Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope.

The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in 'Creating Clinical Guidelines: Our Protocol' by the British Society for Rheumatology.

Short subcutaneous infusions for symptom control in palliative medicine.

OBJECTIVES: To investigate the efficacy and safety of short subcutaneous infusions (SSCIs) for refractory symptoms in the palliative setting. METHODS: A retrospective chart review of SSCIs in a single palliative care centre over an 18-month period. All clinical notes, medication administration records and infusion monitoring documentation were examined to ascertain therapeutic aim, efficacy and tolerability. RESULTS: 111 patients received one or more SSCIs, 28 in the community and 83 in the inpatient hospice (21% of all admissions). SSCIs were used for a wide variety of reasons including loading doses (to achieve steady state and, thus, symptom relief, sooner), as required doses (for medications too irritant to give as bolus SC injections) and regular maintenance doses (where continuous subcutaneous infusion (CSCI), were unnecessary). 84 single drug SSCIs types and 51 admixtures SSCIs types (2 or more medications) were given. One infusion was poorly absorbed, but SSCIs were otherwise well tolerated. CONCLUSIONS: SSCIs appear to be a promising additional option for administering medicines that are too irritant or large in volume for SC bolus injection. For medications with longer half-lives (eg, phenobarbital, valproate, levetiracetam), SSCI loading doses would be expected to achieve steady state and, thus, symptom relief, sooner than CSCIs alone.

Development and Validation of a Measure to Assess Readiness to Advance Health and Equity: The Assessment for Advancing Community Transformation (AACT).

Multi-sector partnerships are core in efforts to improve population health but are often not as fully developed or positioned to advance health and equity in their communities as believed to be. Therefore, measuring the collaborations multi-sector partnerships undertake is important to document the inputs, processes, and outcomes that evolve as they work together towards achieving their goals, which ultimately creates a greater sense of shared accountability. In this study we present the development and validation of the Assessment for Advancing Community Transformation (AACT), a new tool designed to measure readiness to advance health and health equity. Development of the AACT included initial item pool creation, external evaluation from five subject matter experts, and pilot testing (including user feedback surveys) among 103 individuals. Validation of the AACT was performed using a series of confirmatory factor analyses on an expanded dataset representing 352 individuals from 49 multi-sector collaboratives across the United States. The results of our study indicate the items in the AACT align to six domains created during the scale development process, and that the tool demonstrates desirable measurement characteristics for use in research, evaluation, and practice.

Sharing is caring: a call for a new era of rare disease research and development.

Scientific advances in the understanding of the genetics and mechanisms of many rare diseases with previously unknown etiologies are inspiring optimism in the patient, clinical, and research communities and there is hope that disease-specific treatments are on the way. However, the rare disease community has reached a critical point in which its increasingly fragmented structure and operating models are threatening its ability to harness the full potential of advancing genomic and computational technologies. Changes are therefore needed to overcome these issues plaguing many rare diseases while also supporting economically viable therapy development. In "Data silos are undermining drug development and failing rare disease patients (Orphanet Journal of Rare Disease, Apr 2021)," we outlined many of the broad issues underpinning the increasingly fragmented and siloed nature of the rare disease space, as well as how the issues encountered by this community are representative of biomedical research more generally. Here, we propose several initiatives for key stakeholders - including regulators, private and public foundations, and research institutions - to reorient the rare disease ecosystem and its incentives in a way that we believe would cultivate and accelerate innovation. Specifically, we propose supporting non-proprietary patient registries, greater data standardization, global regulatory harmonization, and new business models that encourage data sharing and research collaboration as the default mode. Leadership needs to be integrated across sectors to drive meaningful change between patients, industry, sponsors, and academic medical centers. To transform the research and development landscape and unlock its vast healthcare, economic, and scientific potential for rare disease patients, a new model is ultimately the goal for all.

Developing capacity for learning community systems: Experiences from the 100 Million Healthier Lives SCALE Initiative.

Introduction: This paper explores the capabilities that contribute to community transformation and the common pathways followed by communities in the 100 Million Healthier Lives SCALE (Spreading Community Accelerators through Learning and Evaluation) initiative in their transformation journeys towards a "Culture of Health". Methods: Funded by the Robert Wood Johnson Foundation (RWJF), from 2016 to 2020, between 18 to 24 community coalitions nationwide participated in SCALE, the goal of which was to co-design, implement, test, and scale up a model called the Community of Solutions (COS) Framework, that built community capacity around a set of skills and behaviors to advance culture change and create sustainable improvement in health, well-being, and equity. We adapted and applied two qualitative research techniques, meta-ethnography and participatory action synthesis, to evaluate SCALE initiative data. Results: Eight concepts emerged that represent the knowledge, capabilities and practices commonly acquired and utilized across the communities. Overall, these concepts emphasize individual and team leadership, quality improvement skills, an intentional focus on equity, and partnerships for spread and sustainment. Concepts were linked into lines of arguments which were unique storylines explaining the transformation pathways. Three stories of the transformation process emerged from the data. Causal Loop Diagrams (CLDs) were created to represent non-linear system relationships and visually capture some of the most important dynamics of the process of transformation. Even with vast heterogeneity among the SCALE communities and the diversity of activities that the communities undertook, our analysis showed there were a few basic principles that undergirded the process of building capability for transformation. Conclusions: The knowledge from our findings should be useful to expand further research and practice in community learning systems.

