cotton rats which demonstrated protective efficacy following a homologous prime-boost regimen with our preferred vaccine candidate.

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OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

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OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

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BACKGROUND: Despite new and better treatments for juvenile dermatomyositis (JDM), not all patients with moderate severity disease respond adequately to first-line therapy. Those with refractory disease remain at higher risk for disease and glucocorticoid-related complications. Biologic disease-modifying antirheumatic drugs (DMARDs) have become part of the arsenal of treatments for JDM. However, prospective comparative studies of commonly used biologics are lacking. METHODS: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM biologics workgroup met in 2019 and produced a survey assessing current treatment escalation practices for JDM, including preferences regarding use of biologic treatments. The cases and questions were developed using a consensus framework, requiring 80% agreement for consensus. The survey was completed online in 2020 by CARRA members interested in JDM. Survey results were analyzed among all respondents and according to years of experience. Chi-square or Fisher's exact test was used to compare the distribution of responses to each survey question. RESULTS: One hundred twenty-one CARRA members responded to the survey (denominators vary for each question). Of the respondents, 88% were pediatric rheumatologists, 85% practiced in the United States, and 43% had over 10 years of experience. For a patient with moderately severe JDM refractory to methotrexate, glucocorticoids, and IVIG, approximately 80% of respondents indicated that they would initiate a biologic after failing 1-2 non-biologic DMARDs. Trials of methotrexate and mycophenolate were considered necessary by 96% and 60% of respondents, respectively, before initiating a biologic. By weighed average, rituximab was the preferred biologic over abatacept, tocilizumab, and infliximab. Over 50% of respondents would start a biologic by 4 months from diagnosis for patients with refractory moderately severe JDM. There were no notable differences in treatment practices between respondents by years of experience. CONCLUSION: Most respondents favored starting a biologic earlier in disease course after trialing up to two conventional DMARDs, specifically including methotrexate. There was a clear preference for rituximab. However, there remains a dearth of prospective data comparing biologics in refractory JDM. These findings underscore the need for biologic consensus treatment plans (CTPs) for refractory JDM, which will ultimately facilitate comparative effectiveness studies and inform treatment practices.

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OBJECTIVES: To assess the degree to which removal of FDA' Pregnancy Categories (PC) of medications (A, B, C, and D) from labeling, affects the likelihood that providers will prescribe those medications. METHODS: Over a one-year period a convenience sample of providers was recruited into a randomized, survey-based, study. Two versions of the survey were randomly distributed; version 1 presented clinical vignettes, drug information, and PC, while version 2, presented the identical information without the PC. Respondents were asked to estimate their likelihood of prescribing the drug. A mixed linear model was constructed, with likelihood of prescription as the dependent variable, treated as interval-scaled. RESULTS: Out of 169 surveys given out, 162 (96%) were returned. Simple effects analysis showed that the presence of PC letter significantly affected the decision to prescribe category B (p<0.001) and C drugs (p=0.008) but not the A or D. Participants were significantly less likely to prescribe class B and C drugs when the letters were not available for review. These findings remained significant even when controlling for covariates (p=0.001). CONCLUSIONS: When a PC letter is absent on labeling, physicians were less likely to use category B and C drugs, the most common medications prescribed in pregnancy.

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Cyclic arginyl-glycyl-aspartic acid peptide (cRGD) peptides show a high affinity towards αVß3 integrin, a receptor overexpressed in many cancers. We aimed to combine the versatility of ultrasmall gold nanoparticles (usGNP) with the target selectivity of cRGD peptide for the directed delivery of a cytotoxic payload in a novel design. usGNPs were synthesized with a modified Brust-Schiffrin method and functionalized via amide coupling and ligand exchange and their uptake, intracellular trafficking, and toxicity were characterized. Our cRGD functionalized usGNPs demonstrated increased cellular uptake by αVß3 integrin expressing cells, are internalized via clathrin-dependent endocytosis, accumulated in the lysosomes, and when loaded with mertansine led to increased cytotoxicity. Targeting via cRGD functionalization provides a mechanism to improve the efficacy, tolerability, and retention of therapeutic GNPs.

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The coronavirus disease 2019 (COVID-19) pandemic led to the need for tracking of physical contacts and potential exposure to disease. Traditional contact tracing can be augmented by electronic tools called "electronic contact tracing" or "exposure notification.". Some methods were built to work with smartphones; however, smartphones are not prevalent in some high-contact areas (e.g., schools and nursing homes). We present the design and initial testing of low-cost, highly privacy preserving wearable exposure notification devices. Several devices were constructed based on existing hardware and operated independently of a smartphone. The method (devices and analyses) was not able to reliably use the received signal strength indicator (RSSI) as a proxy for distance between pairs of devices; the accuracy of RSSI as a proxy for distance decreased dramatically outside of the idealized conditions. However, even an imperfect device could be useful for research on how people use and move through spaces. With some improvement, these devices could be used to understand disease spread and human or animal interaction in indoor environments.

