Bailey, Kent R.

Background: The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer’s disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers. Objective: This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women. Methods: A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n = 29), transdermal 17β-estradiol (tE2; n = 21), or oral conjugated equine estrogen (oCEE; n = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1–42 (Aβ1–42), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs. Results: Only the number of microvesicles positive for Aβ1–42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p = 0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p = 0.045). Conclusion: Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition.

AbstractBackgroundThe fasting proinsulin to insulin ratio is elevated in people with type 2 diabetes and has been suggested as a marker of β‐cell health. However, its utility in discriminating between individuals with varying degrees of β‐cell dysfunction is unclear. Proinsulin has a very different half‐life to insulin and unlike insulin does not undergo hepatic extraction prior to reaching the systemic circulation. Given these limitations, we sought to examine the relationship between fasting and postprandial concentrations of β‐cell polypeptides (proinsulin, insulin and C‐peptide) in people with normal and impaired glucose tolerance in differing metabolic environments.DesignSubjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, free fatty acids were elevated (to induce insulin resistance) by infusion of Intralipid with heparin. Proinsulin to insulin and proinsulin to C‐peptide ratios were calculated for the 0‐, 30‐, 60‐ and 240‐minute time points. Insulin action (Si) and β‐cell responsivity (Φ) indices were calculated using the oral minimal model.ResultsThe fasting proinsulin to c‐peptide or fasting proinsulin to insulin ratios did not differ between groups and did not predict subsequent β‐cell responsivity to glucose during the glycerol or Intralipid study days in either group.ConclusionsAmong nondiabetic individuals, the fasting proinsulin to insulin ratio is not a useful marker of β‐cell function.

AbstractBackgroundThe critical‐period theory of menopausal hormone therapy (mHT) suggests that if menopausal hormone therapy begins shortly after menopause, it may have beneficial effects on brain structure and cognitive health. We investigated white matter integrity with diffusion tensor MRI (DTI) 3 years after the end of mHT trial in recently menopausal women who were randomized shortly after menopause.MethodParticipants of this study were enrolled in the Kronos Early Estrogen Prevention Study (aged 42–56 years; 5–36 months past menopause). Participants received the following treatments: 0.45 mg/d oral conjugated equine estrogen (oCEE, n=19); 50 μg/d transdermal 17β‐estradiol (tE2, n=22); or placebo (n=33) for 4 years. Oral progesterone (200 mg/d) was given to hormone therapy groups for 12 days each month. DTI was performed 3 years after the end of 4 years of hormone therapy (n=75), which corresponded to 7 years after randomization. Voxel‐based analysis was performed on DTI to evaluate fractional anisotropy (FA) and mean diffusivity (MD) differences between treatment groups (uncorrected p<0.001).ResultVoxel based analysis showed higher FA, a measure of white matter integrity, in the superior corona radiata, anterior limb of the internal capsule and splenium of the corpus callosum of participants treated with oCEE compared to placebo (p <0.001, Figure 1A). Furthermore, higher FA was observed in the superior corona radiata, anterior limb of internal capsule and thalamus in participants treated with tE2 compared to placebo (p <0.001, Figure 1B). There were no differences in FA findings between oCEE and tE2 groups, and no MD differences between treatments groups.ConclusionA relatively higher FA in a variety of white matter regions in the oCEE and tE2 groups compared to placebo suggest that mHT may have long‐term protective effects on white matter integrity. Previously, we had shown that women in the tE2 group preserved their dorsolateral prefrontal cortex volumes better than the placebo group over 7 years. Our findings suggest that the tracts that connect the dorsolateral prefrontal cortex and the thalamus such as the superior corona radiata and the anterior limb of internal capsule may particularly benefit from mHT.

