Citations

Abstract In the present study, acute onset of severe lupus nephritis was successfully treated in mice using a new, benzamide‐linked, small molecule that targets immune modulation and the NLRP3 inflammasome. Specifically, 6‐(2,4‐difluorophenyl)‐3‐(3‐(trifluoromethyl)phenyl)‐2H‐benzo[e][1,3]oxazine‐2,4(3H)‐dione (Cf‐02) (a) reduced serum levels of IgG anti‐dsDNA, IL‐1β, IL‐6, and TNF‐α, (b) inhibited activation of dendritic cells and differentially regulated T cell functions, and (c) suppressed the NF‐κB/NLRP3 inflammasome axis, targeting priming and activating signals of the inflammasome. Moreover, treatment with Cf‐02 significantly inhibited secretion of IL‐1β in lipopolysaccharide‐stimulated macrophages, but this effect was abolished by autophagy induction. These results recommend Cf‐02 as a promising drug candidate for the serious renal conditions associated with systemic lupus erythematosus. Future investigations should examine whether Cf‐02 may also be therapeutic in other types of chronic kidney disease involving NLRP3 inflammasome‐driven signaling.

Summary Even in the era of highly active combination antiretroviral therapy (cART), patients with HIV have a disproportionate risk of developing aggressive lymphomas that are frequently Epstein‐Barr virus (EBV)‐related. Here, we investigate HIV‐associated diffuse large B‐cell lymphoma (HIV‐DLBCL) and compare EBV‐positive and EBV‐negative cases. HIV‐DLBCL were identified from two academic medical centres and characterised by immunohistochemistry, EBV status, fluorescence in situ hybridisation, cell of origin determination by gene expression profiling, and targeted deep sequencing using a custom mutation panel of 334 genes. We also applied the Lymphgen tool to determine the genetic subtype of each case. Thirty HIV‐DLBCL were identified, with a median patient age of 46 years and male predominance (5:1). Thirteen cases (48%) were EBV‐positive and 14 (52%) EBV‐negative. Nine of the 16 tested cases (56%) had MYC rearrangement, three (19%) had BCL6 (two of which were double hit MYC / BCL6 ) and none had BCL2 rearrangements. Using the Lymphgen tool, half of the cases (15) were classified as other. All HIV‐DLBCL showed mutational abnormalities, the most frequent being TP53 (37%), MYC (30%), STAT3 (27%), HIST1H1E (23%), EP300 (20%), TET2 (20%), SOCS1 (17%) and SGK1 (17%). EBV‐negative cases were mostly of germinal centre B‐cell (GCB) origin (62%), showed more frequent mutations per case (a median of 13·5/case) and significant enrichment of TP53 (57% vs. 15%; P = 0·046), SGK1 (36% vs. 0%; P = 0·04), EP300 (43% vs. 0%; P = 0·02) and histone‐modifying gene (e.g. HIST1H1E , HIST1H1D , 79% vs. 31%; P = 0·02) mutations. EBV‐positive cases were mostly of non‐GCB origin (70%), with fewer mutations per case (median 8/case; P = 0·007), and these tumours were enriched for STAT3 mutations ( P = 0·10). EBV‐positive cases had a higher frequency of MYC mutations but the difference was not significant (36% vs. 15%; P = 0·38). EBV‐association was more frequent in HIV‐DLBCLs, arising in patients with lower CD4 counts at diagnosis (median 46·5 vs. 101, P = 0·018). In the era of cART, approximately half of HIV‐DLBCL are EBV‐related. HIV‐DLBCL are enriched for MYC rearrangements, MYC mutations and generally lack BCL2 rearrangements, regardless of EBV status. Among HIV‐DLBCL, tumours that are EBV‐negative and EBV‐positive appear to have important differences, the latter arising in context of lower CD4 count, showing frequent non‐GCB origin, lower mutation burden and recurrent STAT3 mutations.

