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Redacted protocol for supplementary files

Supplementary Figure 4 shows pharmacokinetic parameters for guadecitabine and decitabine in the dose escalation phase

Purpose:Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers.Patient and Methods:SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2–4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1–5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228.Results:Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1–5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred.Conclusions:The guadecitabine RP2D was 20 mg/m2, days 1–5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.

Supplementary Figure 1 shows a schematic of the treatment cycle

Supplementary Figure 2 shows CONSORT diagrams for both phases of the trial

Supplementary Figure 3 shows promotor methylation status for the indicated genes in cfDNA

To assess PrEP service delivery preferences among Black cis-gender women living in urban and rural settings in Alabama, we conducted a cross-sectional discrete choice experiment survey. Discrete choice experiments included five attributes. Hierarchical Bayes (HB) modeling and latent class analyses (LCA) were used to evaluate attribute preferences. Among 795 Black cis-gender HIV-negative women, almost two-thirds lived in urban settings and reported having at least some college; about a third reported a household income less than $25,000 annually; and reported willingness to use PrEP. Respondents placed the greatest importance on PrEP medication formulation and healthcare facility. LCA showed the group with the highest rural proportion preferred for on-line visits. Black women in the Deep South had distinct preferences regarding PrEP service delivery. These findings can inform tailored interventions to improve PrEP uptake among Black cis-gender women across diverse settings in the South.

BACKGROUND The syndemic of mental health (MH) and substance use disorders (SUDs) is common among persons living with HIV (PLWH) and jeopardize HIV treatment adherence, engagement in care, and viral load suppression. Electronic patient reported outcomes (ePROs), completed via tablet or computer, and telemedicine are evidence- and technology-based interventions that have been used to successfully increase screening and treatment, respectively, a model that holds promise for PLWH. To date, there is limited guidance on implementing ePROs and telemedicine into HIV clinical practice even though it is well-known that these evidence-based tools improve diagnosis and access to care. OBJECTIVE To address this, we are conducting a multicomponent intervention for PLWH, delivery of HIV Services and Telemedicine through Effective ePROs (+STEP), to increase screening and treatment of MH and SUD in Ryan White HIV/AIDS Program (RWHAP)-funded clinics in Alabama. METHODS The Aims of this intervention are to: Aim 1) Conduct a readiness, acceptability, and accessibility assessment and implement +STEP to improve diagnosis and treatment of MH and SUD at RWHAP clinics in Alabama; Aim 2) Describe implementation strategies that address barriers to uptake of +STEP in RWHAP clinics. We will conduct qualitative interviews in years 1 (early implementation), 2 (scale up), and 4 (maintenance) with patients and key staff to evaluate barriers, facilitators, and implementation strategies. Results will enable us to modify strategies to enhance +STEP penetrance over time and inform the implementation blueprint, which we will develop for both RWHAP clinics in AL and future sites; Aim 3) Measure the impact of implementing +STEP on diagnoses, referrals, and healthcare utilization related to MH, SUD, and HIV by comparing clinical outcomes from patients receiving these interventions (ePROs, telemedicine) with historical controls. RESULTS The first study site began implementation in April of 2022. Two additional sites have initiated ePROs. Final results are expected in 2026. The results of this study will provide a foundation for future research expanding access to ePROs for improved diagnosis linked to telemedicine access to accelerate patients along the continuum of care from MH and/or SUD diagnosis to treatment. CONCLUSIONS Achieving the end of the HIV epidemic in the United States necessitates programs that accelerate movement across the MH and SUD care continuum from diagnosis to treatment for PLWH. Scaling these services represents a path towards improved treatment outcomes with both individual health and population level prevention benefits of sustained HIV viral suppression in the era of Undetectable = Untransmittable (U=U). Our study will address this evidence gap through the evaluation of implementation of +STEP to establish necessary systems and processes to screen, identify, and better treat substance use and MH for people living with HIV. CLINICALTRIAL

Social impact investing (SII) is transforming the availability of private capital for nonprofits and social enterprises, but demand is not yet meeting supply. This paper analyzes the perceived barriers faced by nonprofits in engaging with SII, arguing the need to assess differences using a policy field framework. Four parameters of a subsector are conceptualized as shaping participation in SII: the scale of investment required, embeddedness in place, the need for radical innovation, and the configuration of intermediaries (such as loan funds and market brokers). Based on 25 interviews with leaders of nonprofits and intermediaries in affordable housing and community economic development in Canada, the study finds that significant barriers are a lack of knowledge of the market, inadequate financial literacy, and the challenges of measuring and valuing social impacts. In addition, nonprofits report that, in spite of the inherent importance of social impact in this form of investing, they currently make limited use of evaluation and impact metrics, and perceive that intermediaries and investors, particularly in affordable housing, still put a greater emphasis on financial over social returns.

