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Abstract Background Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by iduronate-2-sulfatase gene (IDS) deficiency and downstream glycosaminoglycan accumulation. Two-thirds of patients present with neuronopathic disease and evaluating cognitive function in these patients is challenging owing to limitations of currently available tests. During the clinical development of intrathecal idursulfase (idursulfase-IT), regulatory authorities requested qualitative data to further understand the neurocognitive changes observed by the investigators through the clinical trials. Results This qualitative study consisted of semi-structured interviews with all nine of the principal investigators who participated in the idursulfase-IT phase 2/3 (NCT02055118) and extension (NCT02412787) trials. These investigators enrolled the 56 patients with neuronopathic MPS II who qualified for the extension phase of the trial. The investigators were asked to rate the disease status of their patients. Of the 56 patients, 49 (88%) were rated as having disease that was improved/improving, stabilized or slowing progression compared with the expected outcomes with no treatment. Three patients were rated as worsening, while the remaining four patients were considered to have slowing progression or worsening disease. Similar results were demonstrated for patients aged from 3 to under 6 years at baseline, with 33 of 39 patients (85%) rated as having disease that was improved/improving, stabilized or slowing progression. Of the seven patients rated with slowing progression/worsening or worsening disease, five of them had an IDS variant other than missense, while two had a missense class variant. All the assigned improved/improving ratings were in patients receiving idursulfase-IT from the start of the phase 2/3 trial. Moreover, patients under 3 years of age at baseline were all rated as either improved/improving or stabilized disease. In a blinded review of patient profiles, investigators were requested to assign a disease status rating to 18 patients with large IDS deletions; 67% of these patients were rated as improved/improving or stabilized disease. Conclusions This qualitative analysis provides a snapshot of clinicians’ considerations when evaluating treatment in patients with neuronopathic MPS II, compared with the expected decline in cognitive function in the absence of treatment. The results highlight the importance of robust assessment tools in treatment evaluation.

Abstract Background The associations of adiposity with aggressive prostate cancer risk are unclear. Using two‐sample Mendelian randomization, we assessed the association of metabolically unfavourable adiposity (UFA), favourable adiposity (FA) and for comparison body mass index (BMI), with prostate cancer, including aggressive prostate cancer. Methods We examined the association of these genetically predicted adiposity‐related traits with risk of prostate cancer overall, aggressive and early onset disease using outcome summary statistics from the PRACTICAL consortium (including 15,167 aggressive cases). Results In inverse‐variance weighted models, there was little evidence that genetically predicted one standard deviation higher UFA, FA and BMI were associated with aggressive prostate cancer [OR: 0.85 (95% CI:0.61–1.19), 0.80 (0.53–1.23) and 0.97 (0.88–1.08), respectively]; these associations were largely consistent in sensitivity analyses accounting for horizontal pleiotropy. There was no strong evidence that genetically determined UFA, FA or BMI were associated with overall prostate cancer or early age of onset prostate cancer. Conclusions We did not find differences in the associations of UFA and FA with prostate cancer risk, which suggest that adiposity is unlikely to influence prostate cancer via the metabolic factors assessed; however, these did not cover some aspects related to metabolic health that may link obesity with aggressive prostate cancer, which should be explored in future studies.

Abstract Background Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disease caused by deficient activity of arylsulfatase A (ASA). Treatment options for patients are limited; gene therapy based on haematopoietic stem cell transplantation is the only approved treatment for some subtypes of MLD. Any therapeutic benefit of treatments must be meaningful for patients and their families. We evaluated the clinical meaningfulness of slowing the decline in gross motor function as measured by the Gross Motor Function Classification in MLD (GMFC-MLD) from the caregiver perspective via semi-structured telephone interviews with caregivers of children with late-infantile MLD. We also evaluated the perceived significance of declines in communication abilities measured by the Expressive Language Function Classification in MLD (ELFC-MLD). This work could help to inform the endpoints of a phase 2 clinical trial (NCT03771898) assessing the efficacy of intrathecal recombinant human ASA in MLD. Results Twelve caregivers were recruited, reporting on 12 children with MLD. Children had a mean age of 6.1 years; mean age at symptom onset was 17.6 months. Most children (10/12) progressed from walking without support (categories 0–1) to a loss of locomotion (categories 5–6) in ≤ 2 years. Caregivers felt that GMFC-MLD and ELFC-MLD accurately described motor and language declines in their children, respectively. Most caregivers (10/12) reported that the idea of delaying disease progression would be meaningful. Further, a slowing of motor function decline in GMFC-MLD, from category 1 to category 3 or from category 2 to category 4 over 2 years, was seen as meaningful by all caregivers asked; however, only 3/12 caregivers reported that delayed decline would be meaningful if baseline category was ≥ 3. Caregivers also reported that delaying expressive language decline at any level that did not indicate a complete loss of expressive language (indicated by categories 1–3) would be meaningful. Conclusions Caregivers of children with MLD felt that a delayed decline in gross motor function, as assessed by the GMFC-MLD, would be meaningful, supporting the selection of primary and secondary endpoints for the phase 2 clinical trial. Communication abilities were another area of significance for consideration in future clinical trial design.

