University of Florida Health

Progressive loss of kidney function in chronic kidney disease and end-stage kidney disease leads to distinct pathological changes in mineral and bone metabolism. Historically, the management of these patients focused on lowering their serum phosphate, parathyroid hormone, and normalizing serum calcium. However, persistently high morbidity and mortality of these patients from cardiovascular diseases and after bone fractures call for more specific therapies. Here, we summarize established and emerging therapies for managing the three main domains of mineral bone disorder in patients with advanced chronic kidney disease and end-stage kidney disease: Control of mineral imbalance, management of vascular disease or other soft tissue calcifications, and management of bone disorders.

Inadequate selection of patients for thyroid biopsy contributes and precedes thyroid cancer overdiagnosis. To assess the feasibility of a multicenter randomized trial evaluating a conversation aid for patients with thyroid nodules. Pilot encounter level randomized trial. Two US academic centers. Clinicians who routinely engaged in discussions with patients about thyroid nodules and their eligible patients, i.e., English-speaking adults (aged ≥ 18 years) presenting for initial evaluation of a thyroid nodule. Patients were excluded if they had hyperthyroidism, were pregnant, had already undergone a biopsy of the nodule of interest, or had received counseling for thyroid nodule management within the year before their visit. Encounters were randomized to either usual care alone or usual care plus a conversation aid. The primary outcome was feasibility of implementing study procedures. Secondarily, we assessed the aids’ impact on shared decision-making and clinical outcomes. We used the Observing Patient Involvement in Decision Making (OPTION-12) scale to assess the observed extent to which clinicians sought to involve patients in decision making. During the study, we screened 531 patients scheduled for thyroid nodule evaluation and found 213 (40%) eligible; of these, 120 (56%) attended their clinic visit and were invited to participate. Of those, 90 (75%) agreed to participate. Post-visit surveys were completed by 98% of patients, and clinical visit recordings obtained for 99% of encounters. The trial included 43 patients in each arm, most of whom were women (80%), mean age 57 years (SD 16). Encounter duration averaged 22 min, in both groups. Compared to usual care alone, usual care plus conversation aid yielded higher OPTION-12 scores (34 vs. 21, p < 0.001), more frequent discussion of alternative approaches (91 vs. 65% p = 0.008), and fewer decisions to pursue nodule biopsy (40 vs. 51%, p = 0.386). This study demonstrates the feasibility of procedures needed to conduct a multicenter randomized trial assessing the efficacy of a conversation aid. Preliminary outcomes suggest that the aid may favorably affect the care of patients with thyroid nodules. NCT04463719. Question How feasible are study procedures for a multicenter randomized trial evaluating a conversation aid for patients with thyroid nodules? Preliminarily, what are the effects on shared decision making of this aid? Findings In this feasibility randomized trial, we documented high participation rates from patients and clinicians and successful completion of study procedures. Preliminary evidence suggests the conversation aid promotes shared decision making and influences testing decisions without lengthening the encounter. Meaning Our finding documents both the feasibility of a trial to evaluate the effectiveness of a conversation aid and its efficacy in supporting diagnostic conversations in patients with thyroid nodules.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition whose clinical severity may be influenced by social factors. We aimed to identify distinct COPD clinical phenotypes and assess variation by social determinants of health. In this retrospective cohort study, we identified adults aged 50-80 years with a diagnosis of COPD (n=59 797) at a tertiary academic medical centre in North-Central Florida using codes from International Classification of Diseases. Latent class analysis defined COPD clinical phenotypes using indicators of clinical severity, including frequency of acute care encounters (urgent care, emergency department visits and hospitalisations), presence of COPD as the principal diagnosis, comorbidity burden and use of Global Initiative for Chronic Obstructive Lung Disease Group D medications. Kaplan-Meier survival curves and Cox proportional hazards models assessed mortality across phenotypes. Multinomial logistic regression models estimated associations between phenotype membership and race/ethnicity, income, rurality and smoking status, using the minimal phenotype as reference. Five clinical phenotypes were identified: minimal (20.9%), mild (35.2%), moderate (22.5%), severe (12.2%) and very severe (9.3%). The very severe phenotype had the highest mortality (adjusted HR 2.94; 95% CI 2.72 to 3.18). Odds of very severe COPD were higher among non-Hispanic Black (adjusted OR (aOR) 1.29; 95% CI 1.21 to 1.36) and Hispanic individuals (aOR 1.75; 95% CI 1.63 to 1.87), those in the lowest income communities (aOR 1.25; 95% CI 1.18 to 1.32), rural residents (aOR 1.80; 95% CI 1.68 to 1.92) and individuals who currently smoke (aOR 1.30; 95% CI 1.20 to 1.42). Most patients with COPD had mild disease; however, the very severe phenotype, which was associated with higher mortality, was more common among Black and Hispanic individuals, those residing in lower-income and rural areas and those who currently smoke. These clinical phenotypes highlight sociodemographic differences in COPD severity as reflected in healthcare utilisation and outcomes.

