Self-reported MeasUrement of Physical and PsychosOcial Symptoms Response Tool (SUPPORT-dialysis): systematic symptom assessment and management in patients on in-centre haemodialysis - a parallel arm, non-randomised feasibility pilot study protocol.

INTRODUCTION: Patients with kidney failure experience symptoms that are often under-recognised and undermanaged. These symptoms negatively impact health-related quality of life and are associated with adverse clinical outcomes. Regular symptom assessment, using electronic patient reported outcomes measure (ePROMs) linked to systematic symptom management, could improve such outcomes. Clinical implementation of ePROMs have been successful in routine oncology care, but not used for patients on dialysis. In this study, we describe a pilot study of ePROM-based systematic symptom monitoring and management intervention in patients treated with in-centre haemodialysis. METHODS AND ANALYSIS: This is a parallel-arm, controlled pilot of adult patients receiving in-centre maintenance haemodialysis. Participants in the intervention arm will complete ePROMs once a month for 6 months. ePROMs will be scored real time and the results will be shared with participants and with the clinical team. Moderate-severe symptoms will be flagged using established cut-off scores. Referral options for those symptoms will be shared with the clinical team, and additional symptom management resources will also be provided for both participants and clinicians. Participants in the control arm will be recruited at a different dialysis unit, to prevent contamination. They will receive usual care, except that they will complete ePROMs without the presentation of results to participants of the clinical team. The primary objectives of the pilot are to assess (1) the feasibility of a larger, randomised clinical effectiveness trial and (2) the acceptability of the intervention. Interviews conducted with participants and staff will be assessed using a content analysis approach. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the University Health Network (REB#21-5199) and the William Osler Health System (#23-0005). All study procedures will be conducted in accordance with the standards of University Health Network research ethics board and with the 1964 Helsinki declaration and its later amendments. Results of this study will be shared with participants, patients on dialysis and other stakeholders using lay language summaries, oral presentations to patients and nephrology professionals. We will also be publishing the results in a peer-reviewed journal and at scientific meetings. PROTOCOL VERSION: 4 (16 November 2022). TRIAL REGISTRATION NUMBER: NCT05515991.

Antitumor and chemopreventive role of major phytochemicals against breast cancer development.

Breast cancer continues to be one of the most commonly diagnosed cancers around the world. Despite the decrease in mortality, there has been a steady increase in its incidence. There is much evidence that naturally occurring phytochemicals could prove to be safer alternatives aimed at prevention and development of breast cancer. In the present review, we discuss important phytochemicals, namely capsaicin, alpha-santalol and diallyl trisulphide that are shown to have chemopreventive and anti-tumour properties against breast cancer development. We examined current knowledge of their bioavailability, safety and modulation of molecular mechanisms including their ability to induce apoptotic cell death, promote cell cycle arrest, and inhibit cellular proliferation in different breast cancer cell lines and in vivo models. This review emphasises the importance of these naturally occurring phytochemicals and their potential of becoming therapeutic options in the arsenal against breast cancer development provided further scientific and clinical validation.

Assessing Fatigue in Patients Receiving Kidney Replacement Therapy Using PROMIS Computer Adaptive Testing.

RATIONALE & OBJECTIVE: Fatigue is a debilitating symptom for many patients receiving kidney replacement therapy (KRT). Patient-reported outcome measures can help clinicians identify and manage fatigue efficiently. We assessed the measurement characteristics of the Patient Reported Outcome Measurement Information System (PROMIS)-Fatigue Computer Adaptive Test (PROMIS-F CAT) in patients receiving KRT using the previously validated Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 198 adults treated with dialysis or recipients of a kidney transplant in Toronto, Canada. PREDICTORS: Demographic data, FACIT-F scores, KRT type. OUTCOME: Measurement properties of PROMIS-F CAT T scores. ANALYTICAL APPROACH: Reliability and test-retest reliability were assessed using standard errors of measurement and intraclass correlation coefficient (ICC), respectively. Construct validity was assessed using correlation and comparisons across predefined groups expected to have different levels of fatigue. Receiver operating characteristic (ROC) curves were used to assess the discrimination of PROMIS-F CAT, with clinically relevant fatigue defined by a FACIT-F score of≤30. RESULTS: Of the 198 participants, 57% were male, the mean±SD age was 57±14 years; 65% had received a kidney transplant. Based on the FACIT-F score, 47 patients (24%) had clinically relevant fatigue. PROMIS-F CAT and FACIT-F were strongly correlated (ρ =-0.80, P<0.001). PROMIS-F CAT had excellent reliability (>0.90 for 98% of sample), and good test-retest reliability (ICC=0.85). The ROC analysis demonstrated outstanding discrimination (area under ROC=0.93 [95%, CI 0.89-0.97]). A PROMIS-F CAT cutoff score of≥59 accurately identified most patients with clinically relevant fatigue (sensitivity=0.83; specificity=0.91). LIMITATIONS: A convenience sample of clinically stable patients. FACIT-F items are a part of the PROMIS-F item bank, although there was minimal overlap with only 4 FACIT-F items completed in PROMIS-F CAT. CONCLUSIONS: PROMIS-F CAT has robust measurement properties with low question burden to assess fatigue among patients with KRT.