OBJECTIVE: To identify the perspectives of patients with rheumatoid arthritis (RA) on electronic recording of between-visit disease activity and other patient-reported outcomes (PROs), and sharing this information with health care providers or peers. METHODS: Patients with RA were recruited to participate in focus groups from December 2014 to April 2015. The topic guide and analysis were based on Andersen and Newman’s framework. Sessions were audio recorded, transcribed, independently coded, and analyzed for themes. RESULTS: Thirty-one patients participated in seven focus groups. Their mean age was 51 (SD 13.1); 94% were female, 52% were African Americans, 11% were Hispanics, and 37% were Caucasians. Three themes emerged: 1) provider communication, 2) information seeking about RA, and 3) social and peer support. Participants expressed willingness to track disease activity data to share with health care providers electronically if providers would act on the information. Participants envisioned symptom tracking and information sharing as a mechanism to relay and obtain reliable information about RA. Participants were also interested in electronic communication between visits if it facilitated learning about symptom management and enhanced opportunities for social support among persons with RA. CONCLUSION: Patients with RA may be amenable to electronic collection and sharing of PRO-type data between clinical encounters if it facilitates communication with health care providers, and provides access to reliable information about RA. Providing patients with social support was important for enhancing PROs collection by helping them overcome barriers with using electronic devices and patients’ reservations about the value of this data.

Purpose: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers. Patient and Methods: SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2–4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1–5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228. Results: Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1–5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred. Conclusions: The guadecitabine RP2D was 20 mg/m2, days 1–5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.

Resilience may help people living with HIV (PLWH) overcome adversities to disease management. This study identifies multilevel resilience resources among African American/Black (AA/B) PLWH and examines whether resilience resources differ by demographics and neighborhood risk environments. We recruited participants and conducted concept mapping at two clinics in the southeastern United States. Concept Mapping incorporates qualitative and quantitative methods to represent participant-generated concepts via two-dimensional maps. Eligible participants had to attend ≥75% of their scheduled clinic appointments and did not have ≥2 consecutive detectable HIV-1 viral load measurements in the past two years. Of the 85 AA/B PLWH who were invited, forty-eight participated. Twelve resilience resource clusters emerged - five individual, two interpersonal, two organizational/policy and three neighborhood level clusters. There were strong correlations in cluster ratings for demographic and neighborhood risk environment comparison groups (r ≥ 0.89). These findings could inform development of theories, measures and interventions for AA/B PLWH.

Background Patients with inflammatory arthritis (IA), defined as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), are at increased risk for cardiovascular disease (CVD). The frequency of screening and treatment of hyperlipidemia, a modifiable CVD risk factor, is low in these patients. The reasons for low screening and treatment rates in this population are poorly understood. Our objective was to elicit the barriers and facilitators for screening and treatment of hyperlipidemia from the perspective of patients with IA. Methods We conducted a qualitative study using focus groups of patients with IA, guided by Bandura’s Social Cognitive Theory. We recruited patients with IA aged 40 years and older from a single academic center. Data were analyzed thematically. Results We conducted three focus groups with 17 participants whose mean age was 56 (range 45–81) years; 15 were women. Four themes emerged as barriers: 1) need for more information about arthritis, prognosis, and IA medications prior to discussing additional topics like CVD risk; 2) lack of knowledge about how IA increases CVD risk; 3) lifestyle changes to reduce overall CVD risk rather than medications; and 4) the need to improve doctor-patient communication about IA, medications, and CVD risk. One theme emerged as a facilitator: 5) potential for peer coaches (patients with IA who are trained about concepts of CVD risk and IA) to help overcome barriers to screening and treatment of hyperlipidemia to lower CVD risk. Conclusion Patients with IA identified educational needs about IA, increased CVD risk in IA and the need for improved doctor-patient communication about screening for hyperlipidemia and its treatment. Patients were receptive to working with peer coaches to facilitate achievement of these goals.