Abstract Background/Introduction TAILOR-PCI is the largest cardiovascular genotype-based randomized trial (NCT#01742117) investigating whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes after percutaneous coronary intervention (PCI). The TAILOR-PCI Digital Sub-Study tests the feasibility of extending original follow-up of 1 year to 2 years using state-of-the-art digital solutions. Deep phenotyping acquired during a clinical trial can be leveraged by extending follow-up in an efficient and cost-effective manner using digital technology. Purpose Our objective is to describe onboarding and engagement of participants initially recruited in a large, pragmatic, international, multi-center clinical trial to a digital registry. Methods TAILOR-PCI participants, within 23 months of their index PCI, were invited by letters containing a URL to the Digital Sub-Study website (http://tailorpci.eurekaplatform.org). These invitations were followed by phone calls, if no response to the letter, to determine reason for non-participation. A NIH-funded direct-to-participant digital research platform (the Eureka Research Platform) was used to onboard, consent and enroll participants for the digital follow-up. Participants were asked to answer health-related surveys at fixed intervals using the Eureka mobile app and desktop platform. To capture hospitalizations, participants could enable geofencing to allow background location tracking, which triggered surveys if a hospitalization was detected. Result(s) Letters were mailed to 893 of 929 eligible participants across 22 sites in the United States and Canada leading to 226 homepage visits and 118 registrations. There were 107 consents (12.0% of invited; mean age: 66.4±9.0; 19 females [18%]): 47 (44%) participants consented after the letter, 36 (34%) consented after the 1st call and 24 (22%) consented after a 2nd call. Among those who consented, 100 were eligible (7 did not have a smartphone) 81 downloaded the study mobile app and 73 agreed for geofencing (Figure 1). Among the 722 invited participants who were surveyed, 354 declined participation: due to lack of time (146; 20.2%), lack of smartphone (125; 17.3%), difficulty understanding (41; 5.7%), concern about using smartphone (34; 4.7%), concern of data privacy (14; 1.9%), concerns of location tracking (6; 0.8%) and other reasons (57; 7.9%). Conclusion Extended follow-up of a clinical trial using a digital platform is feasible but uptake in this study population was limited largely due to lack of time or a smartphone among participants. Based on data from other digital studies, uptake may also have been limited since digital follow-up consent was not incorporated at the time of consent for the main trial. Figure 1. Onboarding of the digital substudy Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institute of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

Introduction: The impact of beta blocker use on surgical outcomes of cancer patients receiving immunotherapy is unknown. Hypothesis: Beta blocker use is associated with lower post-operative mortality in cancer patients on immunotherapy. Methods: We used an institutional Advanced Cohort Explorer to identify all patients who underwent any surgical procedure less than 90 days after receiving immunotherapy. Data on the procedure performed as well as the post-operative outcome were collected and analyzed per the pre-operative beta blocker use status. Results: A total of 233 patients underwent surgery between 09/2011-06/2019. Mean age was 64.7 years (range: 16-92). The most common cancer diagnoses were lung (48, 44.4%), melanoma (49, 45.4%) and kidney (11, 10.2%). Immunotherapy medications were pembrolizumab ( 127, 54.5%), nivolumab (51, 21.9%), ipilimumab (43, 18.5%), atezolizumab (11, 4.7%) and avelumab (1, 0.43%). Pre-operative beta blocker use was documented in 140 (60.1%) patients. Most common surgical procedures were skin resection (75, 32.1%), wound repair (47, 20.2%), vascular procedures (36, 15.5%), urethral procedures 16 (6.9%) and sentinel lymph node biopsies (10, 4.3%). The 30-day mortality rate was 10.3% (24 deaths). In a multi-variable logistic regression analysis, pre-operative use of beta blockers was associated with a lower risk of death within 30 days from surgery (OR 0.34, CI 0.13-0.87, P=0.024). 30-day mortality rates were higher in patients undergoing vascular (50%, 17 of 34) versus non-vascular (3.5%, 7 of 199) procedures (P<0.0001) in a Chi Square test. Conclusions: Beta blocker use is associated with a lower 30-day mortality rate after surgical procedures in cancer patients treated with immunotherapy. Further investigation is warranted.

Background Recent investigations suggest that inflammation and autoimmunity might have a role in the pathophysiology of atrial fibrillation (AF). Given that abnormal ventriculovascular coupling often coexists with AF, we hypothesize that autoimmune vasculitis plays a significant role in the pathogenetic mechanism of AF. Methods and Results A standardized retrospective population‐based case–control study was conducted to evaluate the association between autoimmune vasculitis and AF, and all‐cause mortality. The study included 8459 patients with a new diagnosis of AF and 8459 age‐, sex‐, and registration calendar year–matched controls in Olmsted County, Minnesota, between January 1, 1980 and December 31, 2010. The association of each clinical characteristic, diagnosis, and treatment was assessed using conditional logistic regression to account for the matched case–control study design. Cox proportional hazards regression models and Kaplan‐Meier curves were used to detect independent predictors of mortality and examine cumulative survival. Of a total of 16 918 patients (mean age 72.3+14.4 years; 48.7% women), 320 (1.9%) were diagnosed with autoimmune vasculitis before the index date during the 30‐year period. Among the cases, the prevalence of any autoimmune vasculitis was 2.3%, whereas the frequency of autoimmune vasculitis in controls was 1.5% ( P <0.001). After adjusting for potential confounders, the odds of autoimmune vasculitis in AF cases was 1.5 times higher than in controls (odds ratio, 1.47; 95% CI, 1.04–2.01; P =0.03). Patients with AF and autoimmune vasculitis had worse 5‐year survival than those without autoimmune vasculitis or AF (44.7% versus 77.2%; log‐rank P <0.001). Conclusions Autoimmune vasculitis is significantly associated with AF and independently confers worse survival. These observations may represent one mechanism linking autoimmunity and inflammation to the pathogenesis and prognosis of AF.

