A patient-centred and multi-stakeholder co-designed observational prospective study protocol: Example of the adolescent experience of treatment for X-linked hypophosphataemia (XLH).

The importance of patient centricity and keeping the patient at the heart of research design is now well recognised within the healthcare community. The involvement of patient, caregiver and clinician representatives in the study design process may help researchers to achieve this goal and to ensure robust and meaningful data generation. Real-world data collection allows for a more flexible and patient-centred research approach for gaining important insights into the experience of disease and treatments, which is acutely relevant for rare diseases where knowledge about the disease is more likely to be limited. Here, we describe a practical example of a patient-centric, multi-stakeholder approach that led to the co-design of a prospective observational study investigating the lived experience of adolescents with the rare disease, X-linked hypophosphataemia. Specifically, we describe how the knowledge and expertise of a diverse research team, which included expert physicians, research and technology specialists, patients and caregivers, were applied in order to identify the relevant research questions and to ensure the robustness of the study design and its appropriateness to the population of interest within the context of the current clinical landscape. We also demonstrate how a structured patient engagement exercise was key to informing the selection of appropriate outcome measures, data sources, timing of data collection, and to assessing the feasibility and acceptability of the proposed data collection approach.

Cardiac Amyloid Detection by PET/CT Imaging of Iodine (124I) Evuzamitide (124I-p5+14): A Phase 1/2 Study.

BACKGROUND: The noninvasive detection of cardiac amyloid, as well as deposits in other vital organs, is critical for early diagnosis and quantitative disease monitoring. Positron emission tomography is an intrinsically quantitative imaging modality suitable for high-resolution amyloid detection. OBJECTIVES: This study sought to evaluate the safety and efficacy of a novel amyloid-reactive peptide, designated p5+14, labeled with iodine-124 (124I), in patients with diverse types of systemic amyloidosis. METHODS: In a single-site, open label phase 1/2 study (NCT03678259), the safety, biodistribution, and sensitivity of a single intravenous infusion of 124I-evuzamitide was assessed in patients with systemic amyloidosis (n = 50), asymptomatic transthyretin sequence variant carriers (n = 2), and healthy volunteers (n = 5). Subjects were administered 1.4 ± 0.2 mg of 124I-evuzamitide (71.5 ± 12.4 MBq) and positron emission tomography/x-ray computed tomography images acquired at 5.2 hours (Q25-Q75: 4.9-5.4 hours) postinfusion. Images were assessed visually and semi-quantitatively for positive uptake of radiotracer in the heart and other major organs. RESULTS: Uptake of 124I-evuzamitide in the heart and other abdominothoracic organs was consistent with the patient's clinical presentation and the type of amyloidosis. The patient- and cardiac-associated sensitivity for imaging and clinical observations was 93.6% (95% CI: 82.8%-97.8%) and 96.2% (95% CI: 81.8%-99.8%), respectively. Semi-quantitative uptake of the radiotracer correlated significantly with serum N-terminal pro-B-type natriuretic peptide measurements in patients with light chain-associated amyloidosis. Cardiac uptake was not observed in any healthy volunteers. The agent was well tolerated, with 1 drug-related adverse event and no deaths. CONCLUSIONS: 124I-evuzamitide is an amyloid-binding radiotracer capable of detecting cardiac amyloid in patients with high sensitivity.

Epidemiology of Tumor-Induced Osteomalacia in Germany Based on Real World Data.

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused mostly by benign tumors that secrete fibroblast growth factor-23. Because of nonspecific symptoms, the diagnostic delay is long, and therapy can be challenging. Moreover, epidemiological data on TIO are scarce owing to its rarity. Therefore, this study aimed to quantify TIO's incidence rates and prevalence in Germany. Retrospective longitudinal and cross-sectional analyses were conducted using anonymized German claims data from the statutory health insurance (SHI) database. This database, which comprises the data of approximately 5 million insurants, is a representative sample of the German population and supports national projections. As there is no unique International Statistical Classification of Diseases and Related Health Problems (ICD) code for TIO, operational categories based on different surrogates were defined to determine the prevalence and incidence rates of TIO among probable patients. This study showed that TIO has a prevalence of (documented code, advanced imaging, medication, or tumor removal) 0.187 per 100,000 persons and an incidence rate of ≤ 0.094 per 100,000 person years. This analysis provides the first epidemiological insight into German patients with TIO. Despite the general limitations associated with the analysis of SHI claims data of ultra-rare diseases, we believe that this analysis provides a sound basis for further analysis, particularly with regard to the care situation of patients with TIO.

