Citations

LINKED CONTENTThis article is linked to Grover et al and Elwing & Sayuk papers. To view these articles, visit https://doi.org/10.1111/apt.16591 and https://doi.org/10.1111/apt.16603

Background Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results ICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

SummaryBackgroundIrritable bowel syndrome (IBS) patients often experience meal‐associated symptoms. However, the underlying mechanisms are unclear.AimTo determine small intestinal mechanisms of lipid‐induced symptoms and rectal hypersensitivity in IBSMethodsWe recruited 26 IBS patients (12 IBS‐C, 14 IBS‐D) and 15 healthy volunteers (HV). In vivo permeability was assessed using saccharide excretion assay. Rectal sensitivity was assessed using a barostat before and after small bowel lipid infusion; symptoms were assessed throughout. Next, an extended upper endoscopy with probe‐based confocal laser endomicroscopy (pCLE) was performed with changes induced by lipids. Duodenal and jejunal mucosal biopsies were obtained for transcriptomics.ResultsFollowing lipid infusion, a higher proportion of HV than IBS patients reported no pain, no nausea, no fullness and no urgency (P < 0.05 for all). In a model adjusted for sex and anxiety, IBS‐C and IBS‐D patients had lower thresholds for first rectal sensation (P = 0.0007) and pain (P = 0.004) than HV. In vivo small intestinal permeability and mean pCLE scores were similar between IBS patients and HV. Post‐lipid, pCLE scores were higher than pre‐lipid but were not different between groups. Baseline duodenal transient receptor potential vanilloid (TRPV) 1 and 3 expression was increased in IBS‐D, and TRPV3 in IBS‐C. Duodenal TRPV1 expression correlated with abdominal pain (r = 0.51, FDR = 0.01), and inversely with first rectal sensation (r = −0.48, FDR = 0.01) and pain (r = −0.41, FDR = 0.02) thresholds.ConclusionLipid infusion elicits a greater symptom response in IBS patients than HV, which is associated with small intestinal expression of TRPV channels. TRPV‐mediated small intestinal chemosensitivity may mediate post‐meal symptoms in IBS.

How to catch a dynamic state AMP-activated protein kinase (AMPK) is a key sensor of energy status in eukaryotes. Its dynamic structure is regulated by allosteric factors including phosphorylation and binding of nucleotides and metabolites. Yan et al. developed conformation-specific antibodies that trap AMPK in a fully inactive state that has experienced a large, domain-level rotation. Biophysical experiments in cells and in vitro are consistent with the structural work and support a model in which the activation loop is fully exposed in the completely inactive, dephosphorylated state. These structures inform our understanding of the complex allosteric behavior in this crucial metabolic regulator. Science , abe7565, this issue p. 413

Abstract High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma. Significance: These findings demonstrate a novel role for DLST in neuroblastoma aggression and identify the OXPHOS inhibitor IACS-010759 as a potential therapeutic strategy for this deadly disease.

Objectives: Patient involvement in the choice of whether to undergo emergency department observation unit (EDOU) admission and cardiac stress testing or follow-up with a physician could increase knowledge, increase satisfaction, and safely decrease resource use. We test this hypothesis in a randomized trial. Methods: We developed and tested Chest Pain Choice, a decision aid that communicates the pre-test probability of an acute coronary syndrome (ACS) within 45 days and makes management options (EDOU admission and stress testing or 24-72 hr follow-up with a physician) explicit to the patient. Patients with a primary complaint of chest pain and no known coronary artery disease who were being considered for EDOU admission were eligible. Patient-clinician pairs were randomized to intervention (decision aid plus risk estimate) or usual care (no decision aid, no risk estimate). We used patient surveys and 30-day phone follow-up to assess the primary outcome (patient knowledge regarding their short-term risk for ACS), patient satisfaction, safety (delayed or missed ACS defined as acute myocardial infarction, ventricular arrhythmia, cardiogenic shock, or cardiac/unknown death), and resource use. Analysis was by intention to treat. Results: The 205 patients had the following characteristics: mean age (SD) 54.7 (11.8), 59% female, 36% history of HTN and 10% history of diabetes. Compared with usual care patients (n=104), patients receiving the decision aid (n=101) less frequently decided to be admitted to the EDOU for cardiac stress testing (58% vs 77%, absolute difference = 19%, 95% CI 6, 31), had a lower rate of stress testing (74% vs 90%, absolute difference = 16%, 95% CI 6, 26), greater knowledge of their exact pre-test probability of ACS (25% vs 1%, absolute difference = 24%, 95% CI 15, 33) and reported greater satisfaction with the decision-making process (strongly agree: 61% vs 40%, absolute difference = 21%, 95% CI 7, 33). There were no cases of delayed or missed ACS in either arm. Conclusion: Use of a decision aid in ED chest pain patients increased knowledge, increased satisfaction, and safely decreased resource use. In an era of health care reform, shared decision-making is a promising approach that may both increase patient engagement and decrease resource use.Funding(This research has received full or partial funding support from the American Heart Association, National Center)