Older Age is Associated With Lower Utilization of Living Donor Kidney Transplant.

Introduction: Older adults (65 years or older) constitute a substantial and increasing proportion of patients with kidney failure, potentially needing kidney replacement therapy. Living donor kidney transplant (LDKT) offers superior outcomes for suitable patients of all ages. However, exploring LDKT and finding a living donor could be challenging for older adults. Here, we assessed the association between age and utilization of LDKT and assessed effect modification of key variables such as ethnicity and language. Methods: This is a retrospective cohort study of patients with kidney failure referred for kidney transplant (KT) assessment in Toronto between January 2006 and December 2013. The association between age and having a potential living donor identified was assessed using logistic regression and the association between age and the receipt of LDKT was assessed using Cox proportional hazards models. Results: Of the 1617 participants, 50% were middle-aged (45-64 years old), and 17% were ≥65 years old. In our final multivariable adjusted models, compared to young adults, middle-aged and older adults had lower odds of having a potential living donor identified (odds ratio [OR], 0.47; confidence interval [CI], [0.35-0.63]; OR, 0.30; CI, [0.20-0.43]; P < 0.001, for middle-aged and older adults, respectively), and were less likely to receive LDKT (hazard ratio [HR], 0.79; CI, [0.63-0.99]; P = 0.04; HR, 0.47; CI, [0.30-0.72]; P = 0.001, for middle-aged and older adults, respectively.). Conclusion: Age is an independent predictor of receiving LDKT. Considering that nearly 90% of patients with kidney failure in Canada are >45 years of age, these results point to important and potentially modifiable age-related barriers to LDKT.

Psychosocial Distress in Patients With Advanced CKD by Racial Group and Immigrant Status: A Canadian Cross-sectional Study.

RATIONALE & OBJECTIVE: Patients with advanced chronic kidney disease (CKD) have been reported to experience profound psychosocial distress. Other work has established that patients with CKD from marginalized populations (including individuals who on the basis of race often face racism and related discrimination, termed "racialization") experience health care inequities. Given limited information on the intersection of these 2 phenomena, we assessed the association of psychosocial distress with racialized status and immigrant status in Canadians with advanced CKD. STUDY DESIGN: Secondary analysis of cross-sectional data. SETTING & PARTICIPANTS: 536 patients with advanced CKD (estimated glomerular filtration rate<30mL/min/1.73m2, with or without kidney replacement therapy) from multiple clinical centers in Toronto. EXPOSURE: Racialized status (individuals who identify as Asian or as African, Caribbean, or Black Canadian), immigrant status, and combined immigrant-racialized status. OUTCOME: Psychosocial distress, defined as the presence of depression, anxiety, or social difficulties (ie, a score of≥10 points on the Patient Health Questionnaire 9, Generalized Anxiety Disorder 7, or Social Distress 16 scales, respectively). ANALYTICAL APPROACH: The independent associations of racialized status and immigrant status with psychosocial distress, depression, anxiety, and social difficulties were examined using univariable- and multivariable-adjusted logistic regression. RESULTS: Mean age of the 536 participants was 57±16 (SD) years, 62% were male, and 45% were immigrants. Of the sample, 58% were White, 22% were African, Caribbean, or Black Canadian, and 20% were Asian. Psychosocial distress was present in 36% of participants (depression in 19%, anxiety in 12%, and social difficulties in 31%). To assess the combined impact of racialized and immigrant status, we created a variable with mutually exclusive categories: White nonimmigrant, racialized nonimmigrant, White immigrant, and racialized immigrant participants. In our final multivariable-adjusted model, compared with White nonimmigrant participants, racialized immigrant participants were more likely to have psychosocial distress (OR, 2.96 [95% CI, 1.81-4.81]), depression (OR, 1.87 [95% CI, 1.05-3.34]), and social difficulties (OR, 3.36 [95% CI, 2.03-5.57]). Overall similar associations were seen for racialized nonimmigrants and for White immigrants. LIMITATIONS: Convenience sample; small subgroups; combined exposure variable grouping Asian and African, Caribbean, and Black participants together; lack of data about mechanisms. CONCLUSIONS: Both racialized and immigrant status based on self-report of demographic characteristics were associated with psychosocial distress among patients with advanced CKD. These patients may benefit from culturally competent psychosocial support. PLAIN-LANGUAGE SUMMARY: Psychosocial distress is frequent in patients with advanced chronic kidney disease and impacts quality of life and clinical outcomes. Psychosocial distress may be especially scarring in people who are racialized (marginalized on account of their membership in a particular racial group) and/or who are immigrants. We assessed the association of psychosocial distress with racialized and immigrant status in Canadians with advanced chronic kidney disease. Among 536 participants from multiple medical centers in Toronto, we found that racialized and immigrant participants were more likely to have psychosocial distress, depression, and social difficulties compared with White nonimmigrant participants. This is likely related to the multiple intersectional challenges, including experience with racism and discrimination that racialized immigrant patients may face. Further studies are needed to elucidate the specific factors that contribute to more distress. The potential impact of culturally competent and safe support for these patients will also need to be studied.