Development and characterization of a prototypic pan-amyloid clearing agent - a novel murine peptide-immunoglobulin fusion.

Introduction: Systemic amyloidosis is a progressive disorder characterized by the extracellular deposition of amyloid fibrils and accessory proteins in visceral organs and tissues. Amyloid accumulation causes organ dysfunction and is not generally cleared by the immune system. Current treatment focuses on reducing amyloid precursor protein synthesis and slowing amyloid deposition. However, curative interventions will likely also require removal of preexisting amyloid deposits to restore organ function. Here we describe a prototypic pan-amyloid binding peptide-antibody fusion molecule (mIgp5) that enhances macrophage uptake of amyloid. Methods: The murine IgG1-IgG2a hybrid immunoglobulin with a pan amyloid-reactive peptide, p5, fused genetically to the N-terminal of the immunoglobulin light chain was synthesized in HEK293T/17 cells. The binding of the p5 peptide moiety was assayed using synthetic amyloid-like fibrils, human amyloid extracts and amyloid-laden tissues as substrates. Binding of radioiodinated mIgp5 with amyloid deposits in vivo was evaluated in a murine model of AA amyloidosis using small animal imaging and microautoradiography. The bioactivity of mIgp5 was assessed in complement fixation and in vitro phagocytosis assays in the presence of patient-derived amyloid extracts and synthetic amyloid fibrils as substrates and in the presence or absence of human serum. Results: Murine Igp5 exhibited highly potent binding to AL and ATTR amyloid extracts and diverse types of amyloid in formalin-fixed tissue sections. In the murine model of systemic AA amyloidosis, 125I-mIgp5 bound rapidly and specifically to amyloid deposits in all organs, including the heart, with no evidence of non-specific uptake in healthy tissues. The bioactivity of the immunoglobulin Fc domain was uncompromised in the context of mIgp5 and served as an effective opsonin. Macrophage-mediated uptake of amyloid extract and purified amyloid fibrils was enhanced by the addition of mIgp5. This effect was exaggerated in the presence of human serum coincident with deposition of complement C5b9. Conclusion: Immunostimulatory, amyloid-clearing therapeutics can be developed by incorporating pan-amyloid-reactive peptides, such as p5, as a targeting moiety. The immunologic functionality of the IgG remains intact in the context of the fusion protein. These data highlight the potential use of peptide-antibody fusions as therapeutics for all types of systemic amyloidosis.

The International X-Linked Hypophosphatemia (XLH) Registry: first interim analysis of baseline demographic, genetic and clinical data.

BACKGROUND: X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, renal phosphate-wasting disorder characterized by a pathological increase in FGF23 concentration and activity. Due to its rarity, diagnosis may be delayed, which can adversely affect outcomes. As a chronic disease resulting in progressive accumulation of musculoskeletal manifestations, it is important to understand the natural history of XLH over the patient's lifetime and the impact of drug treatments and other interventions. This multicentre, international patient registry (International XLH Registry) was established to address the paucity of these data. Here we present the findings of the first interim analysis of the registry. RESULTS: The International XLH Registry was initiated in August 2017 and includes participants of all ages diagnosed with XLH, regardless of their treatment and management. At the database lock for this first interim analysis (29 March 2021), 579 participants had entered the registry before 30 November 2020 and are included in the analysis (360 children [62.2%], 217 adults [37.5%] and 2 whose ages were not recorded [0.3%]; 64.2% were female). Family history data were available for 319/345 (92.5%) children and 145/187 (77.5%) adults; 62.1% had biological parents affected by XLH. Genetic testing data were available for 341 (94.7%) children and 203 (93.5%) adults; 370/546 (67.8%) had genetic test results; 331/370 (89.5%) had a confirmed PHEX mutation. A notably longer time to diagnosis was observed in adults ≥ 50 years of age (mean [median] duration 9.4 [2.0] years) versus all adults (3.7 [0.1] years) and children (1.0 [0.2] years). Participants presented with normal weight, shorter length or height and elevated body mass index (approximately - 2 and + 2 Z-scores, respectively) versus the general population. Clinical histories were collected for 349 participants (239 children and 110 adults). General data trends for prevalence of bone, dental, renal and joint conditions in all participants were aligned with expectations for a typical population of people with XLH. CONCLUSION: The data collected within the International XLH Registry, the largest XLH registry to date, provide substantial information to address the paucity of natural history data, starting with demographic, family history, genetic testing, diagnosis, auxology and baseline data on clinical presentation.