Background Patient-reported outcomes (PROs) aid in rheumatoid arthritis (RA) management, but it is not well understood which measures would be most relevant to the rheumatologists for making treatment decisions. Methods We recruited rheumatologists nationally to participate in moderated structured group teleconference discussions using the nominal group technique. Participants in each group generated lists of the elements from patient’s history and signs that they use to make treatment recommendations for RA. Each participant then selected the three most important elements from the generated list. The results of each group were then combined and summarized. Results Twenty-five rheumatologists participated in 4 groups (group size ranged from 4 to 8) and 150 available ranking votes across all groups. The statements generated across the 4 groups were categorized into 13 topics (including symptoms, physical function, comorbidities, social aspects, physical findings, response to treatment, treatment adherence, pain management, side effects, tests, access to care, contraception, and organ involvement), 10 of which received ranking votes. Symptoms received the highest ranking (46% of votes), followed by physical function (16%), and physical findings (13%). Among the unranked topics, social aspects had the highest number of statements (8 statements). Conclusion Rheumatologists highly valued patient-reported RA symptoms and physical function to inform their treatment decisions, even above objective data such as physical findings and test results. These results can guide the selection of validated PRO measures to assess these domains to inform the clinical care of patients with rheumatoid arthritis. Electronic supplementary material The online version of this article (10.1186/s41927-019-0087-2) contains supplementary material, which is available to authorized users.

Background In the US, women account for approximately 20% of all new HIV infections, among which two-thirds are Black women. These health disparities are most pronounced in the Deep South. We conducted focus groups in urban and rural settings in Alabama to understand attitudes and preferences for PrEP service delivery among Black women. Methods Our group members consisted of HIV-negative women between the ages of 16–65. Items and analyses were grounded in a conceptual framework using constructs from two behavioral models. Two coders independently conducted inductive and deductive thematic coding to determine major themes. Results 25 rural (median age 44, 48% income Conclusion Black women in the Deep South had differing preferences regarding PrEP service delivery and messaging depending on whether they lived in urban or rural settings. These findings can inform targeted intervention development by emphasizing the need for partnerships with trusted community organizations and utilization of service delivery strategies that allow for anonymity to increase uptake of PrEP especially among rural Black women. Disclosure No significant relationships.

Background: Cardiovascular disease (CVD) is the most common cause of death among patients with inflammatory arthritis (IA) such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS). Objectives: To elicit perspectives of patients with IA to inform the design of a patient-centered intervention for a CVD risk reduction intervention. Methods: This was a qualitative study guided by Bandura’s Social Cognitive Theory, placing special emphasis on knowledge about the relationship between arthritis and CVD as well as barriers and facilitators to receiving healthcare related to CVD risk such as screening and management for hyperlipidemia. We recruited patients from a single academic center with either RA, PsA, or AS to participate in focus groups. Data were analyzed thematically. Results: We conducted three focus groups with a total of 17 participants (5 participants in two and 7 participants in one of the focus groups) of mean age 56 (SD+7.7) years; 15 were women; 3 were on a statin; and 1 previously had a stroke. Barrier Themes 1-2: 1) Need for more information about arthritis, prognosis, and IA medications; 2) Lack of knowledge about how IA increases cardiovascular disease (CVD) risk. Facilitator Themes 3-5: 3) Lifestyle changes to reduce overall CVD risk; 4) Potential roles for peer coaches; and 5) Improving doctor-patient communication about IA, medications, and CVD risk. Patients expressed that improving Themes 2 and 5 could facilitate CVD screening. Conclusion: Education about increased CVD risk could help activate patients with IA engage in CVD risk reduction strategies. Peer coaches appears to be a reasonable tool towards that goal. Disclosure of Interests: Iris Navarro-Millan: None declared, Sarah Young: None declared, Sally Shurbaji: None declared, Chastity McDavid: None declared, Anna Cornelius-Schecter: None declared, Bernadette Johnson: None declared, Andrea Cherrington: None declared, Liana Fraenkel: None declared, Jeffrey Curtis: None declared, Monika Safford Grant/research support from: Amgen

