Citations

AbstractBackgroundAdvanced glycation end products (AGEs) are formed via the nonenzymatic glycation of sugars with amino acids. Two AGEs, Nε-(1-carboxymethyl)-L-Lysine (CML) and pentosidine, have been observed to be elevated in subjects suffering from a multitude of chronic disease states, and accumulation of these compounds may be related to the pathophysiology of disease progression and aging.MethodsWe describe here the development and validation of a specific and reproducible LC-MS/MS method to quantify CML and pentosidine in human serum with lower limits of quantitation of 75 ng/mL and 5 ng/mL, respectively. The analyte calibration curve exhibited excellent linearity at a range of 0–10 900 ng/mL for CML and 0–800 ng/mL for pentosidine. High-low linearity of 5 serum pairs was assessed, with a mean recovery of 103% (range 94—116%) for CML, and 104% (range 97—116%) for pentosidine.ResultsSerum concentrations of CML and pentosidine were quantified in 30 control and 30 subjects with chronic renal insufficiency. A significant increase in both analytes was observed in renal failure compared to control subjects (2.1-fold and 8.4-fold, respectively; P < 0.001 for both). In a separate cohort of 49 control versus 95 subjects with type 2 diabetes mellitus (T2DM), serum CML but not serum pentosidine, was significantly elevated in the T2DM patients, and CML was also correlated with glycemic control, as assessed by hemoglobin A1c (r = 0.34, P < 0.001).ConclusionsThese mass spectroscopy-based assays for serum CML and pentosidine should be useful in accurately evaluating circulating levels of these key AGEs in various disease states.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

Abstract In July 2022, these guidelines were reviewed by an expert work group convened by ASH. Review included limited searches for new evidence and discussion of the search results. Following this review, the ASH Committee on Quality agreed to continue monitoring the supporting evidence rather than revise or retire these guidelines at this time. Limited searches and expert review will be repeated annually going forward until these guidelines are revised or retired. Background: Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes. Objective: Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications. Methods: The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment. Results: The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload. Conclusions: The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.

Significance Statement The quality of a kidney obtained from a living donor is often inferred from the donor’s age, risk factors, and kidney function. Little is known about the influence of a donated kidney’s structural features on the risk of death-censored graft failure in the recipient. In an analysis of 2293 kidney donor-recipient pairs, the authors identified subclinical nephrosclerosis, larger nephron size (but not nephron number), and smaller medullary volume as structural predictors of death-censored graft failure that were independent of both donor and recipient clinical characteristics. These findings provide important insights into the factors that define the “intrinsic quality” of the living kidney donor graft at the time of donation, and support use of intraoperative biopsies to identify donor kidneys that are at higher risk for failure. Background Nephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear. Methods Our study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number. We also determined the death-censored risk of graft failure with each structural feature after adjusting for the predictive clinical characteristics of donor and recipient. Results The analysis involved 2293 donor-recipient pairs. Mean recipient follow-up was 6.3 years, during which 287 death-censored graft failures and 424 deaths occurred. Factors that predicted death-censored graft failure independent of both donor and recipient clinical characteristics included interstitial fibrosis/tubular atrophy, larger cortical nephron size (but not nephron number), and smaller medullary volume. In a subset with 12 biopsy section slides, arteriolar hyalinosis also predicted death-censored graft failure. Conclusions Subclinical nephrosclerosis, larger cortical nephron size, and smaller medullary volume in healthy donors modestly predict death-censored graft failure in the recipient, independent of donor or recipient clinical characteristics. These findings provide insights into a graft’s “intrinsic quality” at the time of donation, and further support the use of intraoperative biopsies to identify kidney grafts that are at higher risk for failure.

Aims Patients with hypertrophic obstructive cardiomyopathy (HOCM) have impaired exercise capacity. The gold standard therapy for patients with HOCM is septal myectomy surgery; however, changes in maximum oxygen uptake (VO2peak) following myectomy are variable, with VO2peak decreasing in some patients. Therefore, we evaluated changes in VO2peak following surgical myectomy to determine clinical predictors of those exhibiting decreased VO2peak post-myectomy. Methods HOCM patients ( N = 295) who performed symptom limited cardiopulmonary exercise testing prior to and following surgical myectomy were included for analysis. The VO2peak non-responder group ( n = 128) was defined as <0% change in VO2peak from pre- to post-myectomy. Step-wise regression models using demographics, clinical, and physiologic characteristics were created to determine predictors of hypertrophic cardiomyopathy patients in the VO2peak non-responder group. Results Independent predictors of the VO2peak non-responder group included higher pre-myectomy VO2peak (% predicted), older age, women, history of dyslipidemia, lack of cardiac rehabilitation enrollment, and lower body mass index (all p < 0.03). Forty-three (14.6%) patients reached the primary end-point of all-cause mortality during a median follow up of 11.25 years (interquartile range 6.94 to 16.40). After adjustment for age, sex, beta-blocker use, coronary artery disease history, and body mass index, the VO2peak non-responder group had greater risk of death compared with the VO2peak responder group (adjusted hazard ratio: 1.77, 95% confidence interval: 1.06–3.34, p = 0.01). Conclusion This large hypertrophic cardiomyopathy cohort demonstrated that demographic (i.e. female sex), lack of cardiac rehabilitation enrollment, and cardiovascular risk factors (i.e. history of dyslipidemia) are predictive of those patients that did not exhibit increases in VO2peak following septal myectomy surgery.