Burosumab Improves Patient-Reported Outcomes in Adults With Tumor-Induced Osteomalacia: Mixed-Methods Analysis.

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused by tumors that secrete fibroblast growth factor 23, leading to chronic hypophosphatemia, poor skeletal health, and impaired physical function. In a phase 2 trial (UX023T-CL201; NCT02304367; n = 14), 48 weeks of burosumab treatment restored phosphate homeostasis, with improvements in skeletal health, functional mobility, and patient-reported pain, fatigue, and health-related quality of life (HRQL) (SF-36 v2). Here, we report an exploratory mixed-methods analysis of change from baseline after 144 weeks of burosumab treatment alongside qualitative data from exit interviews with 8 of 14 trial participants to evaluate meaningful treatment effects from a patient perspective. The interview subset (n = 8) reported pain and fatigue and compromised HRQL at baseline. In the interviews, participants reported that compromised HRQL and pain were the most important aspects of the disease to treat; both were considered more bothersome than fatigue and compromised physical function and activities of daily living. Improvements in pain and fatigue after treatment were reported, some of which achieved statistically and/or clinically meaningful thresholds. Furthermore, improvements in SF-36 v2 scores were most pronounced in the Physical Component Score and its Physical Function and Bodily Pain domains. Overall, the interview subset provided descriptions of symptomatic improvement and its clinical meaningfulness, including physical function, participation in activities of daily living, and mental well-being. Thus, this exploratory mixed-methods analysis provides deeper understanding of patients' perception of clinical meaningfulness beyond that articulated in validated patient-reported outcome instruments. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Craniosynostosis in Patients With X-Linked Hypophosphatemia: A Review.

Craniosynostosis is a rare condition of skull development, manifesting during fetal and early infant development, and is usually congenital. Craniosynostosis secondary to metabolic disorders, such as X-linked hypophosphatemia (XLH), is less common and is typically diagnosed later than congenital craniosynostosis. XLH is a rare, progressive, and lifelong hereditary phosphate-wasting disorder characterized by loss of function of the phosphate-regulating endopeptidase homologue, X-linked gene, which is associated with premature fusion of cranial sutures due to abnormal phosphate metabolism (hypophosphatemia) and altered bone mineralization or elevated levels of fibroblast growth factor 23. This targeted literature review of 38 articles seeks to provide an overview of craniosynostosis in individuals with XLH. The objectives of this review are to increase awareness of the prevalence, presentation, and diagnosis of craniosynostosis in XLH; examine the spectrum of craniosynostosis severity in XLH; discuss the management of craniosynostosis in those with XLH; recognize the complications for patients with XLH; and identify what is known about the burden of craniosynostosis for individuals with XLH. The presentation of craniosynostosis in individuals with XLH tends to manifest slightly later than congenital craniosynostosis and can vary in severity and appearance, making diagnosis difficult and resulting in inconsistent clinical outcomes. Consequently, craniosynostosis in patients with XLH is an underreported and potentially underrecognized condition. There have been no studies investigating the effects of craniosynostosis on the quality of life of people with XLH. Despite a growing awareness among researchers and experienced clinicians, there are still improvements to be made in general awareness and timely diagnosis of craniosynostosis in XLH. The XLH community would benefit from further study into the prevalence of craniosynostosis, the effect of XLH medical therapy on the development of craniosynostosis, and the effects of craniosynostosis on quality of life. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial.