447 Background: Pre-clinical data support a hypothesis that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers including urothelial carcinoma (UC). SPIRE comprised a previously reported phase Ib dose escalation phase for incurable metastatic solid cancers which established a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin (GC) chemotherapy (Crabb et al, ESMO Congress 2018, abstract 425P). We now report the SPIRE phase IIa randomised dose expansion phase which tested neoadjuvant treatment of bladder UC. Methods: Patients had T2-4a N0 M0 bladder UC intended for radical treatment. All patients received an investigator choice of 3 or 4 planned, 21-day, GC cycles (cisplatin 70 mg/m2, IV, day 8; gemcitabine 1000 mg/m2, IV, days 8 and 15). 20 patients were randomised (1:1, open label) to whether they also received guadecitabine 20 mg/m2, SC, on days 1 to 5, and G-CSF prophylaxis 300 µg, SC, on days 15 to 21. The primary objective for the expansion phase was to confirm a safe and biologically effective dose and schedule for this combination for future investigation. Circulating cell free DNA LINE-1 promotor methylation was measured as a guadecitabine pharmacodynamic endpoint. Trial registration: ISRCTN 16332228. Funding: Cancer Research UK, Astex Pharmaceuticals. Sponsor: University Hospital Southampton NHS Foundation Trust. Results: Median age was 68 (interquartile range (IQR) 59-72). 19 (95%) patients were male and 17 (85%) had T2 stage. The commonest grade ≥3 adverse events were neutropenia and thrombocytopenia with one or both affecting 6 (60%) patients in each treatment arm (no grade 5 events). One episode of neutropenic fever occurred (guadecitabine arm). Addition of guadecitabine to GC, versus GC alone, resulted in similar cisplatin dose intensity (median total doses 408 mg (IQR 384-435 mg) and 435 mg (IQR 384-435 mg) respectively) but modestly reduced gemcitabine dose intensity (median total doses 10,450 mg (IQR 9,500-11,400) and 12,768 mg (IQR 9,500-12,768) respectively). All patients completed post-chemotherapy radical treatment (8 cystectomy, 2 radiotherapy, in each arm) with similar timing post chemotherapy and peri-operative morbidity scores. LINE-1 promotor methylation depletion occurred at cycle day 8 in guadecitabine treated patients. Conclusions: Guadecitabine in combination with GC and G-CSF is safe and tolerable in this combination compared to GC alone as neoadjuvant treatment for UC. Radical surgery or radiotherapy delivery, and cisplatin dose intensity, were not compromised. Pharmacodynamic endpoints are optimal with this treatment schedule. Addition of guadecitabine to GC warrants further investigation. Clinical trial information: 16332228.

PURPOSE: To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit.METHODS: Clinical data from 57 patients who received 2.5-5.1 GBq of (186)Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan-Meier curves, log-rank tests, Cox's proportional hazards model and Pearson's correlation coefficients were used for overall survival (OS) and correlation analyses.RESULTS: A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10-0.58, P = 0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r = 0.65, P = 0.001) and the whole-body absorbed dose (r = 0.63, P = 0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of (186)Re-HEDP (P = 0.03) and patient mean absorbed dose (P = 0.01), whilst only the disease volume remained significant in a multivariable analysis (P = 0.004).CONCLUSION: This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated with survival. This study shows the importance of patient stratification to establish absorbed dose-response correlations and indicates the potential to individualise treatment of bone metastases with radiopharmaceuticals according to patient-specific imaging and dosimetry.

This study was supported by Cancer Research UK, AstraZeneca and Pfizer UK. Introduction: Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context. Methods: A total of 26 sites in England, Wales and Scotland, recruited samples from 7814 patients for genetic examination between 2011 and 2013. Tumour types involved were breast, colorectal, lung, prostate, ovarian cancer and malignant melanoma. Centralised molecular testing of surplus material from resections or biopsies of primary/metastatic tissue was performed, with samples examined for 3-5 genetic alterations deemed to be of key interest in site-specific cancers by the National Cancer Research Institute Clinical Study groups. Results: 10 754 patients (98% of those approached) consented to participate, from which 7814 tumour samples were genetically analysed. In total, 53% had at least one genetic aberration detected. From 1885 patients with lung cancer, KRAS mutation was noted to be highly prevalent in adenocarcinoma (37%). In breast cancer (1873 patients), there was a striking contrast in TP53 mutation incidence between patients with ductal cancer (27.3%) and lobular cancer (3.4%). Vast inter-tumour heterogeneity of colorectal cancer (1550 patients) was observed, including myriad double and triple combinations of genetic aberrations. Significant losses of important clinical information included smoking status in lung cancer and loss of distinction between low-grade and high-grade serous ovarian cancers. Conclusion: Nationwide molecular pathology testing in a non-trial setting is feasible. The experience with SMP1 has been used to inform ongoing CRUK flagship programmes such as the CRUK National Lung MATRIX trial and TRACERx. Publisher PDF