Efficacy and safety of subcutaneous clonidine for refractory symptoms in palliative medicine: a retrospective study.

OBJECTIVES: To investigate the efficacy and safety of subcutaneous clonidine for refractory symptoms in the palliative setting. METHODS: A retrospective chart review of the use of subcutaneous clonidine in a single palliative care centre. We reviewed the use of clonidine since it was introduced in our locality 2½ years ago. All clinical notes, medication administration records and infusion monitoring documentation were examined to ascertain therapeutic aim, efficacy and tolerability. RESULTS: Subcutaneous clonidine was administered to 113 patients. Recipients were generally frail (median Karnofsky Score 20%) and in the last weeks of life (median survival 6 days). The the most common indications were opioid poorly responsive pain (59), agitation refractory to antipsychotics and/or benzodiazepines (18) or both (35). Symptoms appeared to improve in the majority (85/113, 75%). Some (36, 32%) required no further medication changes once clonidine was commenced. Clonidine appeared well tolerated although blood pressure was not monitored in the majority, in line with our practice to discontinue such observations in those who are nursed in bed and receiving symptom-focused care. CONCLUSIONS: Subcutaneous administration of clonidine appears to be a promising alternative option for refractory symptoms in the last weeks of life. We suggest some possible next steps for further research.

Self-perceived disease activity was the strongest predictor of COVID-19 pandemic-related concerns in young people with autoimmune rheumatic diseases, irrespective of their gender, with females reporting higher concerns.

Objectives: We report the results of a pilot young patient survey that targeted patients with JSLE and JDM, exploring well-being, resilience and general concern about the coronavirus disease 2019 (COVID-19) pandemic as well as self-assessment of disease activity. Methods: The survey was completed anonymously by patients who had been approached via the automatically generated hospital database between June and December 2020. In addition to disease characteristics, geographic location, education and employment level, we explored young patients' resilience, mood and feelings, mental well-being, self-assessed disease activity and general COVID-19 concerns using validated tools and visual analogue scales. Results: This pilot study found that self-perceived disease activity was the strongest predictor of COVID-19 concern, irrespective of gender, employment and education status or well-being and resilience. Generalized concerns regarding the COVID-19 pandemic were significantly higher in females, although their self-reported DASs were comparable to male respondents. Conclusion: Our findings highlight a gender bias in the generalized concern related to the COVID-19 pandemic, irrespective of the examined potential confounders. This suggests the need for further research around young patient self-reported outcomes outside hospital visits, especially in the context of gender differences and potential challenges of future pandemics.

A learning approach to community response during the COVID-19 pandemic: Applying the Cynefin framework to guide decision-making.

Introduction: The United States has been unsuccessful in containing the rapid spread of COVID-19. The complex epidemiology of the disease and the fragmented response to it has resulted in thousands of ways in which spread has occurred, creating a situation where each community needs to create its own local, context-specific learning model while remaining compliant to county or state mandates. Methods: In this paper, we demonstrate how cross sector collaborations can use the Cynefin Framework, a tool for decision-making in complex systems, to guide community response to the COVID-19 pandemic. Results: We explore circumstances under which communities can inhabit each of the four domains of systems complexity represented in the Cynefin framework: simple, complicated, chaotic, and complex, and describe the decision-making process in each domain that balances health, economic, and social well-being. Conclusion: This paper serves as a call to action for the creation of community learning systems to improve community resilience and capacity to make better-informed decisions to address complex public health problems during the pandemic and beyond.

Beta-blockers for tenacious saliva: a case report.

This case report describes the care of a 75-year-old gentleman with metastatic head and neck cancer who was highly symptomatic with intractable tenacious oropharyngeal secretions. The patient reported subjective benefit from oral atenolol. A literature review was undertaken and identified no previous studies on the use of ß-blockers for secretions in malignant disease, although some anecdotal evidence for their use in motor neuron disease. The proposed underlying mechanism is that ß1-blockade reduced the protein content of salivary secretions, hence reducing its viscosity. Further studies of both the role of ß-adrenoreceptors in the control of secretion viscosity and the potential role of ß-blockers in alleviating symptomatic tenacious secretions are warranted.

Bleeding management in palliative medicine: subcutaneous tranexamic acid - retrospective chart review.