Talimogene laherparepvec (T-VEC) is an oncolytic virus hypothesized to enhance triple-negative breast cancer (TNBC) responses to neoadjuvant chemotherapy (NAC). This article describes the phase 2 trial of T-VEC plus NAC (ClinicalTrials.gov ID: NCT02779855 ). Patients with stage 2-3 TNBC received five intratumoral T-VEC injections with paclitaxel followed by doxorubicin and cyclophosphamide and surgery to assess residual cancer burden index (RCB). The primary end point was RCB0 rate. Secondary end points were RCB0-1 rate, recurrence rate, toxicity and immune correlates. Thirty-seven patients were evaluated. Common T-VEC toxicities were fevers, chills, headache, fatigue and injection site pain. NAC toxicities were as expected. Four thromboembolic events occurred. The primary end point was met with an estimated RCB0 rate = 45.9% and RCB0-1 descriptive rate = 65%. The 2-year disease-free rate is equal to 89% with no recurrences in RCB0-1 patients. Immune activation during treatment correlated with response. T-VEC plus NAC in TNBC may increase RCB0-1 rates. These results support continued investigation of T-VEC plus NAC for TNBC.

Benefit of burosumab in adults with X-linked hypophosphataemia (XLH) is maintained with long-term treatment.

OBJECTIVES: To report the impact of continued burosumab treatment on clinical laboratory tests of efficacy, patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia who continued from a 96-week phase 3 study into a 48-week open-label extension. METHODS: Eligible participants from the phase 3 study continued on the burosumab regimen received at the end of the phase 3 study for a further 48 weeks (n=31). Some (not all) received compassionate burosumab treatment between the two studies (a period of 6-18 months). The primary efficacy outcome was fasting serum phosphate concentration; secondary outcomes were serum 1,25 dihydroxyvitamin D concentration, renal phosphate reabsorption, PROs and ambulatory function. RESULTS: Improvements in fasting serum phosphate, serum 1,25 dihydroxyvitamin D and renal phosphate reabsorption at 96 weeks were maintained through the 48-week extension. Improvements were also maintained in stiffness and physical function measured using the Western Ontario and McMaster Universities Osteoarthritis Index, pain and fatigue endpoints measuring using the Brief Pain Inventory short-form and Brief Pain Inventory, respectively, and in ambulatory function (6-Minute Walk Test).A post-hoc exploratory analysis exploring outcomes in participants who discontinued burosumab treatment between the studies (n=7) and those who received at least one dose (n=23) indicated that the benefits of burosumab on clinical laboratory tests of efficacy, PROs and ambulatory function may be lost when treatment is interrupted but recover over time when treatment is reinstated. CONCLUSION: Continued treatment with burosumab appears necessary for sustained clinical benefit. TRIAL REGISTRATION NUMBERS: Phase 3: NCT02526160; open-label extension: NCT03920072.

Collagen inhibits phagocytosis of amyloid in vitro and in vivo and may act as a 'don't eat me' signal.

BACKGROUND: Systemic amyloidosis refers to a group of protein misfolding disorders characterized by the extracellular deposition of amyloid fibrils in organs and tissues. For reasons heretofore unknown, amyloid deposits are not recognized by the immune system, and progressive deposition leads to organ dysfunction. METHODS: In vitro and in vivo phagocytosis assays were performed to elucidate the impact of collagen and other amyloid associated proteins (eg serum amyloid p component and apolipoprotein E) had on amyloid phagocytosis. Immunohistochemical and histopathological staining regimens were employed to analyze collagen-amyloid interactions and immune responses. RESULTS: Histological analysis of amyloid-laden tissue indicated that collagen is intimately associated with amyloid deposits. We report that collagen inhibits phagocytosis of amyloid fibrils by macrophages. Treatment of 15 patient-derived amyloid extracts with collagenase significantly enhanced amyloid phagocytosis. Preclinical mouse studies indicated that collagenase treatment of amyloid extracts significantly enhanced clearance as compared to controls, coincident with increased immune cell infiltration of the subcutaneous amyloid lesion. CONCLUSIONS: These data suggest that amyloid-associated collagen serves as a 'don't eat me' signal, thereby hindering clearance of amyloid. Targeted degradation of amyloid-associated collagen could result in innate immune cell recognition and clearance of pathologic amyloid deposits.