Abstract Background: The influence of prenatal diethylstilbestrol (DES) exposure on cancer incidence among middle-aged men has not been well-characterized. We investigated whether exposure to DES before birth impacts overall cancer risk, and risk of site-specific cancers. Methods: Men (mean age in 2016 = 62.0 years) who were or were not prenatally DES exposed were identified between 1953 and 1994 and followed for cancer primarily via questionnaire approximately every 5 years between 1994 and 2016. The overall and site-specific cancer rates of the two groups were compared using Poisson regression and proportional hazards modeling with adjustment for age. Results: DES exposure was not associated with either overall cancer [hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.77–1.15] or total prostate cancer rates (HR, 0.95; 95% CI, 0.68–1.33), but was inversely associated with urinary tract cancer incidence (HR, 0.48; 95% CI, 0.23–1.00). Conclusions: There was no increase in either overall or prostate cancer rates among men prenatally DES exposed relative to those unexposed. An unexpected risk reduction was observed for urinary system cancers among the exposed relative to those unexposed. These findings suggest that prenatal DES exposure is unlikely to be an important contributor to cancer development in middle-aged men. Impact: The results of this study could lend reassurance to middle-aged men who were prenatally DES exposed that their exposure does not adversely influence their overall cancer risk.

Abstract This article will review critical components for the successful completion of a multi-institution, multiauthor collaborative paper. Best practices for the creation and publication of a collaborative paper will be addressed.

AbstractBackgroundComprehensive treatment recommendations for Merkel cell carcinoma are complex. We aimed to systematically review the published data on recurrence and mortality rates associated with various treatment approaches for Merkel cell carcinoma.MethodsSearch of MEDLINE, Embase, Web of Science, and Scopus from inception to August 2015. Studies were included that reported comparative survival and recurrence data for two or more treatment modalities. Two reviewers independently reviewed and abstracted recurrence and mortality rates. Event rates for individual treatment arms in each study were pooled and meta‐analyzed across studies using a random‐effects model.ResultsFifty‐two retrospective studies met inclusion criteria, revealing a total of 1,804 patients with primary Merkel cell carcinoma with data available for analyses. The recurrence rate was higher for surgery alone (55.0%) versus a combination of surgery and radiotherapy (39.0%) (odds ratio, 2.089; 95% CI, 1.374–3.177; P < 0.001). Combination therapy including surgery, radiotherapy, and chemotherapy had a higher mortality rate (44.6%) than did combined surgery and radiotherapy (23.2%) (odds ratio, 2.688; 95% CI, 1.196–6.037; P = 0.02).ConclusionsThe treatment of Merkel cell carcinoma with surgery plus adjuvant radiotherapy may produce lower recurrence rates.

Background: One month following a myocardial infarction (MI), more than a third of older adults (age ≥65 years) are frail as demonstrated by slow gait speed (≤ 0.65 m/sec). The prognostic significance of frailty in a cardiovascular population in terms of future health states is unknown. Methods: The TRIUMPH longitudinal registry enrolled 1314 older adults (age ≥65 years) following an acute MI from 24 US centers. Gait speed (m/sec) was determined at one month (to allow for acute recovery) in 329 patients with in-home follow up. Using averages of 3 timed walks over 15-feet, patients were stratified by gait speed into 2 groups: slow (<0.65m/sec) and preserved (≥0.65m/sec). One year basic (mobility, self care) and instrumental activities of daily living (ADL) (phone, meds, travel, money), physical function score (SF12 PCS), quality of life (Seattle Angina Questionnaire (SAQ)), and mortality were assessed. Results: Slow gait speed was present in 38% (N=126) of older adults at 1 month. At 1 year, despite similar survival, frail adults were much more likely to need help with basic and instrumental (ADL), and had lower physical function and quality of life (QOL) compared to non-frail adults. ( table ) Slower gait speed remained a significant predictor of worse physical function at 1 year after adjustment for baseline physical function (p=0.013). Conclusions: Frailty is common in older adults following an MI, and those with frailty are at substantial risk for continued impairment over time. Understanding the mechanisms or reversibility of this vulnerable state would contribute to optimization of independence and quality of life among older adults with cardiovascular disease. Frailty Post MI and 1 Year Outcomes Frail (Gait <0.65m/sec)N=126 Not Frail (Gait ≥0.65m/sec)N=203 P value Mobility ADL (% need help) 45 23 <0.001 Self-Care ADL (% need help) 11 4 <0.001 Instrumental ADLs (% need help) 36 19 0.003 Physical Function (PCS) 39.2 ± 12.0 47.2 ± 9.7 <0.001 SAQ Quality of Life (QOL) 88.0 ± 15.9 91.3 ± 12.1 0.061 Mortality (%) 5.6 4.5 NS