Screening for symptoms of anxiety and depression in patients treated with renal replacement therapy: utility of the Edmonton Symptom Assessment System-Revised.

PURPOSE: The Edmonton Symptom Assessment System-revised (ESASr) is widely used in clinical oncology to screen for physical and emotional symptoms. The performance of the anxiety and depression items (ESASr-A and ESASr-D, respectively) as screening tools have not been evaluated in patients treated with renal replacement therapy. METHODS: Kidney transplant recipients and patients on dialysis were recruited in Toronto. Patients were classified as having moderate/severe depression and anxiety symptoms using the established cut-off score of ≥ 10 on the Patient Health Questionnaire-9 (PHQ-9) and the General Anxiety Disorder-7 (GAD-7) questionnaires. RESULTS: This study included 931 participants; 62% male, mean age (SD) 55(16), and 52% White. All participants completed ESASr, however only 748 participants completed PHQ-9 and 769 participants completed GAD-7. Correlation between ESASr item scores and legacy scores were moderately strong (ESASr-D/PHQ-9: 0.61; ESASr-A/GAD-7: 0.64). We found good discrimination for moderate/severe depression and anxiety [area under the receiver operating characteristics curve (95% CI) ESASr-D 0.82(0.78-0.86); ESASr-A 0.87 (0.82, 0.92)]. The cut-off ≥ 2 for ESASr-D [Sensitivity = 0.76; Specificity = 0.77; Likelihood Ratio (LR) + = 3.29; LR - = 0.31] and ≥ 4 for ESASr-A (Sensitivity = 0.75; Specificity = 0.87; LR + = 5.76; LR - = 0.29) had the best combination of measurement characteristics. CONCLUSION: The identified ESASr-D and ESASr-A cut-off scores may be used to rule out patients without emotional distress with few false negatives. However, the low sensitivity identified in our analysis suggests that neither ESASr-D or ESASr-A are acceptable as standalone screening tools.

Evaluation of PROMIS Preference Scoring System (PROPr) in Patients Undergoing Hemodialysis or Kidney Transplant.