Carer burden in rare inherited diseases: a literature review and conceptual model.

BACKGROUND: Carers of people living with rare diseases report heavy burden and a plethora of unmet needs. A previous parental supportive care needs framework has described the needs of parents of children living with rare diseases, but it is not specific to rare inherited diseases (RIDs) and does not include non-parental carers. We conducted a targeted literature review to: (1) ascertain the burden/supportive care needs of informal carers of people living with RIDs, (2) understand the burden/supportive care needs unique to these carers, and (3) develop a conceptual model based on the findings. METHODS: A targeted literature review searching Embase and Medline between 2000 and 2020 was conducted to identify journal articles describing the burden/supportive care needs of all types of informal carers of people living with RIDs. Thematic analysis was conducted on the articles to develop a conceptual model. RESULTS: After screening and quality appraisal, 31 journal articles were analysed, representing 70 RIDs (including bleeding, bone, central nervous system, multisystem and inherited metabolic disorders). Most articles (74%) focused on parent carer samples. The conceptual model has three overarching domains, encompassing 13 themes: (1) Living with Rare Inherited Disease (Being a Carrier of Rare Disease, Carer Perceptions, Disease Severity); (2) Carer Needs/Burden (Social/Community, Well-being, Information, Practical); and (3) Carer Coping Strategies (Acceptance, Support Systems, Gratitude and Hope, Faith, Quest for Knowledge, Establish a Routine). Our conceptual model uniquely describes carers' transmission guilt, clinically relevant depression and anxiety, worry about future family members living with the RID, and challenging decisions about having more children. Carers often implemented psychological, structural, practical, and social coping strategies to manage their burdens. CONCLUSIONS: The identified burdens underscore the need for the provision of information and social support to these carers. Future research should focus on the (1) potential mediators/moderators of carers' burden, (2) needs of carers within the wider family including siblings and grandparents, (3) needs of carers of adults living with RIDs, including spouses and children, and (4) biopsychosocial effect on carers living with a RID themselves. Our conceptual model offers a potential tool for healthcare professionals to utilise during the provision of support to carers.

Efficacy of Burosumab in Adults with X-linked Hypophosphatemia (XLH): A Post Hoc Subgroup Analysis of a Randomized Double-Blind Placebo-Controlled Phase 3 Study.

The anti-fibroblast growth factor 23 monoclonal antibody burosumab corrects hypophosphatemia in adults with X-linked hypophosphatemia (XLH) and improves pain, stiffness, physical function, and fatigue. This post hoc subgroup analysis used data from the 24-week placebo-controlled period of a phase 3 study in 134 adults with XLH (ClinicalTrials.gov NCT02526160), to assess whether the benefits of burosumab are evident in 14 clinically relevant subgroups defined by baseline demographic and functional criteria, including sex, Brief Pain Inventory-short form (BPI-SF) Average And Worst Pain, region, race, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) Stiffness, Physical Function and Pain domains and total score, use of opioid/other pain medication, active fractures/pseudo-fractures, and 6-min walk test distance. There were no statistically significant interactions between any of the subgroups and treatment arm for any endpoint. Higher proportions of subjects achieved mean serum phosphate concentration above the lower limit of normal (the primary endpoint) with burosumab than with placebo in all subgroups. For the key secondary endpoints (WOMAC Stiffness and Physical Function; BPI-SF Worst Pain) individual subgroup categories showed improvements with burosumab relative to placebo. For additional efficacy endpoints, burosumab was favored in some subgroups but differences were not significant and confidence intervals were wide. For some endpoints the treatment effect is small at 24 weeks in all subjects. This subgroup analysis shows that burosumab was largely superior to placebo across endpoints in the 14 clinically relevant subgroup variables at 24 weeks and is likely to benefit all symptomatic adults with active XLH.

