Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

Considerations for Therapeutic Boundaries When Using the Intimate Medium of Music

Conventional understanding of therapeutic boundaries is a common concept present across a range of health care practices. Many therapists in music and health care work adopt these ideals to govern their ethical behaviour in practice. For some therapists, these practices may still be extremely appropriate. However, music practitioners working in newer therapeutic models or more contemporary contexts, such as community music therapy, may value a much more intuitive and reflexive approach to boundaries. In addition, the influence of culture and context are also important, as well as the impact of music. Music practitioners experience powerful moments of connection through music making with people. Music is a medium that invites intimate and personal interactions, and should also be considered in the context of therapeutic boundaries. The new term musical intimacy may help therapists to be aware of the intimate nature of making music with people and the potential vulnerabilities that it can reveal. In addition, this may encourage therapists to explore and reflect upon the boundary complexities that can be present when using music in health and well-being work.療法的バウンダリーに関する伝統的な理解は、健康ケアの実践の幅広い領域を通じて共通する概念である。音楽と健康ケアのしごとに関わるたくさんの療法士たちも、その実践の倫理的行動を決定する際、これらの考え方を適用している。一部の療法士にとっては、こうした実践の方法が、今もきわめて適切であろう。しかしながら、より新しい療法モデルや、より現代的なコンテクストでしごとをしている療法士たち、例えばコミュニティ音楽療法などでは、バウンダリーに対してもっとずっと直観的で内省的なアプローチに価値を置いていよう。さらに、文化やコンテクスト、そして音楽のもつ力の影響もまた重要である。音楽の実践者たちは、人びととの音楽活動を通じて、つながりの力強い瞬間を経験している。音楽は親密で個人的な相互やりとりを誘発する媒体であり、それは、療法的バウンダリーというコンテクストにおいても考慮されなくてはならない。音楽的親密さという新しい用語は、人びとと音楽活動をする際の親密な性質や、そこに現れうる脆弱生に療法士達が気づく助けとなることだろう。また、それは、健康とウェルビーングのしごとにおいて音楽を使う際に示されるバウンダリーの複雑さについて模索・省察することへと、療法士たちを促すことだろう

Musical intimacy and the negotiation of boundary challenges in contemporary music therapy practice

© 2016 Dr. Laura Julie MedcalfThis thesis details a grounded theory study that examined the new concept of musical intimacy. This research began with an initial interest in therapeutic boundaries, exploring how they interact with music in music therapy practice. Through a critical interpretive synthesis, examining the prevalence and presentation of traditional boundary ideas, musical intimacy emerged as a new boundary theme. Musical intimacy was an interesting concept that seemed to capture the complexities of musical experiences, and their unique interaction with therapeutic boundaries. It was the discovery of this concept that led me to explore it in more detail. A grounded theory study was conducted, interviewing 20 music therapists from locations in Australia, the USA, Canada, the UK, Denmark and Norway. I used intensive interviewing to explore the music therapists’ experiences and understandings of what musical intimacy could be. Through this, I was also keen to examine how the music therapists were managing musical intimacy, and if they had experienced any boundary challenges within that context. The interviews were conducted in person across a three month period. A grounded theory analysis, influenced by both Charmaz’s constructivist grounded theory (2014) and analytic strategies from Corbin and Strauss (2008), was applied to the interview transcriptions. The analysis process included: 1) data collection and initial analysis, 2) initial coding, 3) focussed coding, and 4) synthesizing to form the theoretical framework. Throughout the analysis process, the grounded theory technique of ‘memoing’ was used, as well as many reflexive strategies to reveal my influence on the emerging findings. This analysis allowed me to move back and forth between data and analysis, involving many streams of analysis, where I returned to the data to expand, confirm or challenge my initial ideas and themes. Through this process, a theoretical framework of musical intimacy and boundaries has emerged. The grounded essence of the musically intimate experience emerged as the core defining feature of musical intimacy. The grounded essence is: the therapist experiences a powerful moment of connection in and around the music that triggers an acute sense of vulnerability and reveals the need for boundaries to keep things safe. There were two main themes that emerged, which contributed to the musically intimate experience for these participants. These were: the ‘interpersonal experiences’ and the ‘intrinsic components of music’. The music therapists described a spectrum of experiences, which were a complex web of powerful moments of connection and challenging experiences. They also described their ‘ways of being and responding’ to the musically intimate experiences, which detailed how they managed boundaries in these moments. The most interesting aspect of this research is the emergence and definition of musical intimacy. Musical intimacy captures a complex aspect of music therapy that was experienced by all 20 of the music therapists involved in this study. Musical intimacy provides a way for music therapists to conceptualise boundaries in their practice. It alludes to powerful moments of connection we can experience, and how there can be challenging moments in and around the music in music therapy. The ‘ways of being and responding’ are the beginnings of developing a new understanding of boundaries in music therapy practice. It is my belief that through this theoretical framework of musical intimacy and boundaries, we can begin to understand the complex nature of music and boundaries in a contemporary approach to music therapy practice

Correction: The Kidney Failure Risk Equation for prediction of end stage renal disease in UK primary care: An external validation and clinical impact projection cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1002955.]

