Citations

AbstractAimAchieving the optimal apposition of coronary stents during percutaneous coronary intervention is not always feasible. The risks and benefits of stent postdilation in primary percutaneous coronary intervention (PPCI) in patients with ST‐elevation myocardial infarction (STEMI) have remained controversial. We sought to evaluate the immediate angiographic and long‐term outcomes in patients with and without stent postdilation.MethodsA cohort of patients (n = 1,224) with STEMI, treated with PPCI (n = 500 postdilated; n = 724 controls), were studied. The flow grade, the myocardial blush grade, and the frame count were considered angiographic outcomes. The clinical outcomes were major adverse cardiovascular events (MACE)—comprising cardiac death, nonfatal MI, and repeat revascularization—and the device‐oriented composite endpoint (DOCE)—consisting of cardiac death, target lesion revascularization, and target vessel revascularization.ResultsThe flow and myocardial blush grades were not different between the two groups, and the frame count was significantly lower in the postdilation group (15.7 ± 8.4 vs. 17 ± 10.4; p < .05). The patients were followed up for 348 ± 399 days. DOCE (2.2% vs. 5.8%) and cardiac mortality (1.2% vs. 3.2%) were lower in the postdilation group. In the fully adjusted propensity score‐matched analysis, postdilation was associated with decreased DOCE (HR = 0.40 [0.18–0.87], p = .021).ConclusionsSelective postdilation improved some angiographic and clinical outcomes and could not be discouraged in PPCI on patients with STEMI.

Introduction Diarrhoea is a frequent concern in the intensive care unit (ICU) and is associated with prolonged mechanical ventilation, increased length of ICU stay, skin breakdown and renal dysfunction. However, its prevalence, aetiology and prognosis in the critically ill have been poorly studied. The primary objectives of this study are to determine the incidence, risk factors and consequences of diarrhoea in critically ill adults. The secondary objectives are to estimate the incidence of Clostridium difficile- associated diarrhoea (CDAD) in ICU patients and to validate the Bristol Stool Chart and Bliss Stool Classification System characterising bowel movements in the ICU. Our primary outcome is the incidence of diarrhoea . Our secondary outcomes include: CDAD, ICU and hospital mortality and ICU and hospital length of stay. Methods and analysis This international prospective cohort study will enrol patients over 10 weeks in 12 ICUs in Canada, the USA, Poland and Saudi Arabia. We will include all patients 18 years of age and older who are admitted to the ICU for at least 24 hours and follow them daily until ICU discharge. Our primary outcome is the incidence of diarrhoea based on the WHO definition, during the ICU stay. Our secondary outcomes include: CDAD, ICU and hospital mortality and ICU and hospital length of stay. We will use logistic regression to identify factors associated with diarrhoea (as defined using WHO criteria) and the kappa statistic to measure agreement on diarrhoea rates between the WHO definition and the Bristol Stool Chart and Bliss Stool Classification System. Ethics and dissemination The protocol has been approved by the research ethics board of all participating centres. The diarrhoea interventions, consequences and epidemiology in the intensive care unit (DICE-ICU) study will generate evidence about diarrhoea and its frequency, predisposing factors and consequences, to inform critical care practice and future research. Lay summary Diarrhoea is a frequent clinical problem for hospitalised patients including those who are critically ill in the ICU. Diarrhoea can cause complications such as skin damage, dehydration and kidney problems. It is not clear how common diarrhoea is in the ICU, the factors that cause it or the best way for clinicians to assess it. The DICE-ICU study is an international prospective observational study to examine the frequency, risk factors and outcomes of diarrhoea during critical illness.

ABSTRACT Musculoskeletal infections (MSKI) remain the bane of orthopedic surgery, and result in grievous illness and inordinate costs that threaten healthcare systems. As prevention, diagnosis, and treatment has remained largely unchanged over the last 50 years, a 2nd International Consensus Meeting on Musculoskeletal Infection (ICM 2018, https://icmphilly.com ) was completed. Questions pertaining to all areas of MSKI were extensively researched to prepare recommendations, which were discussed and voted on by the delegates using the Delphi methodology. The questions, including the General Assembly (GA) results, have been published ( GA questions ). However, as critical outcomes include: (i) incidence and cost data that substantiate the problems, and (ii) establishment of research priorities; an ICM 2018 research workgroup (RW) was assembled to accomplish these tasks. Here, we present the result of the RW consensus on the current and projected incidence of infection, and the costs per patient, for all orthopedic subspecialties, which range from 0.1% to 30%, and $17,000 to $150,000. The RW also identified the most important research questions. The Delphi methodology was utilized to initially derive four objective criteria to define a subset of the 164 GA questions that are high priority for future research. Thirty‐eight questions (23% of all GA questions) achieved the requisite > 70% agreement vote, and are highlighted in this Consensus article within six thematic categories: acute versus chronic infection, host immunity, antibiotics, diagnosis, research caveats, and modifiable factors. Finally, the RW emphasizes that without appropriate funding to address these high priority research questions, a 3rd ICM on MSKI to address similar issues at greater cost is inevitable.