A literature review to understand the burden of disease in people living with tumour-induced osteomalacia.

This study reviews publications to describe the signs, symptoms and impact of tumour-induced osteomalacia (TIO) on patients' burden of disease. TIO is associated with a spectrum of signs and symptoms imposing a significant clinical burden, but the psychosocial impact of this rare disease has been poorly researched so far. INTRODUCTION: To describe the signs, symptoms and impacts of tumour-induced osteomalacia (TIO) and summarise the state of research on the burden of disease of this ultra-rare condition. METHODS: A targeted literature review was conducted in PubMed using pre-defined search terms. Relevant articles published between 1980 and 2021 were screened for inclusion. Seventy records were selected for analysis. Data were extracted and grouped into categories and sub-categories to identify recurrent signs, symptoms and impacts of TIO and describe the burden on patients. Chord diagrams were created to analyse the relationships between different TIO outcomes and characterise the presentation of TIO. RESULTS: Although the number of articles on TIO published have been increasing over the past 20 years, most studies were case reports and case series (n = 65/70) and only few were studies with higher quality of evidence (n = 5/70). Most articles were based on data reported by clinicians (n = 67/70). Patients with TIO experienced a combination of outcomes including chronic pain, weakness, skeletal-related manifestations and limitations in mobility. Only a few studies (n = 2/70) analysed the burden of TIO on the emotional wellbeing and on the work life of the patient. CONCLUSION: Patients with TIO present with a spectrum of signs and symptoms that impose a significant burden. The impact on the psychosocial wellbeing of patients should be further investigated, as this has been poorly researched so far. Studies with high quality of evidence should be designed to further the understanding of the burden of disease of TIO from the patient's perspective.

First in Human Evaluation and Dosimetry Calculations for Peptide 124I-p5+14-a Novel Radiotracer for the Detection of Systemic Amyloidosis Using PET/CT Imaging.

PURPOSE: Accurate diagnosis of amyloidosis remains a significant clinical challenge and unmet need for patients. The amyloid-reactive peptide p5+14 radiolabeled with iodine-124 has been developed for the detection of amyloid by PET/CT imaging. In a first-in-human evaluation, the dosimetry and tissue distribution of 124I-p5+14 peptide in patients with systemic amyloidosis. Herein, we report the dosimetry and dynamic distribution in the first three enrolled patients with light chain-associated (AL) amyloidosis. PROCEDURES: The radiotracer was assessed in a single-site, open-label phase 1 study (NCT03678259). The first three patients received a single intravenous infusion of 124I-p5+14 peptide (≤37 MBq). Serial PET/CT imaging was performed during the 48 h post-infusion. Dosimetry was determined as a primary endpoint for each patient and gender-averaged mean values were calculated. Pharmacokinetic parameters were estimated from whole blood radioactivity measurements and organ-based time activity data. Lastly, the biodistribution of radiotracer in major organs was assessed visually and compared to clinically appreciated organ involvement. RESULTS: Infusion of the 124I-p5+14 was well tolerated with rapid uptake in the heart, kidneys, liver, spleen, pancreas, and lung. The gender-averaged whole-body effective radiation dose was estimated to be 0.23 (± 0.02) mSv/MBq with elimination of the radioactivity via renal and gastrointestinal routes. The whole blood elimination t1/2 of 21.9 ± 7.6 h. Organ-based activity concentration measurements indicated that AUClast tissue:blood ratios generally correlated with the anticipated presence of amyloid. Peptide uptake was observed in 4/5 clinically suspected organs, as noted in the medical record, as well as six anatomic sites generally associated with amyloidosis in this population. CONCLUSION: Peptide 124I-p5+14 rapidly distributes to anatomic sites consistent with the presence of amyloid in patients with systemic AL. The dosimetry estimates established in this cohort are acceptable for whole-body PET/CT imaging. Pharmacokinetic parameters are heterogeneous and consistent with uptake of the tracer in an amyloid compartment. PET/CT imaging of 124I-p5+14 may facilitate non-invasive detection of amyloid in multiple organ systems.