BACKGROUND AND OBJECTIVES: A preference-based health utility score (PROPr) can be calculated using Patient-Reported Outcomes Measurement Information System domain scores. We assessed the construct validity of PROPr among patients treated with KRT (hemodialysis or kidney transplant). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a secondary analysis of data collected in multicenter, cross-sectional studies of adults treated with KRT, recruited between April 2016 to March 2020 in Toronto, Canada. All participants provided informed consent. The outcome was the PROPr score. Coadministered outcome variables included the Short-Form Six-Domain (SF-6D) and EuroQol Five-Domain Five-Level (EQ-5D-5L) scores. Socioeconomic and clinical variables included age, sex, diabetes, eGFR, serum albumin, hemoglobin, KRT, and Charlson Comorbidity Index. Construct validity was assessed through correlations between PROPr and SF-6D or EQ-5D-5L, and associations between PROPr and other exposure variables. Health-condition impact estimates (coefficients for health conditions compared with a referent category, e.g., dialysis versus kidney transplant) were calculated using multivariable linear regression. RESULTS: The mean (SD) age of the 524 participants was 57 (17) years, 58% were male, and 45% were White. Median (interquartile range) score was 0.39 (0.24-0.58) for PROPr, 0.69 (0.58-0.86) for SF-6D, and 0.85 (0.70-0.91) for EQ-5D-5L. Large correlations were observed between PROPr versus SF-6D (0.79; 95% confidence interval [95% CI], 0.76 to 0.82) and EQ-5D-5L (0.71; 95% CI, 0.66 to 0.75). Both PROPr and the other utility indices demonstrated health-condition impact in the expected direction. For example, the estimate for PROPr was -0.17 (95% CI, -0.13 to -0.21) for dialysis (versus kidney transplant), -0.05 (95% CI, -0.11 to 0.01; P=0.08) for kidney transplant recipients with an eGFR of <45 versus ≥45 ml/min per 1.73 m2, and -0.28 (95% CI, -0.22 to -0.33) for moderate/severe versus no/mild depressive symptoms. CONCLUSIONS: Our results support the validity of PROPr among patients treated with KRT.

A case of inferior vena cava atresia complicated by bilateral deep vein thrombosis.

In this report, we describe a case of deep vein thrombosis with suspected congenital inferior vena cava atresia treated with thrombolysis, angioplasty, and bilateral "kissing" iliac stent placement. An 18-year-old male presented with left common iliac vein thrombus and suspected congenital inferior vena cava atresia. He was treated over 4 days and discharged on anticoagulation which was continued long-term. These treatments were shown to be clinically successful in treating and preventing re-thrombosis in the context of inferior vena cava atresia initially presenting with symptomatic bilateral lower extremity deep vein thrombosis.

Evaluating symptom burden in kidney transplant recipients: validation of the revised Edmonton Symptom Assessment System for kidney transplant recipients - a single-center, cross-sectional study.

We assessed the validity of the Edmonton Symptom Assessment System (ESAS-r) in kidney transplant recipients (KTR). A cross-sectional sample of 252 KTR was recruited. Individual ESAS-r symptom scores and symptom domain scores were evaluated. Internal consistency, convergent validity, and construct validity were assessed with Cronbach's α, Spearman's rank correlations, and a priori-defined risk group comparisons. Mean (SD) age was 51 (16), 58% were male, and 58% Caucasian. ESAS-r Physical, Emotional, and Global Symptom Scores demonstrated good internal consistency (α > 0.8 for all). ESAS-r Physical and Global Symptom Scores strongly correlated with PHQ-9 scores (0.72, 95% CI: 0.64-0.78 and 0.74, 95% CI: 0.67-0.80). For a priori-defined risk groups, individual ESAS-r symptom score differed between groups with lower versus higher eGFR [pain: 1 (0-3) vs. 0 (0-2), delta = 0.18; tiredness: 3 (1-5) vs. 1.5 (0-4), delta = 0.21] and lower versus higher hemoglobin [tiredness: 3 (1-6) vs. 2 (0-4), delta = 0.27]. ESAS-r Global and Physical Symptom Scores differed between groups with lower versus higher hemoglobin [13 (6-29) vs. 6.5 (0-18.5), delta = 0.3, and 9 (2-19) vs. 4 (0-13), delta = 0.24] and lower versus higher eGFR [11 (4-20) vs. 6.5 (2-13), delta = 0.21, and 7 (2-16) vs. 3 (0-9), delta = 0.26]. These data support reliability and construct validity of ESAS-r in KTR. Future studies should explore its clinical utility for symptom assessment among KTR.

Validation of the Patient-Reported Outcomes Measurement Information System (PROMIS)-57 and -29 item short forms among kidney transplant recipients.