Background Cardiovascular disease (CVD) is the most common cause of death among patients with inflammatory arthritis (IA) such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS). Objectives This study is the formative work to help design a patient-centred intervention for a CVD risk reduction program for patients with IA. Methods We conducted a qualitative study guided by Bandura’s Social Cognitive Theory, placing special focus on knowledge about the relationship between arthritis and CVD as well as barriers and facilitators to receiving healthcare related to CVD risk such as screening and management for hyperlipidemia. Participants had to have either RA, PsA or AS and were recruited from a single academic centre. Data were analysed thematically. Results We conducted three focus groups with a total of 17 participants. Mean age of participants was 56 (SD ±7.7) years; 15 were women; 3 were on a statin; and 1 previously had a stroke. The majority of the participants were Five themes emerged: 1) Need for more information about IA and medications; 2) Lack of education about CVD risk and IA; 3) CVD risk reduction as an integrated lifestyle modification; 4) Uses for peer support around relevant CVD risk factor mitigation approaches; and 5) Improving doctor-patient communication about RA. The themes that emerged in our study showed that the majority of these IA patients were not aware of the relationship between CVD and IA, and were very interested in learning about IA, medication side effects, and prognosis of IA. These participants wanted to learn first about IA and, as a secondary goal, learn about their CVD risk in the context of their IA rather than as a new condition. Conclusions Providing a clear understanding about systemic effects of IA and how to treat it will be needed before focusing on CVD risk reduction. By doing so, there will be better opportunity for the CVD risk reduction program to succeed. Disclosure of Interest I. Navarro-Millan: None declared, S. Young: None declared, S. Shurbaji: None declared, C. McDavid: None declared, A. Cornelius-Schecter: None declared, B. Johnson: None declared, A. Cherrington Grant/research support from: Boehringer Ingleheim, Consultant for: Novo Nordisk, Astra Zeneca, L. Fraenkel: None declared, J. Curtis: None declared, M. Safford Grant/research support from: Amgen, Inc

OBJECTIVE:The aim of this study was to calculate the range of absorbed doses that could potentially be delivered by a variety of radiopharmaceuticals and typical fixed administered activities used for bone pain palliation in a cohort of patients with metastatic castration-resistant prostate cancer (mCRPC). The methodology for the extrapolation of the biodistribution, pharmacokinetics and absorbed doses from a given to an alternative radiopharmaceutical is presented.METHODS:Sequential single photon emission CT images from 22 patients treated with 5 GBq of 186Re-HEDP were used to extrapolate the time–activity curves for various radiopharmaceuticals. Cumulated activity distributions for the delivered and extrapolated treatment plans were converted into absorbed dose distributions using the convolution dosimetry method. The lesion absorbed doses obtained for the different treatments were compared using the patient population distributions and cumulative dose–volume histograms.RESULTS:The median lesion absorbed doses across the patient cohort ranged from 2.7 Gy (range: 0.6–11.8 Gy) for 1100 MBq of 166Ho-DOTMP to 21.8 Gy (range: 4.5–117.6 Gy) for 150 MBq of 89Sr-dichloride. 32P-Na3PO4, 153Sm-EDTMP, 166Ho-DOTMP, 177Lu-EDTMP and 188Re-HEDP would have delivered 41, 32, 85, 20 and 64% lower absorbed doses, for the typical administered activities as compared to 186Re-HEDP, respectively, whilst 89Sr-dichloride would have delivered 25% higher absorbed doses.CONCLUSION:For the patient cohort studied, a wide range of absorbed doses would have been delivered for typical administration protocols in mCRPC. The methodology presented has potential use for emerging theragnostic agents.ADVANCES IN KNOWLEDGE:The same patient cohort can receive a range of lesion absorbed doses from typical molecular radiotherapy treatments for patients with metastatic prostate cancer, highlighting the need to establish absorbed dose response relationships and to treat patients according to absorbed dose instead of using fixed administered activities.

Background Data capture of patient reported outcomes (PROs) is gradually shifting from data collection on paper in medical office settings to use of computer or mobile based technologies between doctor visits. Concerns have been raised that patients may have limited interest in contributing data over time or that they may only record new data when there has been a change in their clinical status. Objectives The objective of this study was to evaluate the patterns and factors associated with longitudinal PRO data capture among participants in the PCORI-funded Patient Powered Research Network for adult rheumatologic conditions, ArthritisPower. Methods Patients in the registry were asked to voluntarily complete PROs including the RAPID3 and 4 PROMIS instruments plus disease-specific information via a mobile application (App) on their smartphone or computer. We evaluated the average time it took the patient to record each of the instruments and the total number of unique days that patients recorded PROs on the smartphone. Given the newness of the registry (launched late 2015), longitudinal data was defined as contributing at least 2 sets of PROs on unique calendar days. We tested the hypothesis that patients would contribute longitudinal data only when at least one of their scores exceeded a minimally important difference (MID) of any of the 5 PROs examined (generally 2–3 units for PROMIS instruments; 3.6 units for RAPID3). Demographic factors associated with multiple PRO reports were identified using logistic regression among patients who had been enrolled in the registry for at least 3 months. Results At the time of analysis, ArthritisPower had recruited 2,103 patients, most (approximately 68%) had RA, and 20% provided their Twitter handle. Average (SD) age was 50 (12); 87% were women. The mean assessment time for each of the PROMIS instruments ranged from a low of 16 seconds (Sleep Disturbance) to a high of 105 seconds (RAPID3). The average score for Pain Interference was 64.3 (SD: 6.3), Physical Function 37.5 (6.5), Sleep Disturbance 59.3 (8.4), Fatigue 64.2 (8.4), and RAPID3 15.7 (5.3). Of 1,946 patients who registered the Smartphone App more than 3 months prior to analysis, 20.6% never contributed any PRO information, 53.3% answered once, and 26.1% answered at least twice. Among patients with longitudinal data (≥2 assessments), the mean change score of PROs between pairwise PRO assessments was Conclusions Multiple factors were associated with patients contributing longitudinal PRO data. Patients were willing to contribute longitudinal PRO data even in the absence of a change in their health state exceeding any MID. Additional efforts are needed to engage patients to contribute PRO data over time. Disclosure of Interest None declared

Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone lesions and to reduce the metastatic burden was investigated in a cohort of 22 patients with bone metastases from castration-resistant prostate cancer. A metastatic burden reduction curve was generated for each patient, which predicts the reduction in metastatic burden as a function of the patient mean absorbed dose, defined as the mean of all the lesion absorbed doses in any given patient. In the patient cohort studied, the median of the patient mean absorbed dose predicted to reduce the metastatic burden by 50% was 89 Gy (interquartile range: 83–105 Gy), whilst a median of 183 Gy (interquartile range: 107–247 Gy) was found necessary to eradicate all metastases in a given patient. The absorbed dose required to eradicate all the lesions was strongly correlated with the variability of the absorbed doses delivered to multiple lesions in a given patient (r = 0.98, P

Background: The neutrophil to lymphocyte ratio (NLR) has been shown to be highly prognostic across many tumor types, and predictive of treatment outcome in advanced prostate cancer, and has been postulated to be an indirect measure of tumor inflammation. We evaluated the effect of low-dose steroids on NLR in men suffering from castrationresistant prostate cancer (CRPC). Patients and Methods: The NLR was evaluated in a prospective randomized phase II trial that compared prednisolone 5 mg twice daily and dexamethasone 0.5 mg daily administered to 75 chemotherapy and abiraterone/enzalutamide-naive CRPC patients. NLR was examined at baseline (BL), after 6 and 12 weeks of corticosteroid treatment; associations with > 50% prostate-specific antigen (PSA) response, duration of response (PSA progression-free interval), and overall survival (OS) were tested using logistic regression and Cox regression analysis. Results: The median NLR for all evaluable patients was 2.6 at BL; 2.9 at 6 weeks; and 4.0 at 12 weeks. After low-dose corticosteroid initiation, 46 patients had a decline in PSA with 24 confirmed responders. BL NLR (log10) associated with a PSA response (odds ratio,.029, 95% confidence interval [CI],.002-. 493; P = .014), and with the extent of the PSA decline (P = .009). A favorable BL NLR (less than median) associated with a 5.5-fold higher odds of a PSA > 50% response (95% CI, 1.3-23.9; P = .02). Higher BL NLR (log10) associated with a shorter time to PSA progression (hazard ratio [HR], 9.5; 95% CI, 2.3-39.9; P = .002). In multivariate analysis BL NLR as a discrete variable was independently associated with PSA progression (HR, 3.5; 95% CI, 1.5-8.1; P = .003). NLR at 6 weeks was also associated with duration of benefit; in the favorable NLR category time to PSA progression was 10.8 months, for those who converted to an unfavorable (greater than median) category 4.5 months, and for those remaining in a unfavorable category only 1.5 months (95% CI, 0.5-2.5; P = .003). OS was 33.1 months (95% CI, 24.2-42.0) and 21.9 months (95% CI, 19.3-24.4) for those with an favorable and unfavorable BL NLR, respectively. Conclusion: Treatment-naive CRPC patients with a high BL or during-treatment NLR appear not to benefit from low-dose corticosteroids. The immunological implications of an unfavorable NLR, and whether corticosteroids might drive prostate cancer progression in patients harboring a high NLR, warrant further study. (C) 2017 Elsevier Inc. All rights reserved.

