Citations

Background: DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study. Methods: We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout. Results: We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan. Conclusions: Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.

65 Background: There is consensus that the proportion of the average-risk US population up-to-date with CRC screening (58-65%) is insufficient. However, estimates of average risk CRC screening rates are inconsistent and impacted by inclusion of higher-risk individuals, and differing study designs. Accurate measurement of population screening rates is key to addressing gaps in care and assessing the impact of newer CRC screening tests. Methods: The study included individuals aged 50-75 years in a large de-identified claims database, with continuous enrollment during year of analysis, and a variable length baseline enrollment of 1-10 years. Average-risk designation excluded higher risk diagnoses (CRC familial syndromes, colorectal polyp or history of colorectal polyp, history of/current CRC, family history of gastrointestinal cancer, and inflammatory bowel disease). Up-to-date status was assessed within guideline-based time periods: colonoscopy (10 years); FIT or FOBT (annually); mt-sDNA (3 years); flexible sigmoidoscopy/CT colonography (5 years). Analyses assessed the proportion estimated as up-to-date and examined the sensitivity to: a) patient population (average-risk only vs. including higher-risk); b) study design (yearly cross-sectional vs. cohort of 50-year-old patients; c) methods (percent in patients with 10 years of enrollment vs. Kaplan Meier (KM) of censored variable pre-screening period). Results: The cross-sectional analysis average-risk population included 5.3 million individuals. Estimates of the proportion of those up-to-date with screening guidelines for average-risk patients varied by study design, population, and estimation method. KM estimates among the average-risk population (50-75) showed 49-50% were up-to-date in each calendar year. Including higher-risk patients in the KM analysis resulted in 70% up-to-date among the mixed average+higher-risk population. Using a cohort study design (average-risk patients aged 60 with 10 years of baseline data), 65% were up-to-date by age 60. Conclusions: In the base case analysis only half of average risk individuals were up-to-date with CRC screening, a rate lower than typically cited. Sensitivity analyses resulted in substantially different estimates and demonstrate the importance of clearly communicating the methodology used to define the study population. Higher rates quoted in the lay press and medical publications may be based on mixed populations of average+higher-risk individuals or on study designs that do not represent the full population at risk.

60 Background: Several colorectal cancer (CRC) screening options are considered in guidelines for individuals at average-risk (IAR). These options differ in aspects such as invasiveness, recommended frequency, and precision that need to be compared and weighed. This study elicited and compared the relative importance that physicians and IAR place on these screening aspects. Methods: Primary care physicians [PCPs] and gastroenterologists [GIs] who recommended/performed ≥1 screening one month prior to study and adult IAR completed a discrete choice experiment (DCE). Participants repeatedly chose between screening tests described by type of test, frequency, true-positive (TP), true-negative (TN), and adenoma TP (physicians only). The instrument was tested in qualitative (physicians: n=6; IAR: n=6) and quantitative pilots (physicians: n=100; IAR: n=202). A mixed logit model was used to estimate relative attribute importance (RAI) and predicted choice probabilities for colonoscopy, multi-target stool DNA (mt-sDNA), fecal immunochemical test (FIT), and methylated septin 9 (mSEPT9) blood test. Generalizability to the population was confirmed. Results: 1,249 IAR and 400 physicians participated. IAR were 46% male and the mean age was 58.9. Physicians were 79% male and their mean age was 53.4. Preferences were most affected by TP rates (IAR RAI=58%; physicians RAI=42%). Physicians also placed high importance (RAI=41%) on adenoma TP rates. TN rates (IAR RAI=33%; physician RAI=9%), frequency (IAR RAI=6%; physician RAI=2%) and type (IAR RAI=4%; physician RAI=6%) were less important. Despite both IAR and physicians placing most importance on precision, preferences for screening modalities differed. On average, physicians preferred colonoscopy, while IAR preferred mt-sDNA over colonoscopy (p<0.001). Both preferred mt-sDNA and colonoscopy over FIT (p<0.001), with a mSEPT9 blood test being least preferred (p<0.001). Preferences of IAR were heterogeneous with individuals who underwent colonoscopy or sigmoidoscopy screening preferring colonoscopy and the rest preferring mt-sDNA (p<0.001). Conclusions: While both GI and PCPs overwhelmingly preferred colonoscopy, preferences of IAR were heterogenous, with mt-sDNA being preferred on average other modalities. Offering choices in addition to colonoscopy could improve screening uptake. [Table: see text]

