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1.  Higher-risk mitral valve operations after previous sternotomy: endoscopic, minimally invasive approach improves patient outcomes 
Canadian Journal of Surgery  2016;59(6):399-406.
Background
Reoperative mitral valve (MV) surgery is associated with significant morbidity and mortality; however, endoscopic minimally invasive surgical techniques may preserve the surgical benefits of conventional mitral operations while potentially reducing perioperative risk and length of stay (LOS) in hospital.
Methods
We compared the outcomes of consecutive patients who underwent reoperative MV surgery between 2000 and 2014 using a minimally invasive endoscopic approach (MINI) with those of patients who underwent a conventional sternotomy (STERN). The primary outcome was in-hospital/30-day mortality. Secondary outcomes included blood product transfusion, LOS in hospital and in the intensive care unit (ICU), and postoperative complications.
Results
We included 132 patients in our study: 40 (mean age 68 ± 14 yr, 70% men) underwent MINI and 92 (62 ± 13 yr, 40% men) underwent STERN. The MINI group had significantly more comorbidities than the STERN group. While there were no significant differences in complications, all point estimates suggested lower mortality and morbidity in the MINI than the STERN group (in-hospital/30-day mortality 5% v. 11%, p = 0.35; composite any of 10 complications 28% v. 41%, p = 0.13). Individual complication rates were similar between the MINI and STERN groups, except for intra-aortic balloon pump requirement (IABP; 0% v. 12%, p = 0.034). MINI significantly reduced the need for any blood transfusion (68% v. 84%, p = 0.036) or packed red blood cells (63% v. 79%, p = 0.042), fresh frozen plasma (35% v. 59%, p = 0.012) and platelets (20% v. 40%, p = 0.024). It also significantly reduced median hospital LOS (8 v. 12 d, p = 0.014). An exploratory propensity score analysis similarly demonstrated a significantly reduced need for IABP (p < 0.001) and a shorter mean LOS in the ICU (p = 0.046) and in hospital (p = 0.047) in the MINI group.
Conclusion
A MINI approach for reoperative MV surgery reduces blood product utilization and hospital LOS. Possible clinically relevant differences in perioperative complications require assessment in randomized clinical trials.
doi:10.1503/cjs.004516
PMCID: PMC5125922
2.  Prevention of necrotizing enterocolitis with probiotics: a systematic review and meta-analysis 
PeerJ  2016;4:e2429.
Context
Necrotizing enterocolitis (NEC) is the most frequent gastrointestinal emergency in neonates. The microbiome of the preterm gut may regulate the integrity of the intestinal mucosa. Probiotics may positively contribute to mucosal integrity, potentially reducing the risk of NEC in neonates.
Objective
To perform an updated systematic review and meta-analysis on the efficacy and safety of probiotics for the prevention of NEC in premature infants.
Data Sources
Structured searches were performed in: Medline, Embase, and the Cochrane Central Register of Controlled Trials (all via Ovid, from 2013 to January 2015). Clinical trial registries and electronically available conference materials were also searched. An updated search was conducted June 3, 2016.
Study Selection
Randomized trials including infants less than 37 weeks gestational age or less than 2,500 g on probiotic vs. standard therapy.
Data Extraction
Data extraction of the newly-identified trials with a double check of the previously-identified trials was performed using a standardized data collection tool.
Results
Thirteen additional trials (n = 5,033) were found. The incidence of severe NEC (RR 0.53 95% CI [0.42–0.66]) and all-cause mortality (RR 0.79 95% CI [0.68–0.93]) were reduced. No difference was shown in culture-proven sepsis RR 0.88 95% CI [0.77–1.00].
Limitations
Heterogeneity of organisms and dosing regimens studied prevent a species-specific treatment recommendation from being made.
Conclusions
Preterm infants benefit from probiotics to prevent severe NEC and death.
doi:10.7717/peerj.2429
PMCID: PMC5068355  PMID: 27761306
Probiotics; Necrotizing enterocolitis; Lactobacillus; Bifidobacterium; Saccharomyces; Extremely premature; Newborn; Infant; Premature; Enterocolitis
3.  The Association of Chronic Kidney Disease with the Use of Renin-Angiotensin System Inhibitors after Acute Myocardial Infarction 
American heart journal  2015;170(4):735-743.