Teacher training programmes that improve teachers’ capacity and confidence to address homophobia in schools will engender non-homophobic school contexts. Currently there is a dearth of educational research on future teachers’ preparation for homophobic school contexts. By drawing on group interviews with student teachers, semi-structured interviews with lecturers and course coordinators and analysing course outlines of Lesbian, Gay, Bisexual, Transsexual and Intersex (LGBTI) offerings at three South African universities, this paper shows that such programmes exist, albeit in a limited form. While they enable greater awareness they do not translate into future teachers being enabled to apply their learning in classrooms, school contexts and in their personal lives. It is recommended that more systematic efforts to capacitate teachers for their role in engendering non-homophobic behaviour in schools is needed in teacher training programmes in South African universities.

This paper describes a series of laboratory tests conducted to assess the performance of a novel fluorescence-based in situ sensor for environmental contaminants. The sensor, which can be deployed downhole in a monitoring well, or incorporated into the shaft of a cone penetrometer, is less than 4 cm in diameter and uses a miniature microchip laser that produces 200 ps pulses of ultraviolet radiation at a high repetition rate 10 kHz to excite fluorescence in a wide range of compounds. Results from laser induced fluorescence tests on single compound aqueous solutions of benzene, toluene, and o-xylene BTX demonstrate the sensor's ability to perform contaminant analyses on compounds with fluorescence lifetimes on the order of 1 ns. A linear relationship between contaminant concen- tration and fluorescence intensity was observed for concentrations over several orders of magnitude from the sensor's detection limit 1 ppm for o-xylene to solutions of pure BTX compounds at aqueous solubility. Owing to the microchip laser's short pulse length, fluorescence lifetimes were obtained directly from measurements without the need for spectral deconvolution. Analysis of data from these tests highlights the importance of differentiating a sensor's ability to detect, identify, and quantify compounds of interest—performance thresholds that ultimately define potential applications for the device.

The aim of this single-site, open-label clinical trial was to determine the biodistribution, pharmacokinetics, absorbed doses, and safety from 2 sequential weight-based administrations of Ra-223-dichloride in patients with bone metastases due to castration-refractory prostate cancer. Methods: Six patients received 2 intravenous injections of Ra-223-dichloride, 6 wk apart, at 100 kBq/kg of whole-body weight. The pharmacokinetics and biodistribution as a function of time were determined, and dosimetry was performed for a range of organs including bone surfaces, red marrow, kidneys, gut, and whole body using scintigraphic imaging; external counting; and blood, fecal, and urine collection. Safety was assessed from adverse events. Results: The injected activity cleared rapidly from blood, with 1.1% remaining at 24 h. The main route of excretion was via the gut, although no significant toxicity was reported. Most of the administered activity was taken up rapidly into bone (61% at 4 h). The range of absorbed doses delivered to the bone surfaces from a emissions was 2,331-13,118 mGy/MBq. The ranges of absorbed doses delivered to the red marrow were 177-994 and 1-5 mGy/MBq from activity on the bone surfaces and from activity in the blood, respectively. No activity-limiting toxicity was observed at these levels of administration. The absorbed doses from the second treatment were correlated significantly with the first for a combination of the whole body, bone surfaces, kidneys, and liver. Conclusion: A wide range of interpatient absorbed doses was delivered to normal organs. Intrapatient absorbed doses were significantly correlated between the 2 administrations for any given patient. The lack of gastrointestinal toxicity is likely due to the low absorbed doses delivered to the gut wall from the gut contents. The lack of adverse myelotoxicity implies that the absorbed dose delivered from the circulating activity may be a more relevant guide to the potential for marrow toxicity than that due to activity on the bone surfaces.

Independence in activities of daily living, self-advocacy and peer support are important aspects of adolescent development. These skills are potentially affected by chronic rheumatic diseases and are worthy of attention by occupational therapists and other members of the multidisciplinary team. An innovative 4-day residential programme for young people diagnosed with chronic rheumatic disease, known as the ‘Independence Break’, was evaluated in order to determine its perceived benefits. The participants were invited to complete a brief evaluation form immediately after the trip to determine the benefits of participation in the programme. The levels of continuing social contact within the group were established 4 months later during a subsequent telephone call. Thirty young people (median age 14 years) attended the 4-day programme and reported friendship and improved performance in activities of daily living as the major benefits. The majority stayed in touch with at least one other person, with more girls staying in touch than boys. The preferred method of communication was text messaging. Overall, the programme was perceived to be a valuable experience and offered the young people an opportunity to develop informal peer support networks. The potential of text messaging within adolescent rheumatology is also highlighted.

