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ABSTRACTAimPatients with autosomal dominant polycystic kidney disease (ADPKD) are at increased risk of premature mortality, morbidities and complications, which severely impair quality of life. However, patient‐centered outcomes are not consistently reported in trials in ADPKD, which can limit shared decision‐making. We aimed to identify outcomes important to patients and caregivers and the reasons for their priorities.MethodsNominal group technique was adopted involving patients with ADPKD and caregivers who were purposively selected from eight centres across Australia, France and the Republic of Korea. Participants identified, ranked and discussed outcomes for trials in ADPKD. We calculated an importance score (0–1) for each outcome and conducted thematic analyses.ResultsAcross 17 groups, 154 participants (121 patients, 33 caregivers) aged 19 to 78 (mean 54.5 years) identified 55 outcomes. The 10 highest ranked outcomes were: kidney function (importance score 0.36), end‐stage kidney disease (0.32), survival (0.21), cyst size/growth (0.20), cyst pain/bleeding (0.18), blood pressure (0.17), ability to work (0.16), cerebral aneurysm/stroke (0.14), mobility/physical function (0.12), and fatigue (0.12). Three themes were identified: threatening semblance of normality, inability to control and making sense of diverse risks.ConclusionFor patients with ADPKD and their caregivers, kidney function, delayed progression to end‐stage kidney disease and survival were the highest priorities, and were focused on achieving normality, and maintaining control over health and lifestyle. Implementing these patient‐important outcomes may improve the meaning and relevance of trials to inform clinical care in ADPKD.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety‐three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

Background: Although inflammation has been implicated in the pathogenesis of Alzheimer’s disease, the effects of systemic inflammation on brain amyloid deposition remain unclear. Objective: We examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) – PET Study. Methods: 339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), 16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome. Results: Our primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13–2.42), and among white (OR 1.33, 95% CI: 1.02–1.75), but not African American, participants ( p-interactions<0.05). Among male participants, those who maintained high CRP levels (≥3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91). Conclusions: Although our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution.

ABSTRACT Recent studies have demonstrated an effect of neurotrophins, particularly brain‐derived neurotrophic factor (BDNF), on airway contractility [ via increased airway smooth muscle (ASM) intracellular calcium [Ca 2+ ] i ] and remodeling (ASM proliferation and extracellular matrix formation) in the context of airway disease. In the present study, we examined the role of BDNF in allergen‐induced airway inflammation using 2 transgenic models: 1 ) tropomyosin‐related kinase B (TrkB) conditional knockin (TrkBKI) mice allowing for inducible, reversible disruption of BDNF receptor kinase activity by administration of 1NMPP1, a PP1 derivative, and 2) smooth muscle‐specific BDNF knockout (BDNF fl/fl /SMMHCll Cre/0 ) mice. Adult mice were intranasally challenged with PBS or mixed allergen ( Altemaria alternata, Aspergillus fumigatus , house dust mite, and ovalbumin) for 4 wk. Our data show that administration of 1NMPP1 in TrkBKI mice during the 4‐wk allergen challenge blunted airway hyper‐responsiveness (AHR) and reduced fibronectin mRNA expression in ASM layers but did not reduce inflammation per se . Smooth muscle‐specific deletion of BDNF reduced AHR and blunted airway fibrosis but did not significantly alter airway inflammation. Together, our novel data indicate that TrkB signaling is a key modulator of AHR and that smooth muscle‐derived BDNF mediates these effects during allergic airway inflammation.—Britt, R. D., Jr., Thompson, M. A., Wicher, S. A., Manlove, L. J., Roesler, A., Fang, Y.‐H., Roos, C., Smith, L., Miller, J. D., Pabelick, C. M., Prakash, Y. S. Smooth muscle brain‐derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma. FASEB J. 33, 3024–3034 (2019). www.fasebj.org

Abstract Infection is a common cause of death in patients with advanced cirrhosis. We aimed to develop a predictive model in Child–Turcotte–Pugh (CTP) class C cirrhotics hospitalized with infection for optimizing treatment and improving outcomes. Clinical information was retrospectively abstracted from 244 patients at Tianjin Third Central Hospital, China (cohort 1). Factors associated with mortality were determined using logistic regression. The model for predicting 90-day mortality was then constructed by decision tree analysis. The model was further validated in 91 patients at Mayo Clinic, Rochester, MN (cohort 2) and 82 patients at Seoul St. Mary's Hospital, Korea (cohort 3). The predictive performance of the model was compared with that of the CTP, model for end-stage liver disease (MELD), MELD-Na, Chronic Liver Failure–Sequential Organ Failure Assessment, and the North American consortium for the Study of End-stage Liver Disease (NACSELD) models. The 3-month mortality was 58%, 58%, and 54% in cohort 1, 2, and 3, respectively. In cohort 1, respiratory failure, renal failure, international normalized ratio, total bilirubin, and neutrophil percentage were determinants of 3-month mortality, with odds ratios of 16.6, 3.3, 2.0, 1.1, and 1.03, respectively (P < .05). These parameters were incorporated into the decision tree model, yielding area under receiver operating characteristic (AUROC) of 0.804. The model had excellent reproducibility in the U.S. (AUROC 0.808) and Korea cohort (AUROC 0.809). The proposed model has the highest AUROC and best Youden index of 0.488 and greatest overall correctness of 75%, compared with other models evaluated. The proposed model reliably predicts survival of advanced cirrhotics with infection in both Asian and U.S. populations.

Background: Increasing evidence points to intracranial atherosclerosis as a risk factor not only for stroke but also for dementia, but whether it is linked to Alzheimer’s disease-specific pathology itself is less understood. In the community-based Atherosclerosis Risk in Communities (ARIC) study, we evaluated the cross-sectional association between intracranial atherosclerosis and cerebral amyloid deposition, in nondemented participants. Methods: In 2011-2014, a subset of participants from the ARIC Neurocognitive Study underwent both a brain MRI, including high-resolution vessel wall imaging, and florbetapir PET, as a marker of amyloid deposition. We analyzed the association between elevated amyloid (defined as a global cortical florbetapir standardized uptake value ratio (SUVR)>1.2) and intracranial arterial plaque presence, frequency, and extent of stenosis, with adjustment for demographic and vascular risk factors. We tested effect modification by APOE ε4 genotype. Results: In 300 participants (mean age of 76y, 44% African-American, 56% female, 31% carriers of at least one APOE ε4 allele), intracranial plaque was found in 105 (35%) participants. Mean SUVR was higher in individuals with vs without plaque (1.34 ± 0.29 vs 1.27 ± 0.23, p=0.03). In adjusted models, plaque presence was not associated significantly with elevated SUVR in the total sample, nor was number of plaques. Associations between plaque presence and extent were generally stronger in APOE ε4 carriers than noncarriers (p<0.05 for interaction for some plaque features; see Table). Conclusions: Although intracranial arterial plaque or stenosis was not definitively associated with brain amyloid in this sample of nondemented older adults, associations with brain amyloid appeared stronger in carriers of an APOE ε4 allele, consistent with studies demonstrating a similar relationship as that seen with other more traditionally measured vascular risk factors.