Using the kidney failure risk equation to predict end-stage kidney disease in CKD patients of South Asian ethnicity: an external validation study

Abstract Background The kidney failure risk equation (KFRE) predicts the 2- and 5-year risk of needing kidney replacement therapy (KRT) using four risk factors — age, sex, urine albumin-to-creatinine ratio (ACR) and creatinine-based estimated glomerular filtration rate (eGFR). Although the KFRE has been recalibrated in a UK cohort, this did not consider minority ethnic groups. Further validation of the KFRE in different ethnicities is a research priority. The KFRE also does not consider the competing risk of death, which may lead to overestimation of KRT risk. This study externally validates the KFRE for patients of South Asian ethnicity and compares methods for accounting for ethnicity and the competing event of death. Methods Data were gathered from an established UK cohort containing 35,539 individuals diagnosed with chronic kidney disease. The KFRE was externally validated and updated in several ways taking into account ethnicity, using recognised methods for time-to-event data, including the competing risk of death. A clinical impact assessment compared the updated models through consideration of referrals made to secondary care. Results The external validation showed the risk of KRT differed by ethnicity. Model validation performance improved when incorporating ethnicity and its interactions with ACR and eGFR as additional risk factors. Furthermore, accounting for the competing risk of death improved prediction. Using criteria of 5 years ≥ 5% predicted KRT risk, the competing risks model resulted in an extra 3 unnecessary referrals (0.59% increase) but identified an extra 1 KRT case (1.92% decrease) compared to the previous best model. Hybrid criteria of predicted risk using the competing risks model and ACR ≥ 70 mg/mmol should be used in referrals to secondary care. Conclusions The accuracy of KFRE prediction improves when updated to consider South Asian ethnicity and to account for the competing risk of death. This may reduce unnecessary referrals whilst identifying risks of KRT and could further individualise the KFRE and improve its clinical utility. Further research should consider other ethnicities

Smallpox Vaccination of Laboratory Workers at US Variola Testing Sites

To evaluate the need to revaccinate laboratory workers against smallpox, we assessed regular revaccination at the US Laboratory Response Network’s variola testing sites by examining barriers to revaccination and the potential for persistence of immunity. Our data do not provide evidence to suggest prolonging the recommended interval for revaccination

Comorbidities and outcomes in South Asian individuals with chronic kidney disease: an observational primary care cohort.

BACKGROUND: South Asian (SA) individuals are more likely to develop end-stage renal disease (ESRD), but how chronic kidney disease (CKD) differs in relation to demographics, comorbidities and outcomes has not been studied. We aimed to study differences in SA individuals with CKD compared with White individuals. METHODS: This was an observational CKD cohort comparing SA with White individuals. Inclusion criteria were ≥18 years of age and two or more Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRs 3 months apart. Individuals with ESRD at baseline were excluded. Baseline characteristics, including eGFR formulae [CKD-EPI and CKD-EPI-Pakistan (CKD-EPI-PK)], were compared. Analysis using competing risk regression for cardiovascular (CV) and ESRD events and Cox proportional hazard model for mortality was performed. RESULTS: From an adult population of 277 248 individuals, 17 248 individuals had CKD, of whom 1990 (11.5%) were of SA ethnicity. Age-adjusted prevalence of CKD was similar between ethnicities. SA individuals were more likely to be male, younger and socioeconomically deprived, and to have diabetes mellitus, CV disease and advanced CKD. Mean CKD-EPI-PK eGFR was 6.5 mL/min/1.73 m2 lower (41.1 versus 47.6, 95% confidence interval for difference 6.47-6.56) than for CKD-EPI. During 5 years of follow-up, 5109 (29.6%) individuals died, 2072 (12.0%) had a CV and 156 (0.90%) an ESRD event. Risk for SA individuals was higher for ESRD, similar to CV events and lower for mortality. Each 1 mL/min/1.73 m2 decrease in CKD-EPI-PK was associated with a 13.1% increased ESRD risk (adjusted subdistribution hazard ratio 0.869, 95% confidence interval 0.841-0.898). CONCLUSIONS: SA individuals with CKD were younger and had more advanced disease than White individuals. Risk of ESRD was higher and CKD-EPI-PK was associated with ESRD risk in SA individuals. Specific CKD interventions, including the use of CKD-EPI-PK, should be considered in SA populations

Using the kidney failure risk equation to predict end-stage kidney disease in CKD patients of South Asian ethnicity: an external validation study