Background
Renin angiotensin system (RAS) inhibitor use after acute myocardial infarction (AMI) is a quality indicator, but there may also be reasons not to use this therapy. We sought to determine how chronic kidney disease (CKD) and acute kidney injury (AKI) affected RAS inhibitor prescription after AMI in patients with and without decreased ejection fraction (EF).
Methods
Participants from the TRIUMPH registry were categorized by admission estimated glomerular filtration rate (eGFR in ml/min/1.73m2; severe [<30], moderate [30–59], mild [60–89] and no [≥90] CKD) and occurrence of AKI (an increase in creatinine ≥0.3mg/dl or ≥50%). RAS inhibitor prescriptions at discharge were compared across categories of CKD, AKI and decreased EF (<40% vs. ≥40%) using a hierarchical modified Poisson model.
Results
Among 4223 AMI patients (mean age 59.0 years, 67.0% male, 67.3% white), RAS inhibitor use decreased significantly with lower eGFR (P <0.001), but there was no effect of decreased EF on this relationship (interaction P = 0.40). Without AKI, severe and moderate CKD were associated with significantly less RAS inhibitor use; relative risks (RRs) = 0.67 (95% CIs, 0.58–0.78) and 0.94 (0.90–0.99), respectively. When AKI occurred, CKD was associated with less RAS inhibitor use: RR 0.84 (0.76–0.93) for mild CKD, 0.78 (0.68–0.88) for moderate CKD, and 0.50 (0.42–0.61) for severe CKD. EF <40% was associated with use (RR 1.11, 1.03–1.18), independent of renal function.
Conclusions
CKD and AKI are associated with fewer RAS inhibitor prescriptions at discharge, but in both AKI and non-AKI patients, eGFR was more strongly associated with use than EF.
doi:10.1016/j.ahj.2015.07.019
PMCID: PMC4745905  PMID: 26386797
Acute myocardial infarction; heart failure; chronic kidney disease; acute kidney injury; renin-angiotensin system inhibitors
4.  Development and validation of a simplified Stroke–Thrombolytic Predictive Instrument 
Neurology  2015;85(11):942-949.
Objectives:
The Stroke–Thrombolytic Predictive Instrument (Stroke-TPI) predicts the probability of good and bad outcomes with and without recombinant tissue plasminogen activator (rtPA). We sought to rebuild and externally validate a simpler Stroke-TPI to support implementation in routine clinical care.
Methods:
Using the original derivation cohort of 1,983 patients from a combined database of randomized clinical trials (NINDS [National Institute of Neurological Disorders and Stroke] 1 and 2; ATLANTIS [Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke] A and B; and ECASS [European Cooperative Acute Stroke Study] II), we simplified the Stroke-TPI by reducing variables and interaction terms and by exploring simpler (3- and 8-item) stroke severity scores. External validation was performed in the ECASS III trial (n = 821).
Results:
The following 6 variables were most predictive of good outcomes: age, systolic blood pressure, diabetes, stroke severity, symptom onset to treatment time, and rtPA therapy. Treatment effect modifiers included onset to treatment time and systolic blood pressure. For the models predicting a bad outcome (modified Rankin Scale [mRS] score ≥5), significant variables included age, stroke severity, and serum glucose. rtPA therapy did not change the risk of a poor outcome. Compared with models using the full NIH Stroke Scale, models using the 3-item severity score showed similar discrimination and excellent calibration. External validation on ECASS III showed similar performance (C statistics 0.75 [mRS score ≤1] and 0.80 [mRS score ≤2]).
Conclusion:
A simpler model using a 3-item stroke severity score, instead of the 15-item NIH Stroke Scale, has similar prognostic value and may be easier to use in routine care. Future studies are needed to test whether it can improve process and clinical outcomes.
doi:10.1212/WNL.0000000000001925
PMCID: PMC4567461  PMID: 26291280
5.  The SMARCA2/4 ATPase domain surpasses the bromodomain as a drug target in SWI/SNF mutant cancers: Insights from cDNA rescue and PFI-3 inhibitor studies 
Cancer research  2015;75(18):3865-3878.