Abstract Background Patient-reported outcome (PRO) measures are important to consider when evaluating treatments, yet there are no PRO measures for patients with acromegaly that have been developed in accordance with US Food and Drug Administration guidance. Acromegaly is a rare, chronic condition caused by hypersecretion of growth hormone. Disease activity is monitored by measurement in serum of growth hormone and insulin-like growth factor-I. The objectives of this research were to develop the Acromegaly Symptom Diary (ASD), establish a scoring algorithm, and evaluate the psychometric measurement properties of the ASD. Methods Semistructured interviews consisting of concept elicitation and cognitive debriefing components were conducted with 16 adult participants with acromegaly. The concept elicitation component identified symptoms important to individuals with acromegaly. The cognitive debriefing component gathered information about the participants’ experience with each proposed item of the ASD, their thought process for answering each question, and their interpretation of the items. The psychometric properties of the draft ASD were then evaluated using data from the ACROBAT Evolve (NCT03792555; n = 13) and ACROBAT Edge (NCT03789656; n = 47) clinical trials. Results The 16 participants from the interviews described ongoing symptoms, with the most frequently reported being joint pain (n = 13) and fatigue (n = 12), followed by swelling (n = 8), headache (n = 7), and mood swings (n = 6), and were able to interpret and understand the ASD items and had no issues with the 24-hour recall period. From data collected in the clinical studies, the psychometric properties of internal consistency (0.91 − 0.80), test-retest reliability with item-level and total ASD scores (> 0.70), baseline construct validity (r ≥ |0.38|) across scales, and responsiveness to change (r = 0.52–0.56) were supported for the ASD. The proposed preliminary threshold range to characterize a meaningful change from the patients’ perspective for the ASD total is a 4- to 6-point change for improvement or worsening out of a total score of 70. Conclusion These findings provide qualitative and quantitative evidence to support the ASD as fit for the purpose of evaluating the symptom experience of patients with acromegaly in clinical trials.

Abstract Background This study evaluates the effectiveness of a targeted telephone-based case management service that aimed to reduce ED attendance amongst frequent attenders, known to disproportionately contribute to demand. Evidence on the effectiveness of these services varies. Methods A 24-month controlled before-and-after study, following 808 patients (128 cases and 680 controls (41 were non-compliant)) who were offered the service in the first four months of operation within a UK ED department. Patients stratified as high-risk of reattending ED within 6 months by a predictive model were manually screened. Those positively reviewed were offered a non-clinical, nurse-led, telephone-based health coaching, consisting of care planning, coordination and goal setting for up to 9 months. Service effectiveness was estimated using a difference-in-differences (DiD) analysis. Incident rate of ED and Minor Injury Unit (MIU) attendances and average length of stay in intervention recipients and controls over 12 months after receiving their service offer following ED attendance were compared, adjusting for the prior 12-month period, sex and age, to give an incidence rate ratio (IRR). Results Intervention recipients were more likely to be female (63.3% versus 55.4%), younger (mean of 69 years versus 76 years), and have higher levels of ED activity (except for MIU) than controls. Mean rates fell between periods for all outcomes (except for MIU attendance). The Intention-to-Treat analysis indicated non-statistically significant effect of the intervention in reducing all outcomes, except for MIU attendances, with IRRs: ED attendances, 0.856 (95% CI: 0.631, 1.160); ED admissions, 0.871 (95% CI: 0.628, 1.208); length of stay for emergency and elective admissions: 0.844 (95% CI: 0.619, 1.151) and 0.781 (95% CI: 0.420, 1.454). MIU attendance increased with an IRR: 2.638 (95% CI: 1.041, 6.680). Conclusions Telephone-based health coaching appears to be effective in reducing ED attendances and admissions, with shorter lengths of stay, in intervention recipients over controls. Future studies need to capture outcomes beyond acute activity, and better understand how services like this provide added value.