Background The kidney failure risk equation (KFRE) predicts the 2- and 5-year risk of needing kidney replacement therapy (KRT) using four risk factors — age, sex, urine albumin-to-creatinine ratio (ACR) and creatinine-based estimated glomerular filtration rate (eGFR). Although the KFRE has been recalibrated in a UK cohort, this did not consider minority ethnic groups. Further validation of the KFRE in different ethnicities is a research priority. The KFRE also does not consider the competing risk of death, which may lead to overestimation of KRT risk. This study externally validates the KFRE for patients of South Asian ethnicity and compares methods for accounting for ethnicity and the competing event of death. Methods Data were gathered from an established UK cohort containing 35,539 individuals diagnosed with chronic kidney disease. The KFRE was externally validated and updated in several ways taking into account ethnicity, using recognised methods for time-to-event data, including the competing risk of death. A clinical impact assessment compared the updated models through consideration of referrals made to secondary care. Results The external validation showed the risk of KRT differed by ethnicity. Model validation performance improved when incorporating ethnicity and its interactions with ACR and eGFR as additional risk factors. Furthermore, accounting for the competing risk of death improved prediction. Using criteria of 5 years ≥ 5% predicted KRT risk, the competing risks model resulted in an extra 3 unnecessary referrals (0.59% increase) but identified an extra 1 KRT case (1.92% decrease) compared to the previous best model. Hybrid criteria of predicted risk using the competing risks model and ACR ≥ 70 mg/mmol should be used in referrals to secondary care. Conclusions The accuracy of KFRE prediction improves when updated to consider South Asian ethnicity and to account for the competing risk of death. This may reduce unnecessary referrals whilst identifying risks of KRT and could further individualise the KFRE and improve its clinical utility. Further research should consider other ethnicities.</p

The association of blood pressure variability with adverse outcomes in a primary care chronic kidney disease cohort

Background: Hypertension is common in individuals with chronic kidney disease and both conditions are associated with adverse outcomes including cardiovascular morbidity. Therefore, it is clinically important to identify methods of risk prediction in individuals with chronic kidney disease. Blood pressure variability has recently emerged as a predictor of cardiovascular events and mortality in the general population, with growing evidence indicating that it may play a similar role in individuals with chronic kidney disease. However, there have been no large studies assessing blood pressure variability in individuals with chronic kidney disease in primary care, where the majority of these patients are managed.Method: Using a retrospective observational study design, we analyzed routinely collected blood pressure readings from 16 999 individuals in The Leicester and County Chronic Kidney Disease cohort. Standard deviation, coefficient of variation and average real variability of SBP were used to calculate blood pressure variability.Results: During a median follow-up of 5.0 (IQR 3.3--5.0) years, 2053 (12.1%) patients had cardiovascular events, death occurred in 5021 (29.6%) individuals and 156 (0.9%) individuals had endstage kidney disease events. In adjusted models, standard deviation and coefficient of variation were associated with cardiovascular events, all-cause mortality and endstage kidney disease. Average real variability was associated with all-cause mortality and cardiovascular events, but not endstage kidney disease.Conclusion: Blood pressure variability may be an accessible, routinely collected, noninvasive measure for stratifying the risk of adverse events in individuals with chronic kidney disease in a primary care setting.</div

Additional file 1 of Using the kidney failure risk equation to predict end-stage kidney disease in CKD patients of South Asian ethnicity: an external validation study

Additional file 1: Supplementary Fig. 1. Kaplan-Meier ESKD-free curves for each risk group, by ethnicity. Supplementary Fig. 2. The observed risk of KRT found using the Kaplan-Meier estimates and Aalen-Johansen estimates. Supplementary Fig. 3. Calibration plots for models 5 and 6 using Aalen-Johansen estimates of incidence of KRT within 5 years.Supplementary Fig. 4. Scatter plot of 5-year predicted risk according to models 5 and 6. Supplementary Table 1. TRIPOD Checklist. Supplementary Table 2. A comparison of the updates made to models 2-4. Supplementary Table 3. Model selection for model 5. Supplementary Table 4. Optimism-adjusted coefficients in models 5 and 6. Supplementary Text 1. Non-North American Kidney Failure Risk Equation for 5-year risk. Supplementary Text 2. Model equations for models 2-5. Model 2a (white cohort) – update 5-year baseline hazard. Model 2b (South Asian cohort) – update 5-year baseline hazard. Model 3a (white cohort) – update 5-year baseline hazard & scale of linear predictor. Model 3b (South Asian cohort) – update 5-year baseline hazard & scale of linear predictor. Model 4 – Addition of ethnicity as a predictor & update 5-year baseline hazard, scale of linear predictor. Model 5 – development of a new model. Supplementary Text 3. Prediction model equation for model 6