Musculoskeletal Features in Adults With X-linked Hypophosphatemia: An Analysis of Clinical Trial and Survey Data.

CONTEXT: Patients with X-linked hypophosphatemia (XLH) experience multiple musculoskeletal manifestations throughout adulthood. OBJECTIVE: To describe the burden of musculoskeletal features and associated surgeries across the lifespan of adults with XLH. METHODS: Three groups of adults were analyzed: subjects of a clinical trial, participants in an online survey, and a subgroup of the online survey participants considered comparable to the clinical trial subjects (according to Brief Pain Inventory worst pain scores of ≥ 4). In each group, the adults were categorized by age: 18-29, 30-39, 40-49, 50-59, and ≥ 60 years. Rates of 5 prespecified musculoskeletal features and associated surgeries were investigated across these age bands for the 3 groups. RESULTS: Data from 336 adults were analyzed. In all 3 groups, 43% to 47% had a history of fracture, with the proportions increasing with age. The overall prevalence of osteoarthritis was > 50% in all 3 groups, with a rate of 23% to 37% in the 18- to 29-year-old group, and increasing with age. Similar patterns were observed for osteophytes and enthesopathy. Hip and knee arthroplasty was reported even in adults in their 30s. Spinal stenosis was present at a low prevalence, increasing with age. The proportion of adults with ≥ 2 musculoskeletal features was 59.1%, 55.0%, and 61.3% in the clinical trial group, survey group, and survey pain subgroup, respectively. CONCLUSION: This analysis confirmed high rates of multiple musculoskeletal features beginning as early as age 20 years among adults with XLH and gradually accumulating with age.

MRI Response to Pre-operative Stereotactic Ablative Body Radiotherapy (SABR) in Early Stage ER/PR+ HER2- Breast Cancer correlates with Surgical Pathology Tumor Bed Cellularity.

OBJECTIVE: This study evaluates breast MRI response of ER/PR+ HER2- breast tumors to pre-operative SABR with pathologic response correlation. METHODS: Women enrolled in a phase 2 single institution trial of SABR for ER/PR+ HER2- breast cancer were retrospectively evaluated for radiologic-pathologic correlation of tumor response. These patients underwent baseline breast MRI, SABR (28.5 Gy in 3 fractions), follow-up MRI 5 to 6 weeks post-SABR, and lumpectomy. Tumor size and BI-RADS descriptors on pre and post-SABR breast MRIs were compared to determine correlation with surgical specimen % tumor cellularity (%TC). Reported MRI tumor dimensions were used to calculate percent cubic volume remaining (%VR). Partial MRI response was defined as a BI-RADs descriptor change or %VR ≤ 70%, while partial pathologic response (pPR) was defined as %TC ≤ 70%. RESULTS: Nineteen patients completed the trial, and %TC ranged 10% to 80%. For BI-RADS descriptor analysis, 12 of 19 (63%) showed change in lesion or kinetic enhancement descriptors post-SABR. This was associated with lower %TC (29% vs. 47%, P = .042). BI-RADS descriptor change analysis also demonstrated high PPV (100%) and specificity (100%) for predicting pPR to treatment (sensitivity 71%, accuracy 74%), but low NPV (29%). MRI %VR demonstrated strong linear correlation with %TC (R = 0.70, P < .001, Pearson's Correlation) and high accuracy (89%) for predicting pPR (sensitivity 88%, specificity 100%, PPV 100%, and NPV 50%). CONCLUSION: Evaluating breast cancer response on MRI using %VR after pre-operative SABR treatment can help identify patients benefiting the most from neoadjuvant radiation treatment of their ER/PR+ HER2- tumors, a group in which pCR to neoadjuvant therapy is rare.

A New Scale of Readiness for Health Care Students to Encounter Partner Abuse.