Importance: Up to 10% of patients with acute myocardial infarction (AMI) have right bundle branch block (RBBB), and RBBB has been associated with a higher risk of mortality. We performed a systematic review and meta-analysis to determine the prognostic significance of RBBB for patients with AMI. Acute coronary syndrome (ACS) Data Sources: We have systematically searched Ovid, Scopus and Web of Science through January 2014. Study Selection: Reviewers working independently and in duplicate screened all eligible abstracts, selecting studies that described all-cause mortality or cardiovascular death in patients with RBBB and suspected ACS. We excluded studies that reported unadjusted outcomes. Knowledge synthesis: We pooled risk ratio with hazard ratio in studies reporting those outcomes. When reported, odds ratio was converted into risk ratio using reported event rate in each study’s unexposed -read: non RBBB- group. Main Outcomes: All-cause mortality and cardiovascular mortality (death). Results: Eighteen studies were found that reported eligible data. All were observational studies, involving over 89,000 patients. In short-term follow up (up to 30 days), RBBB on presentation was associated with higher all-cause mortality rate, compared to patients without RBBB (RR 2.23, 95% CI 1.76-2.82). There was a trend for higher mortality at long-term follow up (range: 6 months-16 years) that did not reach statistical significance (RR 1.45, 95% CI 0.93-2.25). Figure-1 demonstrates the forest plot. Risk of bias was assessed with the Newcastle-Ottawa scale and majority of included studied were deemed moderate to high quality. Conclusion and Relevance: RBBB is associated with a more than 2-fold higher risk of all-cause mortality in patients with AMI at 30 days follow up. Patients with AMI and RBBB represent a high risk group for adverse outcomes. A sentence on the differential findings for new vs. old RBBB and association with outcomes could follow here.

Importance: Right bundle branch block (RBBB) is observed in approximately 5-14% of patients with heart failure (HF). Multiple observational studies have reported the association of RBBB with clinical outcomes in patients with HF. We performed a systematic review and meta-analysis to determine the prognostic significance of RBBB for patients with HF. Data Sources: We have systematically searched MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science and Scopus through January 2014. Study Selection: Reviewers working independently and in duplicate screened all eligible abstracts that described all cause or cardiovascular mortality in patients with RBBB and HF. We excluded studies that reported unadjusted outcome, i.e.: unadjusted event rates. Knowledge synthesis: We pooled reported risk ratio and hazard ratio. Main Outcomes: All-cause mortality and cardiovascular mortality (death). Results: We found 12 relevant observational studies enrolling over 38,000 patients. Risk of bias was assessed using the Newcastle-Ottawa Scale. Included studies had at least a moderate quality. Seven of those evaluated prognosis of patients with RBBB and heart failure. After a mean follow up period of 2.5 years (range: 1-5 years), RBBB was associated with a statistically significant increased risk of all-cause mortality compared to patients with heart failure but no BBB, RR 1.27, 95% CI (1.08-1.50), Figure 1. The other 5 studies evaluated CHF patients receiving cardiac resynchronization therapy (CRT), comparing outcomes of patients with RBBB to those with LBBB. After a mean f/u period of 3 years, patients with RBBB were once again found to have an increased risk of all-cause mortality, RR 1.45, 95% CI 1.12-1.89. Conclusion and Relevance: RBBB in patients with HF is associated with higher all-cause mortality in comparison to patients without inter-ventricular conduction defects, as well as LBBB patients in patients undergoing CRT setting.