The SWI/SNF multi-subunit complex modulates chromatin structure through the activity of two mutually exclusive catalytic subunits, SMARCA2 and SMARCA4, which both contain a bromodomain and an ATPase domain. Using RNAi, cancer-specific vulnerabilities have been identified in SWI/SNF mutant tumors, including SMARCA4-deficient lung cancer, however, the contribution of conserved, druggable protein domains to this anticancer phenotype is unknown. Here, we functionally deconstruct the SMARCA2/4 paralog dependence of cancer cells using bioinformatics, genetic and pharmacological tools. We evaluate a selective SMARCA2/4 bromodomain inhibitor (PFI-3) and characterize its activity in chromatin-binding and cell-functional assays focusing on cells with altered SWI/SNF complex (e.g. Lung, Synovial Sarcoma, Leukemia, and Rhabdoid tumors). We demonstrate that PFI-3 is a potent, cell-permeable probe capable of displacing ectopically expressed, GFP-tagged SMARCA2-bromodomain from chromatin, yet contrary to target knockdown, the inhibitor fails to display an antiproliferative phenotype. Mechanistically, the lack of pharmacological efficacy is reconciled by the failure of bromodomain inhibition to displace endogenous, full-length SMARCA2 from chromatin as determined by in situ cell extraction, chromatin immunoprecipitation and target gene expression studies. Further, using inducible RNAi and cDNA complementation (bromodomain- and ATPase-dead constructs), we unequivocally identify the ATPase domain, and not the bromodomain of SMARCA2, as the relevant therapeutic target with the catalytic activity suppressing defined transcriptional programs. Taken together, our complementary genetic and pharmacological studies exemplify a general strategy for multi-domain protein drug-target validation and in case of SMARCA2/4 highlight the potential for drugging the more challenging helicase/ATPase domain to deliver on the promise of synthetic-lethality therapy.
doi:10.1158/0008-5472.CAN-14-3798
PMCID: PMC4755107  PMID: 26139243
6.  The Association of Smoking Status with Angina and Health-Related Quality of Life After Acute Myocardial Infarction 
Background
Smoking cessation after acute myocardial infarction (AMI) decreases the risk of recurrent AMI and mortality by 30–40%, but many patients continue to smoke. The association of smoking with angina and health-related quality of life (HRQOL) after AMI is unclear.
Methods and Results
Patients in 2 U.S. multicenter AMI registries (n=4003) were assessed for smoking and HRQOL at admission and 1, 6 and 12 months after AMI. Angina and HRQOL were measured with the Seattle Angina Questionnaire (SAQ) and Short Form-12 (SF-12) physical and mental component scales (PCS and MCS). At admission, 29% never had smoked, 34% were former smokers (quit before AMI) and 37% were active smokers, of whom 46% quit by 1 year (recent quitters). In hierarchical, multivariable, regression models that adjusted for sociodemographic, clinical and treatment factors, never and former smokers had similar and the best HRQOL in all domains. Recent quitters had intermediate HRQOL levels, with angina and SF-12 MCS scores similar to never smokers. Persistent smokers had worse HRQOL in all domains compared to never smokers and worse SF-12 MCS scores than recent quitters.
Conclusion
Smoking after AMI is associated with more angina and worse HRQOL in all domains, while smokers who quit after AMI have similar angina levels and mental health as never smokers. These observations may help encourage patients to stop smoking after AMI.
doi:10.1161/CIRCOUTCOMES.114.001545
PMCID: PMC4703446  PMID: 26307130
smoking; angina; quality of life; myocardial infarction
7.  Exosomes in human semen restrict HIV-1 transmission by vaginal cells and block intravaginal replication of LP-BM5 murine AIDS virus complex 
Virology  2015;482:189-201.