514 Background: Poly(ADP-ribose) polymerase 1 (PARP1) senses single strand DNA damage and catalyzes repair mechanisms. PARP inhibitor (PARPi) suppresses PARP1 activity and promotes cell death in BRCA1 or BRCA2 mutated cancers that are homologous recombination repair deficient (HRD) via a phenomenon known as “synthetic lethality”. Utility of PARPi in HRD-negative (HRDn) cancers remain uncertain, although in a preclinical study overexpression—but not endogenous levels—of BRCA2 in mouse hybridoma cells led to HRD and increased sensitivity to DNA crosslinking agents, suggesting potential sensitization to PARPi. In renal cell carcinoma (RCC), HRD mutations are rare and the role of PARPi remains investigational. In this study, PARP1 and BRCA1/2 expression and overall survival (OS) in high risk of recurrence localized clear cell-type renal carcinoma (hrr-ccRCC) were explored. Methods: Batch-corrected bulk mRNA profile (RNA Seq V2 RSEM) and clinical data of HRDn stages II grade 4-only (n = 4) and III (n = 100) ccRCC from The Cancer Genome Atlas Pan-Cancer project were reviewed. Gene expression was classified “high” if mRNA level is higher than median, otherwise it was classified “low”. Survival analyses were Log-rank Kaplan-Meier. Group comparisons were two-tailed Mann-Whitney test. Results: In HRDn hrr-ccRCC (n = 104), BRCA1 and BRCA2 were upregulated by median fold change (mFC) of 1.6 and 3.7, respectively, whereas PARP1 was downregulated by mFC 0.8 compared to normal control (n = 72, all p &lt; 0.0001). BRCA1 and BRCA2 levels were positively correlated (R 2 = 0.71). Median duration of follow-up for OS was 36.5 months (IQR 20.9-60.0). High BRCA2 (n = 54) was associated with superior OS compared to low BRCA2 (n = 50) with hazard ratio (HR) for death at 0.34 (95% CI 0.19-0.63, p = 0.0008). When high BRCA2 group was further stratified by PARP1 level, those with concomitant low PARP1 (n = 16) trended towards a superior OS compared to those with high PARP1 (n = 38) with HR 0.19 (95% CI 0.06-0.60, p = 0.067). Similarly, high BRCA1 (n = 53) was associated with superior OS compared to low BRCA1 (n = 51) with HR 0.53 (95% CI 0.29-0.96, p = 0.04). However, no differential OS was seen when high BRCA1 group was stratified by PARP1 level. No differential OS was seen when low BRCA1 or low BRCA2 groups were stratified by PARP1 level. Conclusions: In this retrospective analysis of HRDn hrr-ccRCC, high BRCA2 was associated with superior OS which was more pronounced with concomitant low PARP1 . High BRCA1 was also associated with superior OS, but PARP1 levels had no influence. The findings of this study may imply a potential therapeutic value of PARP1 suppression with PARPi by mimicking low PARP1 expression in treating HRDn hrr-ccRCC with BRCA2 overexpression. Further investigation is warranted.