Abstract The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial–mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal–epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells. Significance: These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy. See related commentary by Farrington and Narla, p. 1756

Abstract Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

AbstractBackgroundGenetic polymorphisms of cytochrome P450 are contributors to variability in individual response to drugs. Within the P450 family, CYP2D6 is responsible for metabolizing hydrocodone, a widely prescribed opioid for pain management. Alternatively, CYP3A4 and CYP3A5 can form norhydrocodone and dihydrocodeine. We have previously found that in a postcesarean section cohort, the rate of hydromorphone formation was dependent on the genotype of CYP2D6 and that plasma hydromorphone, not hydrocodone, was predictive of pain relief.MethodBlood was obtained from a postcesarean cohort that were surveyed for pain response and common side effects. Plasma samples were genotyped for CYP3A4/5, and their hydrocodone concentrations were measured by LC-MS. R statistical software was used to check for differences in the outcomes due to CYP3A4/5 and CYP2D6, and a multivariate regression model was fit to determine factors associated with pain score.ResultsTwo-way ANOVA between CYP3A4/A5 and CYP2D6 phenotypes revealed that the former variants did not have a statistical significance on the outcomes, and only CYP2D6 phenotypes had a significant effect on total dosage (P = 0.041). Furthermore, a 3-way ANOVA analysis showed that CYP2D6 (P = 0.036) had a predictive effect on plasma hydromorphone concentrations, and CYP3A4/A5 did not have any effect on the measured outcomes.ConclusionsWith respect to total dosages in a cesarean section population, these results confirm that CYP2D6 phenotypes are predictors for plasma hydromorphone concentration and pain relief, but CYP3A4/A5 phenotypes have no influence on pain relief or on side effects.

SummaryBackgroundHepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti‐viral therapy affects survival after HCC diagnosis.MethodsThis was an international multicentre cohort study of 2518 HBV‐related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti‐viral therapy and cirrhosis on patients' risk of death.ResultsApproximately, 48% of patients received anti‐viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti‐viral therapy would have been indicated for >60% of the patients not on anti‐viral therapy based on American criteria. Patients with cirrhosis had lower 5‐year survival (34% vs 46%; P < 0.001) while patients receiving anti‐viral therapy had increased 5‐year survival compared to untreated patients (42% vs 25% with cirrhosis and 58% vs 36% without cirrhosis; P < 0.001 for both). Similar findings were seen for other patient subgroups by cancer stages and cancer treatment types. Anti‐viral therapy was associated with a decrease in risk of death, whether started before or after HCC diagnosis (adjusted HR 0.62 and 0.79, respectively; P < 0.001).ConclusionsAnti‐viral therapy improved overall survival in patients with HBV‐related HCC across cancer stages and treatment types but was underutilised at both US and Asia centres. Expanded use of anti‐viral therapy in HBV‐related HCC and better linkage‐to‐care for HBV patients are needed.

Background. The FilmArray Respiratory Panel (FARP) (BioFire Diagnostics, Inc.) is a multiplex, polymerase chain reaction (PCR) technique that can detect 17 respiratory viruses and 3 bacterial targets in a single reaction. Immunocompromised hosts (ICH) with respiratory illnesses often undergo bronchoscopy with bronchoalveolar lavage (BAL). This prospective study aimed to evaluate the yield and concordance of NP and BAL FARP testing when performed on the same patient concurrently. Methods. From February to December 2016, 125 patients (100 ICH and 25 non-ICH) were enrolled. NP swabs and BAL samples were sent for FARP testing. Results. The yield of the BAL FARP among ICH and non-ICH was 24% (24/100) and 8% (2/25), respectively. The yield of positive NP swabs in ICH was 27% (27/100) versus 4% (1/25) in non-ICH. The majority of patients (89%; 111/125) had concordant results between NP and BAL specimens. Of the 24 ICH patients who had a positive BAL FARP, the majority (79%) had the same pathogen detected from the NP swab. Conclusion. The FARP may be useful in the ICH. Given the high concordance, in patients whom a pathogen is identified on the NP FARP, a FARP performed on BAL will likely yield the same result. However, if the NP FARP is negative, performing the test on a BAL sample may have an incremental yield.