OBJECTIVE: The Patient-Reported Outcomes Measurement Information System (PROMIS) aims to address the lack of generalizable and universal measure of patient-reported outcomes to assess health-related quality of life. It has not been validated for patients with chronic kidney disease. We aim to validate the PROMIS-57 and PROMIS-29 questionnaires among kidney transplant recipients. METHODS: A cross-sectional sample of stable kidney transplant recipients was recruited. Each participant completed PROMIS-57, a 57-question instrument covering seven domains-physical function, anxiety, depression, fatigue, pain, sleep disturbance, and social functioning-alongside validated legacy questionnaires [Patient Health Questionnaire (PHQ9), General Anxiety Disorder (GAD7), Edmonton Symptom Assessment Scale revised (ESASr), and Kidney Disease Quality of Life (KDQoL-36)]. PROMIS-29, a 29-question instrument, is nested within PROMIS-57 and measures the same domains. Structural validity of PROMIS was assessed with confirmatory factor analysis, reported using the Comparative Fit Index (CFI). Construct validity was assessed with known-groups comparisons. Internal consistency was evaluated with Cronbach's α and convergent validity was assessed with Spearman's Rho. Test-retest reliability was assessed through the intraclass correlation coefficient (ICC). RESULTS: Mean (± SD) age of the 177 participants was 50 (± 17), 57% were male and 55% Caucasian. Internal consistency of each domain was high (Cronbach's α > 0.88). Confirmatory factor analysis showed good structural validity for most domains (CFI > 0.95, RMSEA < 0.05). Test-retest reliability indicated good agreement (ICC > 0.6). Known-groups comparisons by clinical and socio-demographic differences were found as hypothesized. CONCLUSIONS: Our results provide evidence that PROMIS-57 and PROMIS-29 are highly reliable and valid instruments among kidney transplant recipients. We propose it as a valuable tool to assess important domains of the illness experience.

Exploring the use of tablet computer-based electronic data capture system to assess patient reported measures among patients with chronic kidney disease: a pilot study.

BACKGROUND: Collecting patient reported outcome measures (PROMs) via computer-based electronic data capture system may improve feasibility and facilitate implementation in clinical care. We report our initial experience about the acceptability of touch-screen tablet computer-based, self-administered questionnaires among patients with chronic kidney disease (CKD), including stage 5 CKD treated with renal replacement therapies (RRT) (either dialysis or transplant). METHODS: We enrolled a convenience sample of patients with stage 4 and 5 CKD (including patients on dialysis or after kidney transplant) in a single-centre, cross-sectional pilot study. Participants completed validated questionnaires programmed on an electronic data capture system (DADOS, Techna Inc., Toronto) on tablet computers. The primary objective was to evaluate the acceptability and feasibility of using tablet-based electronic data capture in patients with CKD. Descriptive statistics, Fischer's exact test and multivariable logistic regression models were used for data analysis. RESULTS: One hundred and twenty one patients (55% male, mean age (± SD) of 58 (±14) years, 49% Caucasian) participated in the study. Ninety-two percent of the respondents indicated that the computer tablet was acceptable and 79% of the participants required no or minimal help for completing the questionnaires. Acceptance of tablets was lower among patients 70 years or older (75% vs. 95%; p = 0.011) and with little previous computer experience (81% vs. 96%; p = 0.05). Furthermore, a greater level of assistance was more frequently required by patients who were older (45% vs. 15%; p = 0.009), had lower level of education (33% vs. 14%; p = 0.027), low health literacy (79% vs. 12%; p = 0.027), and little previous experience with computers (52% vs. 10%; p = 0.027). CONCLUSIONS: Tablet computer-based electronic data capture to administer PROMs was acceptable and feasible for most respondents and could therefore be used to systematically assess PROMs among patients with CKD. Special consideration should focus on elderly patients with little previous computer experience, since they may require more assistance with completion.

Identification of xenopus CENP-A and an associated centromeric DNA repeat.

Kinetochores are the proteinaceous complexes that assemble on centromeric DNA and direct eukaryotic chromosome segregation. The mechanisms by which higher eukaryotic cells define centromeres are poorly understood. Possible molecular contributors to centromere specification include the underlying DNA sequences and epigenetic factors such as binding of the centromeric histone centromere protein A (CENP-A). Frog egg extracts are an attractive system for studying centromere definition and kinetochore assembly. To facilitate such studies, we cloned a Xenopus laevis homologue of CENP-A (XCENP-A). We identified centromere-associated DNA sequences by cloning fragments of DNA that copurified with XCENP-A by chromatin immunoprecipitation. XCENP-A associates with frog centromeric repeat 1 (Fcr1), a 174-base pair repeat containing a possible CENP-B box. Southern blots of partially digested genomic DNA revealed large ordered arrays of Fcr1 in the genome. Fluorescent in situ hybridization with Fcr1 probes stained most centromeres in cultured cells. By staining lampbrush chromosomes, we specifically identified the 11 (of 18) chromosomes that stain consistently with Fcr1 probes.