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We discuss the measurement of aggregate levels of encounters in a population, a concept we call encounter metrics. Encounter metrics are designed so that they can be deployed while preserving the privacy of individuals. To this end, encounters are labeled with a random number that cannot be linked to anything that is broadcast at the time of the encounter. Among the applications of encounter metrics is privacy-preserving exposure notifcation, a system that allows people to obtain a measure of their risk due to past encounters with people who have self-reported to be positive with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-19), the cause of coronavirus disease 2019 (COVID-19). The precise engineering of a system for exposure notifcation should be targeted to particular environments. We outline a system for use in the context of a workplace such as the National Institute of Standards and Technology (NIST).

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Gold nanoparticles are promising drug delivery agents with the potential to deliver chemotherapeutic agents to tumour sites. The highly cytotoxic maytansinoid tubulin inhibitor DM1 has been attached to gold nanoparticles and shows tumour growth inhibition in mouse models of hepatocellular carcinoma. Attempting to improve the stability of the gold-cytotoxin bond led to the design and synthesis of novel maytansinoids with improved potency in cell viability assays and improved in vivo tolerability compared to the DM1 analogues. These novel maytansines may also have applications in other methods of drug delivery, for example as the cytotoxic component of antibody drug conjugates.

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BACKGROUND: New consultants consistently feel better prepared for the clinical rather than non-clinical aspects of their role. However, deficiencies in generic competencies have been linked to burnout and patient complaints. This study explored how higher specialty training prepares doctors for the transition to consultant in genitourinary medicine. RESULTS: New consultants felt less prepared for non-clinical aspects of their role. Prior practical experience was the greatest influencing factor in levels of preparedness, with increased responsibility and leadership driving deeper learning. Observation of others helped individuals develop a professional identity but also learn about the wider processes within their service. The learning environment positively influenced preparedness but highlighted a need for dedicated time to learn non-clinical aspects. CONCLUSION: To ensure future trainees feel prepared for the non-clinical aspects of the consultant role, practical experience of non-clinical areas with high levels of leadership and responsibility within a supportive learning environment is essential.

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Amidst rising economic inequality and mounting evidence of its pernicious social effects, what motivates opposition to inequality? Five studies (n = 34,442) show that attributing poverty to situational forces is associated with greater concern about inequality, preference for egalitarian policies and inequality-reducing behaviour. In Study 1, situational attributions for poverty were associated with reduced support for inequality across 34 countries. Study 2 replicated these findings with a nationally representative sample of Americans. Three experiments then tested whether situational attributions for poverty are malleable and motivate egalitarianism. Bolstering situational attributions for poverty through a writing exercise (Study 3) and a computer-based poverty simulation (Studies 4a and b) increased egalitarian action and reduced support for inequality immediately (Studies 3 and 4b), 1 d later and 155 d post-intervention (Study 4b). Causal attributions for poverty offer one accessible means of shaping inequality-reducing attitudes and actions. Situational attributions may be a potent psychological lever for lessening societal inequality.

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BACKGROUND: Rising healthcare costs have emphasized the need to teach cost-conscious care in graduate medical education. OBJECTIVE: To teach high-value care and diagnostic evaluation of pediatric musculoskeletal complaints to residents and rotating medical students through online cases. METHODS: Six online cases were developed and tested at the University Hospitals Cleveland Medical Center. Learners completed modules in one of two groups, those who saw itemized costs of diagnostic tests or those who did not. All learners completed a post-simulation survey. Measured outcomes included presumed diagnosis, cost of evaluation, tests ordered, and perceptions toward high-value care. Simulation outcomes were assessed using paired t-tests. Survey data was analyzed with Chi-squared tests. Outcomes separated by training year were analyzed using ANOVA and post-hoc Tukey test. RESULTS: Thirty-nine residents and medical students participated and were randomly assigned to complete the cases with costs (n = 19) or no costs (n = 20) displayed during workup. Overall, learners who saw costs spent less money on diagnostics ($1511.11 mean per learner versus $2311.35, p = 0.01). Arrival at the correct diagnosis was associated with lower costs in 3 of 6 cases. When compared to the no cost group, learners in the costs group reported feeling more knowledgeable about the price of diagnostic tests (p = 0.04) and were more likely to factor costs into their practice moving forward (p = 0.03). Third year or above residents demonstrated a statically significant increase in correctly diagnosed cases as opposed to medical students. CONCLUSIONS: Interventions that challenge learners to integrate costs into decision-making can potentially change future practice.

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The k-subset sum problem over finite fields is a classical NP-complete problem. Motivated by coding theory applications, a more complex problem is the higher m-th moment k-subset sum problem over finite fields. We show that there is a deterministic polynomial time algorithm for the m-th moment k-subset sum problem over finite fields for each fixed m when the evaluation set is the image set of a monomial or Dickson polynomial of any degree n. In the classical case m=1, this recovers previous results of Nguyen-Wang (the case m=1, p>2) [24] and the results of Choe-Choe (the case m=1, p=2) [3].