Background: Some individuals living with obesity may be relatively metabolically healthy, whilst others suffer from multiple conditions that may be linked to adverse metabolic effects or other factors. The extent to which the adverse metabolic component of obesity contributes to disease compared to the non-metabolic components is often uncertain. We aimed to use Mendelian randomisation (MR) and specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects on diseases. Methods: We selected 37 chronic diseases associated with obesity and genetic variants associated with different aspects of excess weight. These genetic variants included those associated with metabolically ‘favourable adiposity’ (FA) and ‘unfavourable adiposity’ (UFA) that are both associated with higher adiposity but with opposite effects on metabolic risk. We used these variants and two sample MR to test the effects on the chronic diseases. Results: MR identified two sets of diseases. First, 11 conditions where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here, MR with the FA and UFA genetics showed opposing effects on risk of disease: coronary artery disease, peripheral artery disease, hypertension, stroke, type 2 diabetes, polycystic ovary syndrome, heart failure, atrial fibrillation, chronic kidney disease, renal cancer, and gout. Second, 9 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) are likely a cause. Here, MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, both indicated higher disease risk: osteoarthritis, rheumatoid arthritis, osteoporosis, gastro-oesophageal reflux disease, gallstones, adult-onset asthma, psoriasis, deep vein thrombosis, and venous thromboembolism. Conclusions: Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects, including the risks to individuals with high body mass index who may be relatively metabolically healthy. Funding: Diabetes UK, UK Medical Research Council, World Cancer Research Fund, National Cancer Institute.

Abstract Background and methods Metachromatic leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disease caused by deficient activity of arylsulfatase A. Neurological involvement results in severe disability and premature death, but understanding of the natural history of the disease remains limited. In this study, 32 caregivers of patients with MLD in the USA (16 with late-infantile MLD; 16 with juvenile MLD) were interviewed about their experiences of the disease. Qualitative analysis of the interview transcripts was performed to gain insights into symptom onset, the diagnostic process and disease progression, with a focus on the differences between late-infantile and juvenile MLD. Results The mean ages of patients at interview were 7.6 years and 20.7 years for individuals with late-infantile and juvenile MLD, respectively. Patients with late-infantile MLD had a mean age of 1.5 years at symptom onset and 2.6 years at diagnosis. The most common initial symptoms in this group related to problems with gross motor function (12/16 patients); 11 patients never learned to walk independently. For patients with juvenile MLD, the mean ages at symptom onset and diagnosis were 8.7 years and 11.6 years, respectively. Cognitive or social/behavioural problems were the most common first reported symptoms in this group (9/16 and 7/16 patients, respectively); these were generally followed by deterioration in motor function. The rate of functional decline was more rapid in patients with late-infantile MLD than those with juvenile MLD; the mean time from first symptom to first functional loss was 1 year versus 6.1 years, respectively. Nine patients with juvenile MLD and three with late-infantile MLD had undergone a haematopoietic stem cell transplant; outcomes following transplant were variable. Conclusions Our data highlight clear overall differences in symptom profiles and disease progression between late-infantile and juvenile MLD, but also indicate some degree of interindividual variability within each subtype. These findings are broadly consistent with previously published descriptions of MLD and enhance our knowledge of the natural history of the disease, which ultimately should help to improve patient care and aid assessments of the effectiveness of disease-related interventions in the future.

IntroductionAlthough shortcomings in clinician–family communication and decision making for incapacitated, critically ill patients are common, there are few rigorously tested interventions to improve outcomes. In this manuscript, we present our methodology for the Pairing Re-engineered Intensive Care Unit Teams with Nurse-Driven Emotional support and Relationship Building (PARTNER 2) trial, and discuss design challenges and their resolution.Methods and analysisThis is a pragmatic, stepped-wedge, cluster randomised controlled trial comparing the PARTNER 2 intervention to usual care among 690 incapacitated, critically ill patients and their surrogates in five ICUs in Pennsylvania. Eligible subjects will include critically ill patients at high risk of death and/or severe long-term functional impairment, their main surrogate decision-maker and their clinicians. The PARTNER intervention is delivered by the interprofessional ICU team and overseen by 4–6 nurses from each ICU. It involves: (1) advanced communication skills training for nurses to deliver support to surrogates throughout the ICU stay; (2) deploying a structured family support pathway; (3) enacting strategies to foster collaboration between ICU and palliative care services and (4) providing intensive implementation support to each ICU to incorporate the family support pathway into clinicians’ workflow. The primary outcome is surrogates’ ratings of the quality of communication during the ICU stay as assessed by telephone at 6-month follow-up. Prespecified secondary outcomes include surrogates’ scores on the Hospital Anxiety and Depression Scale, the Impact of Event Scale, the modified Patient Perception of Patient Centredness scale, the Decision Regret Scale, nurses’ scores on the Maslach Burnout Inventory, and length of stay during and costs of the index hospitalisation.We also discuss key methodological challenges, including determining the optimal level of randomisation, using existing staff to deploy the intervention and maximising long-term follow-up of participants.Ethics and disseminationWe obtained ethics approval through the University of Pittsburgh, Human Research Protection Office. The findings will be published in peer-reviewed journals.Trial registration numberNCT02445937