Partner abuse (PA) is associated with significant morbidity and mortality worldwide. Health care practitioners regularly encounter patients experiencing PA and require comprehensive education on how to respond. This study describes the creation and validation of a new measure of readiness to encounter patients experiencing PA for health care practitioners and students.Initial item development and content validation were informed by expert feedback. Psychometric properties were assessed using data collected from Australian health care students, using Principal Components Analysis (PCA) and Confirmatory Factor Analysis (CFA). Internal consistency, inter-scale correlations, and test-retest analysis were performed.An initial pool of 67 items was reduced to 48 following content validation by 5 experts as a measure of construct validity. A total of n = 926 responses were collected, which were randomly split into two groups to perform a PCA and CFA. The PCA resulted in a 31-item version, which was further reduced to a 27-item version following the CFA, containing four factors. Internal consistency and test-retest analyses demonstrated good reliability.The produced scale is a 27-item measure of readiness to encounter patients experiencing PA, which has demonstrated good psychometric properties with a sample of Australian health care students. Results indicate that self-efficacy and Emotional-readiness are a large component of readiness. The scale may be used to measure the readiness of a cohort, or as a pre and post-intervention measure, and results may provide insight into the educational needs of a cohort.

The Readiness of Australian Health Care Students to Encounter Patients Experiencing Partner Abuse.

Partner abuse is a significant contributor to mortality and morbidity worldwide, and has been identified as a priority health care issue. Most health care students rarely receive education on partner abuse and report not feeling ready to encounter patients experiencing partner abuse. Analysis of the current readiness of health care students and can inform educational needs to address this gap. The READIness to encounter partner abuse patients Scale was delivered to a convenience sample of Australian prequalification health care students. Participant demographics and estimated hours of education were also reported. Mean readiness scores were calculated by discipline. The relationship between hours of education and readiness scores was calculated using linear regression. A total of 926 participants were included in the analysis. Approximately half of the participants (47.5%) reported less than two hours of education. Mean readiness of students was 4.99 out of 7 (SD 0.73, range 4.39-5.95). Linear regression revealed a significant association between hours of education and readiness, r(925) = .497, p < .000. Australian health care students receive little education about partner abuse, and do not report feeling ready to encounter patients experiencing partner abuse. An individual's confidence and belief in their abilities appear to be the key factor influencing overall readiness. Participants indicated a strong belief that responding to partner abuse was part of their professional role, which is a positive change from previous research. Higher hours of education is associated with higher readiness, though which educational methodologies are most impactful remains unclear.

Quantitative Changes in Intratumoral Habitats on MRI Correlate With Pathologic Response in Early-stage ER/PR+ HER2- Breast Cancer Treated With Preoperative Stereotactic Ablative Body Radiotherapy.

Objective: To quantitatively evaluate intratumoral habitats on dynamic contrast-enhanced (DCE) breast MRI to predict pathologic breast cancer response to stereotactic ablative body radiotherapy (SABR). Methods: Participants underwent SABR treatment (28.5 Gy x3), baseline and post-SABR MRI, and breast-conserving surgery for ER/PR+ HER2- breast cancer. MRI analysis was performed on DCE T1-weighted images. MRI voxels were assigned eight habitats based on high (H) or low (L) maximum enhancement and the sequentially numbered dynamic sequence of maximum enhancement (H1-4, L1-4). MRI response was analyzed by percent tumor volume remaining (%VR = volume post-SABR/volume pre-SABR), and percent habitat makeup (%HM of habitat X = habitat X voxels/total voxels in the segmented volume). These were correlated with percent tumor bed cellularity (%TC) for pathologic response. Results: Sixteen patients completed the trial. The %TC ranged 20%-80%. MRI %VR demonstrated strong correlations with %TC (Pearson R = 0.7-0.89). Pre-SABR tumor %HMs differed significantly from whole breasts (P = 0.005 to <0.00001). Post-SABR %HM of tumor habitat H4 demonstrated the largest change, increasing 13% (P = 0.039). Conversely, combined %HM for H1-3 decreased 17% (P = 0.006). This change correlated with %TC (P < 0.00001) and distinguished pathologic partial responders (≤70 %TC) from nonresponders with 94% accuracy, 93% sensitivity, 100% specificity, 100% positive predictive value, and 67% negative predictive value. Conclusion: In patients undergoing preoperative SABR treatment for ER/PR+ HER2- breast cancer, quantitative MRI habitat analysis of %VR and %HM change correlates with pathologic response.