OBJECTIVES: To investigate the efficacy and safety of subcutaneously (SC) administered tranexamic acid. METHODS: A retrospective chart review of the use of SC tranexamic acid in a single palliative care centre. We reviewed the use of this approach since it was introduced in our locality 2 years ago. All clinical notes, medication administration records and infusion monitoring documentation were examined to ascertain therapeutic aim, efficacy and tolerability. RESULTS: SC tranexamic acid was administered to 22 patients. The most common causes of bleeding were coagulopathy (5), bleeding tumours (9) and thrombocytopaenia (5). The therapeutic aim was either to prevent (6) or treat (16) bleeding and was achieved in 17/22 patients. During this 2-year period, our experience evolved resulting in a greater use of short bolus infusions to achieve more rapid control of bleeding events. Both short and continuous SC infusions were well tolerated with no instances of SC site reactions. One patient developed a suspected arterial thrombus in the last hours of life around the time of converting from oral (PO) to SC tranexamic acid. CONCLUSIONS: SC administration of tranexamic acid appears to be an effective and well tolerated alternative option for the palliative management of bleeding when the PO and intravenous routes are not available. Further research is needed to clarify tranexamic acid's safety in palliative populations.

90-day nose-only inhalation toxicity study of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Sprague-Dawley rats.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the key tobacco-specific nitrosamines that plays an important role in human lung carcinogenesis. Repeated dose inhalation toxicity data on NNK, particularly relevant to cigarette smoking, however, is surprisingly limited. Hence, there is a lack of direct information available on the carcinogenic and potential non-carcinogenic effects of NNK via inhalational route exposure. In the present study, the subchronic inhalation toxicity of NNK was evaluated in Sprague Dawley rats. Both sexes (9-10 weeks age; 23 rats/sex/group) were exposed by nose-only inhalation to air, vehicle control (75% propylene glycol), or 0.2, 0.8, 3.2, or 7.8 mg/kg body weight (BW)/day of NNK (NNK aerosol concentrations: 0, 0, 0.0066, 0.026, 0.11, or 0.26 mg/L air) for 1 h/day for 90 consecutive days. Toxicity was evaluated by assessing body weights; food consumption; clinical pathology; histopathology; organ weights; blood, urine, and tissue levels of NNK, its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and their glucuronides (reported as total NNK, tNNK, and total NNAL, tNNAL, respectively); tissue levels of the DNA adduct O6-methylguanine; blood and bone marrow micronucleus (MN) frequency; and bone marrow DNA strand breaks (comet assay). The results showed that NNK exposure caused multiple significant adverse effects, with the most sensitive endpoint being non-neoplastic lesions in the nose. Although the genotoxic biomarker O6-methylguanine was detected, genotoxicity from NNK exposure was negative in the MN and comet assays. The Lowest-Observed-Adverse-Effect-Level (LOAEL) was 0.8 mg/kg BW/day or 0.026 mg/L air of NNK for 1 h/day for both sexes. The No-Observed-Adverse-Effect-Level (NOAEL) was 0.2 mg/kg BW/day or 0.0066 mg/L air of NNK for 1 h/day for both sexes. The results of this study provide new information relevant to assessing the human exposure hazard of NNK.

Telemedicine in rheumatology: a mixed methods study exploring acceptability, preferences and experiences among patients and clinicians.

OBJECTIVES: The Covid-19 pandemic necessitated a rapid global transition towards telemedicine; yet much remains unknown about telemedicine's acceptability and safety in rheumatology. To help address this gap and inform practice, this study investigated rheumatology patient and clinician experiences and views of telemedicine. METHODS: Sequential mixed methodology combined analysis of surveys and in-depth interviews. Between and within-group differences in views of telemedicine were examined for patients and clinicians using t-tests. RESULTS: Surveys (patients n = 1340, clinicians n = 111) and interviews (patients n = 31, clinicians n = 29) were completed between April 2021 and July 2021. The majority of patients were from the UK (96%) and had inflammatory arthritis (32%) or lupus (32%). Patients and clinicians rated telemedicine as worse than face-to-face consultations in almost all categories, although >60% found it more convenient. Building trusting medical relationships and assessment accuracy were great concerns (93% of clinicians and 86% of patients rated telemedicine as worse than face-to-face for assessment accuracy). Telemedicine was perceived to have increased misdiagnoses, inequalities and barriers to accessing care. Participants reported highly disparate telemedicine delivery and responsiveness from primary and secondary care. Although rheumatology clinicians highlighted the importance of a quick response to flaring patients, only 55% of patients were confident that their rheumatology department would respond within 48 hours. CONCLUSION: Findings indicate a preference for face-to-face consultations. Some negative experiences may be due to the pandemic rather than telemedicine specifically, although the risk of greater diagnostic inaccuracies using telemedicine is unlikely to be fully resolved. Training, choice, careful patient selection, and further consultation with clinicians and patients is required to increase telemedicine's acceptability and safety. TRIAL REGISTRATION: This telemedicine study is part of a pre-registered longitudinal multi-stage trial, the LISTEN study (ISRCTN-14966097), with later Covid-related additions registered in March 2021, including a pre-registered statistical analysis plan.