Objective: We aimed to discern clinico-demographic predictors of large (≥8) tracheostomy tube size placement, and, secondarily, to assess the effect of large tracheostomy tube size and other parameters on odds of decannulation before hospital discharge. Summary of Background Data: Factors determining choice of tracheostomy tube size are not well-characterized in the current literature, despite evidence linking large tracheostomy tube size with posttracheotomy tracheal stenosis. The effect of tracheostomy tube size on timing of decannulation is also unknown, an important consideration given reported associations between endotracheal tube size and probability of failed extubation. Methods: We collected information pertaining to patients who underwent tracheotomy at 1 of 10 U.S. health care institutions between 2010 and 2019. Tracheostomy tube size was dichotomized (≥8 and <8). Multivariable logistic regression models were fit to identify predictors of (1) large tracheostomy tube size, and (2) decannulation before hospital discharge. Results: The study included 5307 patients, including 2797 (52.7%) in the large tracheostomy cohort. Patient height (odds ratio [OR] = 1.060 per inch; 95% confidence interval [CI] 1.041–1.070) and obesity (1.37; 95% CI 1.1891.579) were associated with greater odds of large tracheostomy tube; otolaryngology performing the tracheotomy was associated with significantly lower odds of large tracheostomy tube (OR = 0.155; 95% CI 0.131–0.184). Large tracheostomy tube size (OR = 1.036; 95% CI 0.885–1.213) did not affect odds of decannulation. Conclusions: Obesity was linked with increased likelihood of large tracheostomy tube size, independent of patient height. Probability of decannulation before hospital discharge is influenced by multiple patient-centric factors, but not by size of tracheostomy tube.

AbstractAchievement of a complete response (CR) in multiple myeloma (MM) correlates with improvement in survival outcomes; however, its impact on prognostic variables at baseline outside of clinical trial settings is not well described. We sought to determine the impact of achieving a CR within 2 years from diagnosis, its effect on the prognostic value of fluorescence in situ hybridization (FISH) and International Staging System (ISS) risk, and examined additional predictors of outcome among those achieving a CR in a routine clinical setting. We evaluated 1869 newly diagnosed MM patients who had ≥ 2 monoclonal protein immunofixation studies in the serum and urine available within 24 months from diagnosis, categorizing those with ≥ 2 negative serum and urine immunofixations as achieving CR. With a landmark at 24 months, median progression‐free survival (PFS) for CR versus non‐CR patients was 29.8 versus 20.9 months (p ≤ .0002); median overall survival (OS) was 104 versus 70 months (p < .0001). The impact of achieving a CR was retained after adjusting for FISH, ISS, sex, transplant status, and involved heavy chain. Baseline FISH and ISS stage were not associated with PFS or OS among patients achieving a CR. The following variables were found as predictors of inferior OS within the CR cohort: age > 75 years, male gender, hypoalbuminemia, and non‐immunoglobulin G involved heavy chain. Our study confirms that achievement of CR within 2 years from diagnosis is associated with improvement in survival outcomes and neutralization of the impact of FISH and ISS risk, thereby confirming observations from the clinical trial setting among a clinical practice cohort.

Abstract Introduction The National Institute on Aging Late‐Onset Alzheimer's Disease Family Based Study (NIA‐LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD). Methods Recruitment focused on families with two living affected siblings and a third first‐degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E ( APOE ) genotypes, genome‐wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families. Results APOE genotype modified the age‐at‐onset in many large families. Novel variants and known variants associated with early‐ and late‐onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics. Discussion The NIA‐LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age‐at‐onset provides opportunities to investigate the complexity of familial AD.

Abstract Background Nocardia more commonly causes infection in immunocompromised individuals, notably with a relapse rate of approximately 5%. Solid organ transplant recipients will often receive post-treatment prophylaxis as the underlying immunosuppression is unable to be completely removed. However, data supporting this practice is sparse. We sought to evaluate recurrence of nocardiosis in solid organ transplant recipients, specifically evaluating the role of post-treatment prophylaxis. Methods We conducted a retrospective cohort study of solid organ transplant (SOT) recipients at our medical center diagnosed with nocardiosis from 2000 through 2020. We included adult SOT recipients who completed their course of Nocardia therapy. Patients were excluded if they had not yet completed therapy, died prior to completing therapy, or there was no post-therapy follow-up. The primary outcome was Nocardia recurrence. Continuous variables were presented as mean or median with interquartile range (IQR). Results 108 patients meeting inclusion criteria were analyzed. 72 (66.7%) were male and median age was 60 years (IQR 52-65). Most common SOT types were kidney (47.2%), heart (17.6%), kidney-pancreas (11.1%), and lung (11.1%). Median time from transplantation to diagnosis of nocardiosis was 396 days (IQR 154-1071). Most common sites of infection were lung (88.0%), skin (16.7%), brain (13.9%), and blood (6.5%). Multi-organ infection was present in 22.2% and 24.1% were on trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis at diagnosis. Post-treatment prophylaxis was utilized in 55 (50.9%) patients (Table 1). TMP-SMX was the most common prophylaxis (87.3%; Figure 1). Four patients experienced Nocardia recurrence, 2 of which were receiving TMP-SMX prophylaxis at time of relapse (Table 2). These were dosed as double strength tablet daily and weekly, respectively. Median time from treatment completion to relapse was 255.5 days (range 107-871). Figure 1. Post-Treatment Prophylaxis Regimens for Nocardia in 55 Patients Conclusion Nocardia recurrence in solid organ transplant recipients is an uncommon occurrence. Double strength daily and weekly TMP-SMX prophylaxis does not appear to be entirely protective and relapse may be dependent upon other factors such as primary treatment length. Further study into the use of post-treatment prophylaxis is warranted. Disclosures All Authors: No reported disclosures