Citations

Objective To provide evidence‐based recommendations and expert guidance for the management of Kawasaki disease (KD), focusing on clinical scenarios more commonly addressed by rheumatologists. Methods Sixteen clinical questions regarding diagnostic testing, treatment, and management of KD were developed in the Patient/Population, Intervention, Comparison, and Outcomes (PICO) question format. Systematic literature reviews were conducted for each PICO question. We used the Grading of Recommendations, Assessment, Development and Evaluation method to assess the quality of evidence and formulate recommendations. Each recommendation required consensus from at least 70% of the Voting Panel. Results We present 1 good practice statement, 11 recommendations, and 1 ungraded position statement to guide the management of KD and clinical scenarios of suspected KD. These recommendations for KD are focused on situations in which input from rheumatologists may be requested by other managing specialists, such as in cases of treatment‐refractory, severe, or complicated KD. The good practice statement affirms that all patients with KD should receive initial treatment with intravenous immunoglobulin (IVIG). In addition, we developed 7 strong and 4 conditional recommendations for the management of KD or suspected KD. Strong recommendations include prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in the setting of unexplained macrophage activation syndrome or shock. Conditional recommendations include use of IVIG with other adjuvant agents for patients with KD and high‐risk features of IVIG resistance and/or coronary artery aneurysms. These recommendations endorse minimizing risk to the patient by using established therapy promptly at disease onset and identifying situations in which adjunctive therapy may be warranted. Conclusion These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and use of echocardiography in patients with suspected or confirmed KD.

26 Background: The underrepresentation of minority populations in clinical trials negatively impacts cancer and widens inequities. We aimed to quantify the enrollment disparities in prostate cancer (PC) clinical trials over the last three decades. Methods: MEDLINE and Embase were searched to identify primary reports of prostate cancer RCTs (1989-2020). Data for trial characteristics, the proportion of trials reporting race, ethnicity and age, and the proportion of patients by race, ethnicity and age enrolled in trials were summarized using descriptive statistics. Enrollment incidence ratios (EIR), which compare trial enrollment against global estimates of incidence in age-related subgroups (acquired from the Global Burden of Disease database) and U.S. population-based estimates of racial/ethnic subgroups (acquired from the SEER 18 incidence database) were calculated. Individual trial EIRs were pooled using random-effects meta-analyses to account for the substantial heterogeneity between trials. Multivariable meta-regression was used to explore associations between key trial characteristics and EIR. Annual percentage changes (APC) over the last three decades in enrollment disparities were analyzed using the Joinpoint Regression Analysis. Results: 281 trials from 1989 to 2020 with 99,588 patients were included in this analysis. 107 trials reported race (38%), of which only 25 trials (9%) reported data on all 5 U.S. racial categories (Black, White, Asian, Pacific Islander and Native American. 255 (91%) trials reported mean or median but only 71 trials (25%) specifically reported the enrollment proportion of older adults (age > 65 years). Clinical outcomes by race and age were reported in 9 (8%) and 37 (14%) trials, respectively. Results from meta-analyses showed that Black patients (summary EIR: 0.42 [95% CI: 0.35 - 0.51]), Hispanics (summary EIR: 0.50 [95% CI: 0.37 - 0.68]) and older adults (summary EIR: 0.95 [95% CI: 0.91 - 0.99]) were underrepresented in trials relative to their population estimates. Significantly fewer Black participants (EIR for Black patients = 0.42, EIR for White patients = 0.99; p < 0.0001), Hispanic participants (EIR for Hispanics = 0.50, EIR for non-Hispanics = 1.00; p = 0.001) and older adults (EIR for older adults = 0.95, EIR for younger adults = 1.06; p = 0.037) were enrolled. Representation of Black patients decreased significantly from 1989-2019 (APC: -4.25), while Hispanic representation increased significantly from 2000-2020 (APC: 5.89). Meta-regression showed Black patients were particularly underrepresented in larger-size trials (p < 0.0001). Conclusions: Black representation in PC clinical trials is less than 50% of their expected share based on cancer incidence and it has consistently decreased over last three decades, contributing to the disparities experienced by the population.

Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is a substrate for a number of nonredox enzymes. NAD is fundamental to a variety of cellular processes including energy metabolism, cell signaling, and epigenetics. NAD homeostasis appears to be of paramount importance to health span and longevity, and its dysregulation is associated with multiple diseases. NAD metabolism is dynamic and maintained by synthesis and degradation. The enzyme CD38, one of the main NAD-consuming enzymes, is a key component of NAD homeostasis. The majority of CD38 is localized in the plasma membrane with its catalytic domain facing the extracellular environment, likely for the purpose of controlling systemic levels of NAD. Several cell types express CD38, but its expression predominates on endothelial cells and immune cells capable of infiltrating organs and tissues. Here we review potential roles of CD38 in health and disease and postulate ways in which CD38 dysregulation causes changes in NAD homeostasis and contributes to the pathophysiology of multiple conditions. Indeed, in animal models the development of infectious diseases, autoimmune disorders, fibrosis, metabolic diseases, and age-associated diseases including cancer, heart disease, and neurodegeneration are associated with altered CD38 enzymatic activity. Many of these conditions are modified in CD38-deficient mice or by blocking CD38 NADase activity. In diseases in which CD38 appears to play a role, CD38-dependent NAD decline is often a common denominator of pathophysiology. Thus, understanding dysregulation of NAD homeostasis by CD38 may open new avenues for the treatment of human diseases.

AbstractStudy ObjectiveThe primary objective of this retrospective safety study was to determine the incidence of torsades de pointes (TdP) or death following perioperative administration of low‐dose, 4 mg, ondansetron for postoperative nausea and vomiting.Design and SettingThis is a single‐center retrospective clinical trial.PatientsThe authors identified 32,737 patients who received 37,589 doses of ondansetron during a 2‐year time frame between March 2009 and February 2011 for surgical nausea prophylaxis or treatment of nausea.Measurements and Main ResultsPatients were cross‐matched with an electrocardiogram and adverse outcome database; this identified 4759 patients with documentation of a QTc >450 milliseconds (ms), all ventricular tachycardias including TdP within 48 hours of receiving ondansetron, or death within 7 days of receiving ondansetron. No patients developed TdP or died as a direct result of ondansetron administration (n = 0; event rate = 0.0 per 10,000, 95% CI 0.0 to 1.1 per 10,000). Forty‐six of 32,737 surgical patients had documented monomorphic ventricular tachycardia (VT) (n = 14; event rate = 4.3 per 10,000, 95% CI 2.3 to 7.2 per 10,000) or died (n = 32; event rate = 9.8 per 10,000, 95% CI 6.7 to 13.8 per 10,000) within 48 h of ondansetron administration. All monomorphic VT episodes were precipitated by existing cardiovascular disease; and 7 of 14 patients had documented monomorphic VT prior to receiving ondansetron. Of the 32 surgical patients who died, all deaths were precipitated by pre‐existing disease.ConclusionNo episodes of TdP were identified in patients receiving ondansetron perioperatively. This suggests that low‐dose ondansetron does not contribute to the development of TdP.

Objectives Penile urethral stricture disease not associated with hypospadias is rare, and there is a wide range of commonly used surgical repair techniques for this disease. We sought to compile a multi‐institutional database of patients who had surgical correction of strictures in the penile urethra not limited to the meatus, and who had no history of hypospadias, for analysis using the Trauma and Urologic Reconstructive Network of Surgeons length, urethral segment and etiology classification system. Methods A retrospective database from 13 institutions was compiled of patients who had undergone surgical correction of Trauma and Urologic Reconstructive Network of Surgeons length, urethral segment and etiology urethral stricture segments S2b/S2c and excluding E5, with a minimum follow‐up time of 4 months. Failure was defined as cystoscopically confirmed recurrence of a stricture measuring less than 16‐Fr. Results We analyzed 222 patients with a median age of 57 years and a follow‐up of 49 months. The overall surgical success rate was 80.2%. On multivariate analysis, the two variables identified that were predictive of surgical success were stricture length ≤2 cm as well as use of a buccal mucosa graft as compared to use of a fasciocutaneous flap, which had success rates of 83% and 52%, respectively ( P = 0.0004). No statistically significant differences were found based on incisional approach or surgical technique, nor were outcomes different based on etiology or preoperative patient demographics. Conclusions Surgical repair of penile urethral strictures of non‐hypospadiac origin have a favorable overall success rate, at 80.2%. Regardless of incisional approach or surgical technique, all operations appear to have similar outcomes other than repairs using fasciocutaneous flap, which were statistically less successful than those using buccal mucosa graft.

