Citations

Significance Cardiac arrhythmias often occur in heart failure (HF) patients, but drug therapies using selective ion channel blockers have failed clinical trials and effective drug therapies remain elusive. Here we systematically study the major ionic currents during the cardiac action potential (AP) and arrhythmogenic Ca 2+ release in postinfarction HF. We found that changes in any individual current are relatively small, and alone could mislead as to consequences. However, differential changes in multiple currents integrate to shorten AP in the infarct border zone but prolong AP in the remote zone, increasing AP repolarization inhomogeneity. Our findings help explain why single channel-blocker therapy may fail, and highlight the need to understand the integrated changes of ionic currents in treating arrhythmias in HF.

PurposeDespite the intra- and intertumoral heterogeneity seen in glioblastoma multiforme (GBM), there is little definitive data on the underlying cause of the differences in patient survivals. Serial imaging assessment of tumor growth allows quantification of tumor growth kinetics (TGK) measured in terms of changes in the velocity of radial expansion seen on imaging. Because a systematic study of this entire TGK phenotype—growth before treatment and during each treatment to recurrence —has never been coordinately studied in GBMs, we sought to identify whether patients cluster into discrete groups on the basis of their TGK.Patients and MethodsFrom our multi-institutional database, we identified 48 patients who underwent maximally safe resection followed by radiotherapy with imaging follow-up through the time of recurrence. The patients were then clustered into two groups through a k-means algorithm taking as input only the TGK before and during treatment.ResultsThere was a significant survival difference between the clusters ( P = .003). Paradoxically, patients among the long-lived cluster had significantly larger tumors at diagnosis ( P = .027) and faster growth before treatment ( P = .003) but demonstrated a better response to adjuvant chemotherapy ( P = .048). A predictive model was built to identify which cluster patients would likely fall into on the basis of information that would be available to clinicians immediately after radiotherapy (accuracy, 90.3%).ConclusionDichotomizing the heterogeneity of GBMs into two populations—one faster growing yet more responsive with increased survival and one slower growing yet less responsive with shorter survival—suggests that many patients who receive standard-of-care treatments may get better benefit from select alternative treatments.

Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing. Here we survey the US landscape of research programs in PGx implementation, review current advances and clinical applications of PGx, summarize the obstacles that have hindered PGx implementation, and identify the critical knowledge gaps and possible studies needed to help to address them.

Microglia are a major cellular component of gliomas, and abundant in the centre of the tumour and at the infiltrative margins. While glioma is a notoriously infiltrative disease, the dynamics of microglia and glioma migratory patterns have not been well characterized. To investigate the migratory behaviour of microglia and glioma cells at the infiltrative edge, we performed two-colour time-lapse fluorescence microscopy of brain slices generated from a platelet-derived growth factor-B (PDGFB)-driven rat model of glioma, in which glioma cells and microglia were each labelled with one of two different fluorescent markers. We used mathematical techniques to analyse glioma cells and microglia motility with both single cell tracking and particle image velocimetry (PIV). Our results show microglia motility is strongly correlated with the presence of glioma, while the correlation of the speeds of glioma cells and microglia was variable and weak. Additionally, we showed that microglia and glioma cells exhibit different types of diffusive migratory behaviour. Microglia movement fit a simple random walk, while glioma cell movement fits a super diffusion pattern. These results show that glioma cells stimulate microglia motility at the infiltrative margins, creating a correlation between the spatial distribution of glioma cells and the pattern of microglia motility.

Objective A gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures. Design Based on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed. Results We comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease. Conclusion Careful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry.

BACKGROUND: Inhaled nitric oxide (iNO) is increasingly prescribed to extremely premature neonates with respiratory distress syndrome (RDS). Most of this off-label use occurs during the first week of life. We studied this practice, hypothesizing that it would not be associated with improved survival. METHODS: We queried the Pediatrix Medical Group Clinical Data Warehouse to identify all neonates born at 22 to 29 weeks’ gestation from 2004 to 2014. In our study sample, we included singletons who required mechanical ventilation for treatment of RDS and excluded those with anomalies. The primary outcome was death before discharge. Through a sequential risk set approach, each patient who received iNO during the first 7 days of life (“case patient”) was matched by using propensity scores to a patient who had not received iNO at a chronological age before the case patient’s iNO initiation age (defined as the index age for the matched pair). The association between iNO status and in-hospital mortality was evaluated in a Cox proportional hazards regression model by using age as the time scale with patients entering the risk set at their respective index age. RESULTS: Among 37 909 neonates in our study sample, we identified 993 (2.6%) who received iNO. The 2 matched cohorts each contained 971 patients. We did not observe a significant association between iNO exposure and mortality (hazard ratio, 1.08; 95% confidence interval, 0.94–1.25; P = .29). CONCLUSIONS: Off-label prescription of iNO is not associated with reduced in-hospital mortality among extremely premature neonates with RDS.

Background Malignancy after liver transplant (LT) is a leading cause of mortality, but data is limited. The aim of this study was to identify patients at higher risk for de novo malignancies after LT in a large multicenter database. Methods The Scientific Registry of Transplant Recipients database comprising all 108 412 LT recipients across the United States between 1987 and March 2015 was analyzed with a median follow-up of 6.95 years. Potential risk factors for malignancies after LT were assessed using Cox regression analysis for the outcome of time to first malignancy. Results Mean age 51.9 ± 10.8 years, 64.6% male, 74.5% white, and 15.8% with previous malignancy. Malignancies during follow-up were 4,483 (41.3%) skin, 1519 (14.0%) hematologic, and 4842 (44.7%) solid organ. The 10-year probability of de novo malignancy was 11.5% (11.3-11.8%). On multivariable analysis, age by decade (hazard ratio [HR], 1.52; P < 0.001), male sex (HR, 1.28; P < 0.001), white race (compared with other races: HR, 1.45-2.04; P < 0.001), multiorgan transplant (HR, 1.35; P < 0.001), previous malignancy (HR, 1.34; P < 0.001), and alcoholic liver disease, autoimmune, nonalcoholic steatohepatitis (HR, 1.35; P < 0.001), and primary sclerosing cholangitis pre-LT (compared with hepatitis C virus, P < 0.001) were associated with higher risk of post-LT malignancy, but type of immunosuppression was not (P = NS). Conclusions This large data set demonstrates the effects of ethnicity/race and etiologies of liver disease, particularly nonalcoholic steatohepatitis as additional risk factors for cancer after LT. Patients with these high-risk characteristics should be more regularly and diligently screened.