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Past research has documented myriad pernicious psychological effects of high economic inequality, prompting interest into how people perceive, evaluate, and react to inequality. Here we propose, refine, and validate the Support for Economic Inequality Scale (SEIS)-a novel measure of attitudes towards economic inequality. In Study 1, we distill eighteen items down to five, providing evidence for unidimensionality and reliability. In Study 2, we replicate the scale's unidimensionality and reliability and demonstrate its validity. In Study 3, we evaluate a United States version of the SEIS. Finally, in Studies 4-5, we demonstrate the SEIS's convergent and predictive validity, as well as evidence for the SEIS being distinct from other conceptually similar measures. The SEIS is a valid and reliable instrument for assessing perceptions of and reactions to economic inequality and provides a useful tool for researchers investigating the psychological underpinnings of economic inequality.

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Previous research has shown that demographics, beliefs, and self-reported own health influence TTO values. Our hypothesis is that attitudes towards length and quality of life influence TTO values, but should no longer affect a set of related choices that are based on respondents' own TTO scores. A representative sample of 1339 respondents was asked their level of agreement to four statements relating to the importance of quality and length of life. Respondents then went on to value 4 EQ-5D 5L states using an online interactive survey and a related set of 6 pairwise health-related choice questions, set up, so that respondents should be indifferent between choice options. We explored the impact of attitudes using regression analysis for TTO values and a logit model for choices. TTO values were correlated with the attitudes and were found to have a residual impact on the choices. In particular, those respondents who preferred quality of life over length of life gave less weight to the differences in years and more weight to differences in quality of life in these choice. We conclude that although the TTO responses reflect attitudes, these attitudes continue to affect health-related choices.

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Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with poor prognosis and limited options for treatment. Life expectancy after diagnosis is short; the currently available treatments are not well tolerated and have limited clinical benefit. There is a clear unmet clinical need for the development of new treatments. In this study, ultrasmall, 2 nm gold core nanoparticles (MidaCore) conjugated with the potent maytansine analogue DM1 (MTC-100038) were assessed as a systemic nanomedicine for the treatment of hepatocellular carcinoma. The platform improved overall tolerability of DM1, permitting ∼3-fold higher levels of drug to be administered compared to free drug. Dose for dose, MTC-100038 also facilitated delivery of ∼2.0-fold higher ( p = 0.039) levels of DM1 to the tumor compared to free DM1. MTC-100038 produced significant efficacy (tumor growth index ∼102%; p = <0.0001), in several murine xenograft models of HCC, and was superior to both free DM1 and the current standard of care, sorafenib. Furthermore, MTC-100038 displayed potent (nM) in vitro activity in various HCC primary patient derived cell lines and across various other different cancer cell types. These data demonstrate the potential of MidaCore nanoparticles to enhance tumor delivery of cytotoxic drugs and indicate MTC-100038 is worthy of further investigation as a potential treatment for HCC and other cancer types.

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OBJECTIVES: Previous studies demonstrated associations between reduced serum 25-hydroxyvitamin D (25OHD), inflammation and disease activity in paediatric systemic lupus erythematosus (pSLE). The goal of this study was to assess parathyroid hormone (PTH) in its relationship to vitamin D and inflammation, as well as to better understand the role of human cathelicidin (LL-37) in pSLE. METHODS: Frozen serum samples collected at baseline of the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) study were assayed to determine 25OHD, PTH and LL-37 levels. Pearson's correlations and Χ2 tests were used to evaluate the relationships between 25OHD, PTH, LL-37, inflammation, disease activity and infection using baseline values collected as part of the APPLE study. RESULTS: 201/221 APPLE participants had serum available for analysis. Serum 25OHD was inversely associated with serum PTH, but not LL-37. Serum PTH was not associated with high sensitivity C-reactive protein, carotid intima media thickness or high-density lipoprotein (HDL) or low-density lipoprotein (LDL) cholesterol, but was negatively associated with lipoprotein(a) levels. Despite no association with serum 25OHD, LL-37 was negatively associated with total cholesterol, HDL and LDL cholesterol and positively associated with age. There was no significant difference in mean LL-37 levels in participants with reported infection as an adverse event during the 3-year APPLE study. CONCLUSIONS: Despite links to vitamin D levels in other studies, LL-37 levels were not associated with baseline serum 25OHD concentrations in paediatric patients with pSLE. Despite the lack of correlation with 25OHD, LL-37 levels in this study were associated with cholesterol levels. Some subjects with pSLE have significantly elevated levels of LL-37 of unknown significance. These exploratory results addressing the role of LL-37 levels in pSLE appear worthy of future study.