Anemia is common during critical illness, is associated with adverse clinical outcomes, and often persists after hospitalization. The goal of this investigation is to assess the relationships between post-hospitalization hemoglobin recovery and clinical outcomes after survival of critical illness. This is a population-based observational study of adults (≥18 years) surviving hospitalization for critical illness between January 1, 2010 and December 31, 2016 in Olmsted County, Minnesota, United States with hemoglobin concentrations and clinical outcomes assessed through one-year post-hospitalization. Multi-state proportional hazards models were utilized to assess the relationships between 1-month post-hospitalization hemoglobin recovery and hospital readmission or death through one-year after discharge. Among 6460 patients that survived hospitalization for critical illness during the study period, 2736 (42%) were alive, not hospitalized, and had available hemoglobin concentrations assessed at 1-month post-index hospitalization. Median (interquartile range) age was 69 (56, 80) years with 54% of male gender. Overall, 86% of patients had anemia at the time of hospital discharge, with median discharge hemoglobin concentrations of 10.2 (9.1, 11.6) g/dL. In adjusted analyses, each 1 g/dL increase in 1-month hemoglobin recovery was associated with decreased instantaneous hazard for hospital readmission (HR 0.87 [95% CI 0.84-0.90]; p < 0.001) and lower mortality (HR 0.82 [95% CI 0.75-0.89]; p < 0.001) through one-year post-hospitalization. The results were consistent in multiple pre-defined sensitivity analyses. Impaired early post-hospitalization hemoglobin recovery is associated with inferior clinical outcomes in the first year of survival after critical illness. Additional investigations are warranted to evaluate these relationships.

OBJECTIVES: To assess disparities in hypoxemia detection by pulse oximetry across self-identified racial groups and associations with clinical outcomes. DESIGN: Observational cohort study from May 5, 2018, to December 31, 2020. SETTING: Three academic medical centers in the United States. PATIENTS: Adults greater than or equal to 18 years who self-identified as White, Black, Asian, or American Indian admitted to the ICU or undergoing surgery during inpatient hospitalization with simultaneous measurements of pulse oximetry-estimated oxygen saturation and arterial blood gas-derived oxygen saturation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Multivariable models were employed to assess the relationships between race, occult hypoxemia (i.e., arterial blood gas-derived oxygen saturation < 88% despite pulse oximetry-estimated oxygen saturation ≥ 92%), and clinical outcomes of hospital mortality and hospital-free days. One-hundred twenty-eight–thousand two-hundred eighty-five paired pulse oximetry-estimated oxygen saturation–arterial blood gas-derived oxygen saturation measurements were included from 26,603 patients. Pulse oximetry-estimated oxygen saturation on average overestimated arterial blood gas-derived oxygen saturation by 1.57% (1.54–1.61%). Black, Asian, and American Indian patients were more likely to experience occult hypoxemia during hospitalization (estimated probability 6.2% [5.1–7.6%], 6.6% [4.9–8.8%], and 6.6% [4.4–10.0%], respectively) compared with White patients (3.6% [3.4–3.8%]). Black patients had increased odds of occult hypoxemia compared with White patients after adjustment (odds ratio, 1.65; 1.28–2.14; p < 0.001). Differences in occult hypoxemia between Asian and American Indian patients compared with White patients were not significant after adjustment (odds ratio, 1.53; 0.95–2.47; p = 0.077 and odds ratio, 1.31; 0.80–2.16; p = 0.288, respectively). Occult hypoxemia was associated with increased odds of mortality in surgical (odds ratio, 2.96; 1.20–7.28; p = 0.019) and ICU patients (1.36; 1.03–1.80; p = 0.033). Occult hypoxemia was associated with fewer hospital-free days in surgical (–2.5 d [–3.9 to –1.2 d]; p < 0.001) but not ICU patients (0.4 d [–0.7 to 1.4 d]; p = 0.500). CONCLUSIONS: Occult hypoxemia is more common in Black patients compared with White patients and is associated with increased mortality, suggesting potentially important outcome implications for undetected hypoxemia. It is imperative to validate pulse oximetry with expanded racial inclusion.