Introduction: If integrated care approaches are to be properly adapted to local contexts, a better understanding is required of key determinants of implementation and how these might be appropriately supported. Purpose: This study applied the Canadian Context and Capabilities for Integrating Care (CCIC) Framework to investigate factors influencing the implementation and outcomes of a complex integrated care change programme in Torbay and South Devon (TSD) and, more specifically, in one of five sub-localities, Coastal. Methods: A case study method using embedded ‘Researchers in Residence’ to conduct action-based participatory research and deploying mixed qualitative methods. Results: The relative importance of some domains differ between the English and Canadian studies. In this case study, physical features (structural and geographic) were found to be very pertinent to the relative success of the Coastal Locality, as were empowered clinical leadership, with readiness for change being expressed through processes and cultures that were risk-enabling, strengths-based, person-/outcome-focused. Conclusions: The CCIC Framework provided a useful tool capturing key elements of complex system change with key domains being transferable across settings, while also finding local variation in the UK. This would encourage its wider application so that further comparisons can be made of the ways in which different contextual and implementation properties impact upon delivery and outcomes.

Abstract Background Metachromatic leukodystrophy (MLD) is a rare disease with three forms based on the age at onset of signs and symptoms. The objective of this study was to develop a caregiver-reported clinical outcome assessment that measures impairments in physical functioning related to activities of daily living in patients with juvenile MLD. Methods A targeted literature review and exploration of proprietary research, including a conceptual model, were conducted. Concept elicitation interviews were conducted to elicit additional concepts related to impairments in patients’ physical functioning with caregivers of five individuals with juvenile MLD. Based on the research review and concept elicitation interviews, the conceptual model was updated and the Impact of Juvenile Metachromatic Leukodystrophy on Physical Activities (IMPA) scale draft items were created. Cognitive debriefing interviews were conducted with six additional caregivers to finalize the conceptual model and to refine the IMPA scale. Results Initially, 17 potentially important concepts were identified and addressed in the draft IMPA scale. Following the cognitive debriefing interviews, 15 activities/items remained: brush teeth, comb/brush hair, bathe/shower, dress self, eat, drink, use pencil/crayon, sit upright, use toilet, get on/off toilet, walk, use stairs, get in/out of bed, get in/out of chair/wheelchair, and get in/out of vehicle. Items that did not uniquely contribute to the purpose of the instrument were removed. Conclusion The IMPA scale, developed according to regulatory standards, provides a means of detecting changes in activities of daily living in individuals with juvenile MLD and can hence be used in future studies to measure benefits of therapeutic interventions.

Written clarity and conciseness are desired by employers and emphasized in business communication courses. We developed and tested the efficacy of a cueing tool--Scribe Bene--to help students reduce their use of imprecise and ambiguous words and wordy phrases. Effectiveness was measured by comparing cue word usage between a treatment group given the tool and a control group without the tool. In written assignments, the treatment group used 16 of 23 cue words significantly less than the control group and this effect persisted over time. Implications for using automated cueing tools in teaching written communication skills are discussed.

Movements precipitated by humanitarian crises have implications that touch upon immigration control and national interests, human rights, humanitarian and development principles, and the frameworks for international protection, cooperation and burden sharing. Existing legal and institutional frameworks manifest limited capacity to accommodate all those with protection needs. Even when frameworks exist, in practice there are considerable gaps in implementation.

2011 marks the anniversary of two important events in refugee protection. In 1951, the United Nations adopted the UN Convention Relating to the Status of Refugees. Forty years later, in 1991, the Executive Committee of the Office of the UN High Commissioner for Refugees (UNHCR) adopted Guidelines on the Protection of Refugee Women. Since 1991, there has been both progress and setbacks in providing equal and effective protection to both male and female refugees. The article concludes that the gap between rhetoric and reality for women and girls is still very large. Following a brief discussion of the demographic profile of refugees, the article discusses issues related to legal protection, physical security, and social and economic rights for refugee and displaced women. The article call for renewed efforts to implement fully the various legal instruments and guidelines that set out norms and standards of protection for refugees generally and women and girls specifically and to ensure that refugee and displaced women are able to participate actively in decisions that affect them and their families.