Abstract Despite increasing legalization and use of marijuana, there is no consensus among pediatric heart transplant institutions or providers regarding users' eligibility for cardiac transplant. We sent a survey to pediatric and ACHD transplant providers (physicians, surgeons, transplant coordinators, and pharmacists) assessing their current institution's policies and their personal opinions about marijuana use in patients being considered for heart transplantation. Of the respondents, 84% practice in the United States and Canada. Most providers (80%) care for both pediatric and ACHD patients. Respondents included cardiologists (77%) and surgeons (11%), with the remaining being coordinators and pharmacists. Most providers (73%) reported their institution had no policy regarding marijuana use in heart transplant candidates. Only 20% of respondents' institutions consider mode of consumption, with 87% and 53% approving of oral and transdermal routes, respectively, and only 7% approving of vaporized or smoked routes. While 73% of providers would consider illegal marijuana use an absolute/relative contraindication to heart transplant listing, the number decreases to 57% for legal recreational users and 21% for legal medical users. Most providers personally believe marijuana to be physically and mentally/emotionally harmful to pediatric patients (67% and 72%, respectively). Many institutions lack a policy regarding marijuana use in pediatric and ACHD heart transplant candidates, and there is considerable disagreement among providers on the best practice. With increasing legalization and use of marijuana, each institution will have to address this issue thoughtfully to continue to provide high‐quality, consistent, and equitable care for pediatric and ACHD heart transplant candidates.

OBJECTIVE The extent of resection has been shown to improve outcomes in patients with meningiomas. However, resection can be complicated by constraining local anatomy, leading to subtotal resections. An understanding of the natural history of residual tumors is necessary to better guide postsurgical management and minimize recurrence. This study seeks to identify predictors of recurrence and high growth rate following subtotal resection of intracranial meningiomas. METHODS Adult patients who underwent primary surgical resection of a WHO grade I meningioma at a tertiary care institution from 2007–2017 were retrospectively reviewed. Volumetric tumor measurements were made on patients with subtotal resections. Stepwise multivariate proportional hazards regression analyses were performed to identify factors associated with time to recurrence, as well as stepwise multivariate regression analyses to assess for factors associated with high postoperative growth rate. RESULTS Of the 141 patients (18%) who underwent radiographic subtotal resection of an intracranial meningioma during the reviewed period, 74 (52%) suffered a recurrence, in which the median (interquartile range, IQR) time to recurrence was 14 (IQR 6–34) months. Among those tumors subtotally resected, the median pre- and postoperative tumor volumes were 17.19 cm 3 (IQR 7.47–38.43 cm 3 ) and 2.31 cm 3 (IQR 0.98–5.16 cm 3 ), which corresponded to a percentage resection of 82% (IQR 68%–93%). Postoperatively, the median growth rate was 0.09 cm 3 /year (IQR 0–1.39 cm 3 /year). Factors associated with recurrence in multivariate analysis included preoperative tumor volume (hazard ratio [HR] 1.008,95% confidence interval [CI] 1.002–1.013, p = 0.008), falcine location (HR 2.215, 95% CI 1.179–4.161, p = 0.021), tentorial location (HR 2.410, 95% CI 1.203–4.829, p = 0.024), and African American race (HR 1.811, 95% CI 1.042–3.146, p = 0.044). Residual volume (RV) was associated with high absolute annual growth rate (odds ratio [OR] 1.175, 95% CI 1.078–1.280, p < 0.0001), with the maximum RV benefit at < 5 cm 3 (OR 4.056, 95% CI 1.675–9.822, p = 0.002). CONCLUSIONS By identifying predictors of recurrence and growth rate, this study helps identify potential patients with a high chance of recurrence following subtotal resection, which are those with large preoperative tumor volume, falcine location, tentorial location, and African American race. Higher RVs were associated with tumors with higher postoperative growth rates. Recurrences typically occurred 14 months after surgery.