Summary Background: Candida mediastinitis is rare, but mortality has been reported as high as 50%. There are no clinical trials evaluating treatment of Candida mediastinitis and there are only a limited number of reports in the literature. Case Report: We present two cases of mediastinitis after coronary artery bypass grafting due to Candida albicans. Immunosuppression and long surgical procedures were likely risk factors for the infections. After multiple hospitalizations and debridements there was concern for the development of resistance. However, the isolates were determined to be fluconazole-susceptible and the patients were treated with long-term oral fluconazole. Conclusions: Candida mediastinitis is difficult to treat. Even with appropriate treatment, patients may require numerous surgical debridements.

Universities of Technology in South Africa have emerged from a low research base. Despite this, it is argued that it is possible to develop a research culture at such institutions especially through Research Communities of Practice. This is evident from the data analysed of Research Capacity Development Programmes hosted at the institution from 2008 to 2011. The results show that a research culture is emerging at the institution but that for a research culture to be institutionalised, institutional attributes need to be strengthened. Of particular importance is the development of the research leadership of Heads of Department. DOI: 10.5901/mjss.2014.v5n1p151

The use of lasers to induce fluorescence in environmental contaminants such as fuels offers the potential for real-time, in situ chemical characterization in a variety of environmental media. This paper describes the first reported use of a passively Q-switched, fiber-coupled microlaser in situ for fuel-contamination characterization in subsurface soil. A 266 nm microlaser-based probe mounted in a cone penetrometer was tested at an area contaminated by both aviation and heating fuels. By examining the spectral and temporal fluorescence characteristics as the probe was pushed into soil, we identified BTEX compounds, as well as moderate-weight and heavy aromatic hydrocarbons, and were able to map an underground contamination plume in real time. Specifically, BTEX compounds were identified by their unique fluorescence signatures (wavelengths less than approximately 315 nm and lifetimes less than 7 to 10 ns) and by comparison with extensive laboratory studies of BTEX and fuel-contaminated soils. These tests demonstrate that the microlaser-based probe offers the potential for in situ, real-time characterization of soils and groundwater in a compact, inexpensive package.

Background While healthcare provider priorities often coalesce around clinical concerns, little has been done to explore the most pressing educational concerns among rheumatic disease patients. Objectives To identify healthcare education topics most important to patients with inflammatory arthritis and other rheumatic conditions. Methods Participants were recruited from within the membership registry of the rheumatology patient community, CreakyJoints, to participate in one of six nominal groups held in June 2015. Each of the six groups generated a set of educational topics or questions (“items”), and then rank-ordered them within each focus group. Items were aggregated into common topic groups, redundant items de-duplicated, and then categorized into common topic groups and themes. Based on the qualitative work, a survey describing items from all nominal groups was created and deployed more widely to the CreakyJoints membership. Demographics and other disease-related features were captured. Results From the nominal groups, 8 educational themes emerged that were related to 28 unique educational topics (see Table 1). Overall, “Lifestyle changes and patient environment modifications” was the most valued theme, receiving 14% of votes. Medication data (drug dosing, interactions, performance, etc.), physician selection, and knowledge of disease/disease progression were also strongly emphasized at 12%, 11%, and 10%, respectively. Themes of least interest included friend/family/community support, financial concerns (including insurance), and social interactions, with nominal group vote percentages of 3%, 2%, and 1%, respectively. Among 400 participants who completed the survey, mean (SD) age was 55 (11.5) years with 86% being women and 82% being white. Participant health conditions (not mutually exclusive) included rheumatoid arthritis (74%), osteoarthritis (45%), fibromyalgia (26%), osteoporosis (18%), psoriatic arthritis (8%), lupus (5%), and ankylosing spondylitis (5%). The top 10 items rated as “Extremely Important” by a majority of patients were: How arthritis affects more than just your joints (86%); What are the signs that the medication is not working (84%); Importance of knowing about how the disease will progress, even if the news is bad (83%); What are the side effects of available drugs, and how do the drugs interact with each other (82%); What are the available medications and treatments for your case (80%); How to understand the results of tests used to monitor your condition (79%); How to find the right rheumatologist (76%); How to take an active role in decisions about your care (76%); How your life will change as your disease progresses (74%); and How to speak up and help manage your care when your perspective is different from your doctor9s (73%). Conclusions Patients with rheumatic diseases are concerned about a variety of topics, which include lifestyle changes/patient environment modifications, medication data, and physician choice. Patient-centered research should maximally respond to addressing questions of importance to patients, and this survey is a first step in identifying and prioritizing the topics that matter most to patients. Acknowledgement This work was supported by educational grants from Bristol-Myers Squibb and Pfizer. Disclosure of Interest None declared