Background: Participation in cardiac rehabilitation (CR) has been shown to decrease mortality following acute myocardial infarction (MI), but its impact on rehospitalizations requires examination. Methods: We included patients who were hospitalized with first-ever MI in Olmsted County Minnesota from 1987-2010 and survived to hospital discharge. Participation in CR within the first 30 days following MI was determined using billing data and was analyzed as a time-dependent covariate. The association between CR participation and all-cause rehospitalization was analyzed using Andersen-Gill models to account for repeated events. As CR participation is a non-randomized intervention, we adjusted for propensity to participate after fitting a logistic regression model using 13 factors significantly associated with participation on univariate analysis. Patients were censored at the time of death or last follow-up. Results: Among 2991 patients (mean age 67 years, 59% male, 31% ST elevation MI), 1480 (49%) participated in CR following acute MI hospital discharge (first session occurred at a mean of 9 days post-discharge). Most patients (75%) were rehospitalized at least once during a mean follow-up of 7.6 years, and CR participation was associated with reduced risk of rehospitalization. The rehospitalization rates were 39% and 59% at one year for participants and non-participants, respectively. In unadjusted analysis, CR participation was associated with a markedly decreased risk of rehospitalization (HR 0.51, 95% CI 0.49-0.53, p<0.001). After adjusting for propensity to participate, the association between CR participation and all-cause rehospitalization persisted (HR 0.70, 95% CI 0.67-0.73, p<0.001). Conclusions: CR participation is associated with a markedly reduced risk of rehospitalization after incident MI. In addition to reducing mortality, improving CR participation rates may have a large impact post-MI healthcare resource use.

Introduction: Cardiac rehabilitation (CR) is an effective but highly underutilized therapy for heart disease. Efforts are underway to increase CR referral and enrollment, but little is known about the potential capacity for growth in CR utilization in the United States. To address this concern, we estimated the current national capacity of CR programs across the United States and assessed obstacles to potential growth. Methods: We surveyed all CR Program Directors listed in the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) database in November of 2012. Respondents reported current enrollment levels, current program capacity, program capacity given reasonable expansion, and obstacles to growth. Results: Of 812 Program Directors in the AACVPR database, 290 (36%) completed the full survey. Respondents represented somewhat larger programs compared to non-respondents (4.0 vs. 4.6 full time employees, p = 0.01), but were otherwise similar. Current enrollment levels demonstrated a median [IQ range] of 140 [75,232] patients per year and a current estimated capacity of 192 [100,300] patient per year. Respondents estimated that programs could expand services by 25% to 240 [141,380] patients annually, assuming a significant increase in patient demand and a feasible increase in resources. We estimate that if programs filled to their current capacity, national CR utilization rates would increase from 34.7% to 46.4% (95% CI, 43.9 to 48.9) of eligible US patients each year. Given feasible program expansion, utilization could increase to a maximum of 58.4% (95% CI, 55.2 to 61.6) of qualifying patients. Capacity projections based upon absolute patient numbers and national statistics revealed concordant results. The most commonly cited obstacles to increasing patient participation are shown in the figure. As seen, the majority (88%) are controllable system-related factors unrelated to patient behavior. Conclusions: Even with substantial expansion of all existing CR programs, there is currently insufficient capacity in current CR programs to meet national service needs. Solutions to this problem will likely include the creation of new CR programs, and new policies that improve reimbursement for CR and also embrace new models of CR delivery.