14-Day Nose-Only Inhalation Toxicity and Haber's Rule Study of NNK in Sprague-Dawley Rats.

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the key tobacco-specific nitrosamines that plays an important role in human lung carcinogenesis. However, repeated inhalation toxicity data on NNK, which is more directly relevant to cigarette smoking, are currently limited. In the present study, the subacute inhalation toxicity of NNK was evaluated in Sprague Dawley rats. Both sexes (9-10 weeks age; 16 rats/sex/group) were exposed by nose-only inhalation to air, vehicle control (75% propylene glycol), or 0.8, 3.2, 12.5, or 50 mg/kg body weight (BW)/day of NNK (NNK aerosol concentrations: 0, 0, 0.03, 0.11, 0.41, or 1.65 mg/L air) for 1 h/day for 14 consecutive days. Toxicity was evaluated by assessing body and organ weights; food consumption; clinical pathology; histopathology observations; blood, urine, and tissue levels of NNK, its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and their glucuronides (reported as total NNK, tNNK, and total NNAL, tNNAL, respectively); O6-methylguanine DNA adduct formation; and blood and bone marrow micronucleus frequency. Whether the subacute inhalation toxicity of NNK followed Haber's Rule was also determined using additional animals exposed 4 h/day. The results showed that NNK exposure caused multiple significant adverse effects, with the most sensitive endpoint being non-neoplastic histopathological lesions in the nose. The lowest-observed-adverse-effect level (LOAEL) was 0.8 mg/kg BW/day or 0.03 mg/L air for 1 h/day for both sexes. An assessment of Haber's Rule indicated that 14-day inhalation exposure to the same dose at a lower concentration of NNK aerosol for a longer time (4 h daily) resulted in greater adverse effects than exposure to a higher concentration of NNK aerosol for a shorter time (1 h daily).

Toxicokinetic and Genotoxicity Study of NNK in Male Sprague Dawley Rats Following Nose-Only Inhalation Exposure, Intraperitoneal Injection, and Oral Gavage.

The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5 × 10-5, 5 × 10-3, 0.1, or 50 mg/kg body weight (BW) of NNK, 75% propylene glycol (vehicle control), or air (sham control) was administered to male Sprague-Dawley (SD) rats (9-10 weeks age) via nose-only inhalation (INH) exposure for 1 h. For comparison, the same doses of NNK were administered to male SD rats via intraperitoneal injection (IP) and oral gavage (PO). Plasma, urine, and tissue specimens were collected at designated time points and analyzed for levels of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and tissue levels of DNA adduct O6-methylguanine by LC/MS/MS. TK data analysis was performed using a non-linear regression program. For the genotoxicity subgroup, tissues were collected at 3 h post-dosing for comet assay analysis. Overall, the TK data indicated that NNK was rapidly absorbed and metabolized extensively to NNAL after NNK administration via the three routes. The IP route had the greatest systemic exposure to NNK. NNK metabolism to NNAL appeared to be more efficient via INH than IP or PO. NNK induced significant increases in DNA damage in multiple tissues via the three routes. The results of this study provide new information and understanding of the TK and genotoxicity of NNK.

Data silos are undermining drug development and failing rare disease patients.

Data silos are proliferating while research and development activity explode following genetic and immunological advances for many clinically described disorders with previously unknown etiologies. The latter event has inspired optimism in the patient, clinical, and research communities that disease-specific treatments are on the way. However, we fear the tendency of various stakeholders to balkanize databases in proprietary formats, driven by current economic and academic incentives, will inevitably fragment the expanding knowledge base and undermine current and future research efforts to develop much-needed treatments. The proliferation of proprietary databases, compounded by a paucity of meaningful outcome measures and/or good natural history data, slows our ability to generate scalable solutions to benefit chronically underserved patient populations in ways that would translate to more common diseases. The current research and development landscape sets too many projects up for unnecessary failure, particularly in the rare disease sphere, and does a grave disservice to highly vulnerable patients. This system also encourages the collection of redundant data in uncoordinated parallel studies and registries to ultimately delay or deny potential treatments for ostensibly tractable diseases; it also promotes the waste of precious time, energy, and resources. Groups at the National Institutes of Health and Food and Drug Administration have started programs to address these issues. However, we and many others feel there should be significantly more discussion of how to coordinate and scale registry efforts. Such discourse aims to reduce needless complexity and duplication of efforts, as well as promote a pre-competitive knowledge ecosystem for rare disease drug development that cultivates and accelerates innovation.