Abstract Purpose: Young age at breast cancer diagnosis correlates with unfavorable clinicopathologic features and worse outcomes compared with older women. Understanding biological differences between breast tumors in young versus older women may lead to better therapeutic approaches for younger patients. Experimental Design: We identified 100 patients ≤35 years old at nonmetastatic breast cancer diagnosis who participated in the prospective Young Women's Breast Cancer Study cohort. Tumors were assigned a surrogate intrinsic subtype based on receptor status and grade. Whole-exome sequencing of tumor and germline samples was performed. Genomic alterations were compared with older women (≥45 years old) in The Cancer Genome Atlas, according to intrinsic subtype. Results: Ninety-three tumors from 92 patients were successfully sequenced. Median age was 32.5 years; 52.7% of tumors were hormone receptor-positive/HER2-negative, 28.0% HER2-positive, and 16.1% triple-negative. Comparison of young to older women (median age 61 years) with luminal A tumors (N = 28 young women) revealed three significant differences: PIK3CA alterations were more common in older patients, whereas GATA3 and ARID1A alterations were more common in young patients. No significant genomic differences were found comparing age groups in other intrinsic subtypes. Twenty-two patients (23.9%) in the Young Women's Study cohort carried a pathogenic germline variant, most commonly (13 patients, 14.1%) in BRCA1/2. Conclusions: Somatic alterations in three genes (PIK3CA, GATA3, and ARID1A) occur at different frequencies in young versus older women with luminal A breast cancer. Additional investigation of these genes and associated pathways could delineate biological susceptibilities and improve treatment options for young patients with breast cancer. See related commentary by Yehia and Eng, p. 2209

Purpose: Lower urinary tract symptoms among adult men can significantly impact quality of life. We evaluated complications based on prostate size following plasmakinetic enucleation of the prostate. Materials and Methods: Patients were grouped into the small prostate group (SPG, <75 g) and large prostate group (LPG, >75 g) based on preoperative imaging. Patient data on demographics, comorbidities, preoperative international prostate symptom score (IPSS), bother index (BI), prostate-specific antigen (PSA) if indicated, postvoid residual volume (PVR), indwelling catheter or self-catheterization status, and any prior surgical intervention were evaluated. Postoperative IPSS, BI, and PVR values were assessed at 6 weeks, 4 months, and yearly. Postoperative urge urinary incontinence (UUI), stress urinary incontinence (SUI), and pad use were assessed. Results: Between September 2015 and December 2020, 296 patients who underwent bipolar enucleation with minimum follow-up of 4 months were evaluated. Postoperative IPSS, BI, PVR, and PSA values at all time points were significantly decreased compared with preoperative values ( p < 0.05). There was no significant difference in the complications between groups. Univariable and multivariable analysis found that size <75 g was predictive of stricture formation and bladder neck contracture (BNC). UUI was more common at 6 weeks in the SPG, and SUI was more common at 6 weeks in the LPG, but no difference was noted at the 4-month and 1-year time points. Pad use was equal between the two groups at all time points. Conclusions: Plasmakinetic enucleation of the prostate provides an effective treatment option for prostates of all sizes; however, prostates <75 g have a higher rate of BNC and urethral strictures compared with those >75 g.