Background: Cardiac Rehabilitation (CR) is an effective but highly underutilized treatment for heart disease. Prior studies have demonstrated that the use of strategies such as systematic referral (as part of an order set that does not depend on physician initiative or memory, usually with an opt-out option), liaison facilitated referral (a specific staff member who discusses the program, encourages attendance, and facilitates referral), an early appointment (< 2 weeks), and telephone appointment reminder calls can all improved enrollment rates. However, it is unclear how frequently these strategies are utilized across the United States, how often CR programs monitor their participation rates, and how often quality improvement (QI) projects designed to improve participation rates are performed. Methods: We surveyed all CR program directors in the American Association of Cardiovascular and Pulmonary Rehabilitation’s (AACVPR) database. We assessed basic program features, use of systematic referral, liaison facilitated referral, early appointments, and telephone reminder calls and QI projects. We also assessed self-reported referral, enrollment, and completion rates. Results: Response rate was 36% (290/812). Non-response bias analysis showed reasonable survey representativeness. Over the past 5 years, 49% of programs measured hospital referral, 21% office/clinic referral, 71% program enrollment, and 74% program completion rates. Self-reported rates (interquartile range) were 68 [32 to 90]% for hospital referral, 35 [15 to 60]% for office/clinic referral, 70[46 to 80]% for program enrollment, and 75[62 to 82]% for program completion. Programs reported utilizing a hospital-based systematic referral, liaison facilitated referral, or inpatient CR program 64%, 68%, and 60% of the time, respectively. Early appointments (< 2 weeks) were utilized by 35% and consistent phone call appointment reminders were utilized by 50%. Over the past 5 years, the percent or programs performing QI projects were 62% for hospital referral, 42% for clinic referral, 60% for program enrollment, and 57% for program completion. Measurement of participation rates was highly correlated with performing QI projects (p < 0.0001.) Conclusions: Although programs are aware of participation rate gaps, the monitoring of participation rates is suboptimal, quality improvement initiatives are infrequent, and proven strategies for increasing patient participation are inconsistently utilized. Awareness in outpatient clinical settings is particularly low. These issues likely contribute to the national CR participation gap and may prove to be useful targets for national QI initiatives.

Background: With increasing options for treating atrial fibrillation (AF), it is important to understand and quantify patient symptoms and quality of life (QoL), as improving symptoms and maximizing QoL are primary treatment goals. However, little is known about the factors associated with QoL. Methods: The Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) is a disease-specific QoL tool for AF, with domain and summary scores ranging from 0 (the worst health status) to 100. Using hierarchical pseudo-binomial regression, we evaluated factors associated with baseline AFEQT Summary and Subscale scores in the ORBIT AF registry. Adjusted associations were reported as odds ratios (OR) and 95% confidence intervals (CI). Results: AFEQT was assessed in 2,007 AF outpatients from 99 sites. Median age and interquartile range (IQR) was 76 (67-82); 43% were female; and the median CHA2DS2-VASC score was 4 (3-5). Median AFEQT summary score was 82 (67, 94). Median symptom score was 92 (78-100) and daily activity score was 77 (52-94). Female sex, younger age, new onset AF, higher heart rate, obstructive sleep apnea, and CAD were all associated with reduced QoL. (Table) Similar trends were seen for the symptoms subscale: female sex [OR 0.57 CI (0.48, 0.68)], younger age [OR 1.10 CI (1.06, 1.15)], and new onset AF [OR 0.55 CI (0.43, 0.70)] were associated with worse symptoms. Likewise, for the daily activities subscale, Other race [OR 0.54 CI (0.36-0.80)] and higher BMI [OR 0.98 CI (0.98-0.99)] were associated with decreased activity. Conclusions: In the largest community-based assessment of QoL in patients with AF, we found several patient factors to be associated with low QoL, including female sex, new onset AF, younger age, higher heart rate, and certain cardiopulmonary comorbidities. Understanding patient characteristics associated with worse QoL can be a foundation for eradicating disparities and tailoring treatment.