ABSTRACT Introduction: We hypothesize that a patient (pt) with accelerated thrombin generation, time to peak height (ttPeak), will have a greater odds of meeting critical administration threshold (CAT) criteria (> 3 packed red blood cell [pRBC] transfusions [Tx] per 60 min interval), within the first 24 h after injury, independent of international normalized ratio (INR). Methods: In a prospective cohort study, trauma patients were enrolled over a 4.5-year period and serial blood samples collected at various time points. We retrospectively stratified pts into three categories: CAT+, CAT− but receiving some pRBC Tx, receiving no Tx within the first 24 h. Blood collected prior to Tx was analyzed for thrombin generation parameters and prothrombin time (PT)/INR. Results: A total of 484 trauma pts were analyzed: injury severity score = 13 [7,22], age = 48 [28, 64] years, and 73% male. Fifty pts met criteria for CAT+, 64 pts CAT−, and 370 received no Tx. Risk factors for meeting CAT+: decreased arrival systolic blood pressure (OR 2.82 [2.17, 3.67]), increased INR (OR 2.09, [1.66, 2.62]) and decreased time to peak OR 2.27 [1.74, 2.95]). These variables remained independently associated with increased risk of requiring Tx in a multivariable logistic model, after adjusting for sex and trauma type. Conclusions: Pts in hemorrhagic shock, who meet CAT+ criteria, are characterized by accelerated thrombin generation. In our multivariable analysis, both ttPeak and PT/INR have a complementary role in predicting those injured patients who will require a high rate of Tx.

BackgroundAcute invasive fungal sinusitis (AIFS) is a potentially life‐threatening diagnosis in immunocompromised patients. Identifying patients who could benefit from evaluation and intervention can be challenging for referring providers and otolaryngologists alike. We aimed to develop and validate an accessible diagnostic tool to estimate the probability of AIFS.MethodsRetrospective chart review from 1999 to 2017 identified all patients evaluated for possible AIFS at a tertiary care center. AIFS was diagnosed by pathologic confirmation of fungal tissue angioinvasion. Stepwise selection and univariate logistic regression were used to screen risk factors for a multivariable predictive model. Model performance was assessed using Tukey's goodness‐of‐fit test and the area under the receiver operator characteristic curve (AUC). Model coefficients were internally validated using bootstrapping with 1000 iterations.ResultsA total of 283 patients (244 negative controls, 39 with AIFS) were included. Risk factors in our final diagnostic model included: fever ≥38°C (log‐odds ratio [LOR] 1.72; 95% CI, 0.53 to 2.90), unilateral facial swelling, pain, or erythema (LOR 2.84; 95% CI, 1.46 to 4.23), involvement of the orbit or pterygopalatine fossa on imaging (LOR 3.02; 95% CI, 1.78 to 4.26), and mucosal necrosis seen on endoscopy (LOR 5.52; 95% CI, 3.81 to 7.24), with p < 0.01 for all factors. The model had adequate goodness of fit (p > 0.05) and discrimination (AUC = 0.96).ConclusionWe present an internally validated diagnostic tool to stratify the risk for AIFS. The estimated risk may help determine which patients can be observed with serial nasal endoscopy, which ones could be biopsied, and which ones would benefit from immediate surgical intervention.

AbstractBackgroundWe compared the utility of existing and modified versions of high‐resolution manometry for diagnosing defecatory disorders (DD).MethodsIn 64 healthy and 136 constipated women, we compared left lateral (LL) and seated manometry, and analyzed with existing (ManoView™) and new methods, for discriminating between constipated patients with normal and prolonged rectal balloon expulsion time (BET). In both positions, the rectoanal gradient (RAG) and, for the new analysis, the pressure topography pattern during evacuation were used to discriminate between constipated patients without and with DD.Key ResultsThe BET was prolonged, suggestive of a DD, in 52 patients (38%). During evacuation, rectoanal pressures and the RAG were greater in the seated than the LL position (P≤.001). The new analysis identified 4 rectoanal pressure patterns. In the seated position, the BET was associated with the pattern (P=.0001), being prolonged in, respectively, 45%, 15%, 53%, and 0% of patients with minimal change, anal relaxation, paradoxical contraction, and transmission. Within each pattern, the RAG was greater (ie, less negative, P<.0001) in patients with a normal than a prolonged BET. Compared to the ManoView™ RAG in the LL position, the integrated analysis (ie, pattern and new RAG) in the LL position (P<.01) and the seated ManoView™ gradient (P=.02) were more effective for discriminating between constipated patients without and with DD.Conclusions & InferencesAnorectal HRM ideally should be performed in the more physiological seated position and analyzed by a two‐tier approach, which incorporates the overall pattern followed by the rectoanal gradient. These findings reinforce the utility of manometry for diagnosing DD.