Citations

Abstract Background Celiac disease (CeD) has an estimated prevalence of 1%–3%. The classical clinical presentation is malabsorption, but now patients may present with more subtle symptoms such as constipation, osteoporosis, or iron deficiency anemia. Children may also present with poor growth. CeD has a strong genetic component, and high-risk groups include first-degree relatives with CeD, patients with co-existing autoimmune diseases, and patients with chromosomal aberrations. Content Diagnostic tests for CeD include duodenal histology, serology, and genetic testing. Duodenal histology has traditionally been the gold standard of diagnosis. However, serological tests, especially IgA tissue transglutaminase antibodies (TTG-IgA), are widely used and diagnostic algorithms are based primarily on TTG-IgA as a starting point. Human leukocyte antigen typing may also be incorporated to determine genetic risk for CeD. Guidelines for children endorse biopsy avoidance provided high levels of TTG-IgA, with diagnostic accuracy being comparable to duodenal biopsy. Confirmation may be achieved by identifying IgA endomysial antibodies in a separate blood sample. Subjects with low positive TTG-IgA levels and subjects with IgA deficiency need a biopsy to establish a diagnosis of CeD. The clinical follow-up of CeD usually includes a repeat TTG-IgA examination. In adults, healing may be delayed or incomplete, and a rare consequence of refractory celiac disease is transformation to enteric T-cell lymphoma. Summary Laboratory testing, in particular TTG-IgA, plays a central role in the diagnosis and has an accuracy comparable to histology. Diagnostic algorithms utilizing laboratory testing are critical for the development of novel strategies to improve diagnosis.

Background Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Methods and Results We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM‐HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity–Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β‐2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein–outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), or high‐sensitivity cardiac troponin. Conclusions Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON‐HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. Registration URL: https://www.clinicaltrials.gov ; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

AbstractIn academia, particularly in science, technology, engineering, and mathematics (STEM), writing accountability groups have emerged as an effective technique to enhance writing productivity by offering structure, increasing the commitment to write, and fostering social commitment. The rapid development of technology has introduced a new challenge across STEM fields: technostress, where individuals face heightened stress due to novel applications of technology. To address this, we introduce Technology Accountability Groups (TAGs), a novel form of community support for graduate students and faculty. TAGs are tailored to help individuals navigate technological innovations, alleviate technostress, acquire new skills, motivate, and connect with leaders in the field. This paper presents a framework for establishing, implementing, and sustaining TAGs in STEM.

4017 Background: Combined MEK inhibition (MEKi) and PD-L1 blockade significantly improved progression-free survival (PFS) versus PD-L1 monotherapy in patients with advanced biliary tract cancer (BTC) following first-line chemotherapy (NCT03201458). Further study has shown MEKi enhances tumor immunogenicity but impairs host T cell activation/priming. The addition of immune agonists, e.g. a CD27 agonist, can rescue T cell function in the setting of systemic MEKi in vivo and may be an effective strategy to optimize MEKi’s immunomodulatory potential when used in combination with checkpoint blockade. Methods: We conducted a randomized ph 2 trial (NCT04941287) evaluating Atezolizumab in combination with the CD27 immune agonist (CDX-1127 [Varlilumab]) with or without the addition of a MEKi (Cobimetinib) in patients with unresectable, previously treated, BTC. Adults with pathologically-confirmed BTC, s/p at least 1 prior line (no more than 2) of systemic therapy, measurable disease, and ECOG PS ≤1 were enrolled. Patients who had received previous PD-[L]1 were eligible. The study was planned for 64 evaluable subjects randomized in a 1:1 ratio, stratified by BTC site, to either AV (Atezolizumab [840mg IV days 1,15])+ Varlilumab [3mg/kg IV days 1, 15]) or CAV (Cobimetinib [60mg oral daily days 1-21, off 22-28] + Atezolizumab + Varlilumab). Overall response rate (ORR) and PFS were co-primary endpoints. The primary correlative outcome was treatment-related changes in CD8+ infiltrating T cells. Results: A preplanned interim analysis based on objective response rates did not meet the threshold for continuance in either treatment arm, so the trial was closed early for futility. In total, 57 patients were enrolled (n = 29 [CAV], n = 28 [AV], 67% had intrahepatic cholangiocarcinoma, and 33% had received previous PD-[L]1. Both CAV and AV regimens were well-tolerated without new safety signals. Adding CDX-1127 did not appear to meaningful increase immunotoxicity beyond established PD-L1 toxicity profiles. ORR was 0% (CAV) and 4% (AV). With a median follow up time of 6.2 months, median PFS was 2.2 (CAV) and 1.8 (AV) months (HR 0.71 [0.40,1.25]). In PD[L]1-experienced patients, median PFS was 3.6 (CAV) and 1.7 (AV) months (HR 0.44 [0.14,1.33]). Median OS was 10.2 (CAV) and 6.1 (AV) months (HR 0.76 [0.37,1.55]). In PD[L]1-experienced patients, median OS was 6.4 (CAV) and 4.4 (AV) months for CAV and AV (HR 0.68 [0.19,2.42]). Primary correlative endpoint and updated survival will be reported at time of meeting. Conclusions: The combination of Atezolizumab and Varlilumab with or without Cobimetinib was safe but did not improve clinical outcomes in advanced stage BTC patients treated in later lines. Though not statistically significant, treatment with CAV demonstrated numerically favorable PFS/OS compared AV among immunotherapy-experienced patients. Clinical trial information: NCT03201458 .

Background: Causal graphs are an important tool for covariate selection but there is limited applied research on how best to create them. Here, we used data from the Coronary Drug Project trial to assess a range of approaches to directed acyclic graph (DAG) creation. We focused on the effect of adherence on mortality in the placebo arm, since the true causal effect is believed with a high degree of certainty. Methods: We created DAGs for the effect of placebo adherence on mortality using different approaches for identifying variables and links to include or exclude. For each DAG, we identified minimal adjustment sets of covariates for estimating our causal effect of interest and applied these to analyses of the Coronary Drug Project data. Results: When we used only baseline covariate values to estimate the cumulative effect of placebo adherence on mortality, all adjustment sets performed similarly. The specific choice of covariates had minimal effect on these (biased) point estimates, but including nonconfounding prognostic factors resulted in smaller variance estimates. When we additionally adjusted for time-varying covariates of adherence using inverse probability weighting, covariates identified from the DAG created by focusing on prognostic factors performed best. Conclusion: Theoretical advice on covariate selection suggests that including prognostic factors that are not exposure predictors can reduce variance without increasing bias. In contrast, for exposure predictors that are not prognostic factors, inclusion may result in less bias control. Our results empirically confirm this advice. We recommend that hand-creating DAGs begin with the identification of all potential outcome prognostic factors.

Abstract Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer’s Disease Neuroimaging Initiative, n = 53) and who had Alzheimer’s disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer’s Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer’s disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.

AbstractObjectivesThere remains an unmet need for a laser‐enabled tissue coring device that can effectively improve face and neck skin laxity and rhytides. We investigate a novel 2910 nm erbium‐doped fluoride glass fiber laser (2910 nm fiber laser) (UltraClear; Acclaro Medical) for laser‐coring of submental tissue.MethodsFive subjects, Glogau scale III−IV, were treated with a single pulse of the laser‐coring mode of the 2910 nm fiber laser in the submentum. A 4 mm punch biopsy was immediately performed. Biopsy specimens were sectioned and stained with hematoxylin and eosin and placed on glass slides. All sections were reviewed, and sections containing the center of the transected core were analyzed for depth and diameter of the ablative microchannel and width of the surrounding zone of coagulation.ResultsA total of 15 intact micro‐cores were analyzed. Histological analysis revealed an average ± standard deviation microchannel diameter of 242.5 ± 65.2 µm, an average ablative depth of 980 ± 318.8 µm, and an average zone of coagulation of 104 ± 32 µm.ConclusionsLaser‐enabled tissue coring with a novel 2910 nm fiber laser can safely achieve a wider microchannel diameter with ablative depth extending to the mid and deep dermis, which has the potential for collagen contraction and tissue tightening. Laser‐coring to this ablation diameter and depth and with the surrounding zone of coagulation was found to be safe without adverse effects of post‐inflammatory erythema or scarring in our study.

Abstract Rationale Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM (P < 0.05). Conclusions Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.

Abstract Background and Aims Non‐invasive tests (NITs) are underutilized for diagnosis and risk stratification in metabolic dysfunction‐associated steatotic liver disease (MASLD), despite good accuracy. This study aimed to identify challenges and barriers to the use of NITs in clinical practice. Methods We conducted a qualitative exploratory study in Germany, Italy, United Kingdom and United States. Phase 1 participants (primary care physicians, hepatologists, diabetologists, researchers, healthcare administrators, payers and patient advocates; n = 29) were interviewed. Phase 2 participants (experts in MASLD; n = 8) took part in a group discussion to validate and expand on Phase 1 findings. Finally, we triangulated perspectives in a hybrid deductive/inductive thematic analysis. Results Four themes hindering the use of NITs emerged: (1) limited knowledge and awareness; (2) unclear referral pathways for patients affected by liver conditions; (3) uncertainty over the value of NITs in monitoring and managing liver diseases; and (4) challenges justifying system‐level reimbursement. Through these themes, participants perceived a stigma associated with liver diseases, and primary care physicians generally lacked awareness, adequate knowledge and skills to use recommended NITs. We identified uncertainties over the results of NITs, specifically to guide lifestyle intervention or to identify patients that should be referred to a specialist. Participants indicated an ongoing need for research and development to improve the prognostic value of NITs and communicating their cost‐effectiveness to payers. Conclusions This qualitative study suggests that use of NITs for MASLD is limited due to several individual and system‐level barriers. Multi‐level interventions are likely required to address these barriers.