Exosomes are membranous extracellular nanovesicles secreted by diverse cell types. Exosomes from healthy human semen have been shown to inhibit HIV-1 replication and to impair progeny virus infectivity. In this study, we examined the ability of healthy human semen exosomes to restrict HIV-1 and LP-BM5 murine AIDS virus transmission in three different model systems. We show that vaginal cells internalize exosomes with concomitant transfer of functional mRNA. Semen exosomes blocked the spread of HIV-1 from vaginal epithelial cells to target cells in our cell-to-cell infection model and suppressed transmission of HIV-1 across the vaginal epithelial barrier in our trans-well model. Our in vivo model shows that human semen exosomes restrict intravaginal transmission and propagation of murine AIDS virus. Our study highlights an antiretroviral role for semen exosomes that may be harnessed for the development of novel therapeutic strategies to combat HIV-1 transmission.
doi:10.1016/j.virol.2015.03.040
PMCID: PMC4461544  PMID: 25880110
Exosome; semen; vaginal epithelia; HIV; murine AIDS; mAIDS; LP-BM5 virus
8.  Clinical Relevance of Rehospitalizations for Unstable Angina and Unplanned Revascularization Following Acute Myocardial Infarction 
Background
Rehospitalizations following acute myocardial infarction for unplanned coronary revascularization and unstable angina (UA) are often included as parts of composite end points in clinical trials. Although clearly costly, the clinical relevance of these individual components has not been described.
Methods and Results
Patients enrolled in a prospective, 24‐center, US acute myocardial infarction registry were followed for 1 year after an acute myocardial infarction for rehospitalizations, that were independently adjudicated by experienced cardiologists. Patients who did and did not experience UA or revascularization rehospitalization were propensity matched using greedy matching. Among 3283 patients with acute myocardial infarction who were included, mean age was 59 years, 33% were female, and 70% were white. Rehospitalization rates for UA and unplanned revascularization at 1 year were 5.0% and 4.1%, respectively. After propensity matching, we included 2433 patients in the UA rehospitalization group and 2410 in the unplanned revascularization group. Using weighted proportional hazards Cox regression, there was no significant association between a rehospitalization for UA and 5‐year all‐cause mortality (9.6% versus 13.8%; adjusted hazard ratio 0.87, 95% CI 0.60–1.16). Patients rehospitalized for unplanned revascularization had a lower 5‐year mortality risk (7.0% versus 15.1%; hazard ratio 0.68, 95% CI 0.50–0.92) compared with those without such rehospitalizations. Nevertheless, patients with UA and unplanned revascularization had a substantially greater hazard of subsequent rehospitalizations compared with patients without such events (UA: hazard ratio 4.36, 95% CI 3.48–5.47; revascularization: hazard ratio 4.38, 95% CI 3.53–5.44).
Conclusions
Rehospitalizations for UA and unplanned revascularization in the year after an acute myocardial infarction are associated with higher risks of subsequent rehospitalizations but not with mortality.
doi:10.1161/JAHA.115.003129
PMCID: PMC5015270  PMID: 27543798
morbidity/mortality; myocardial infarction; Acute Coronary Syndromes; Coronary Artery Disease; Mortality/Survival
9.  Comparison of isoflurane and sevoflurane in cardiac surgery: a randomized non-inferiority comparative effectiveness trial 
Canadian Journal of Anaesthesia  2016;63(10):1128-1139.
Purpose
Volatile anesthetics possess cardioprotective properties, but it is unknown if the cardioprotective effects extend equally to all members of the class. Although sevoflurane is a relatively newer anesthetic than isoflurane, its introduction into practice was not preceded by a head-to-head comparison with isoflurane in a trial focusing on clinically important outcomes. Our objective was to determine whether sevoflurane was non-inferior to isoflurane on a clinically important primary outcome in a heterogeneous group of adults undergoing cardiac surgery.
Methods
This was a pragmatic randomized non-inferiority comparative effectiveness clinical trial in 464 adults having coronary artery bypass graft and/or single valve surgery during November 2011 to March 2014. The intervention was maintenance of anesthesia with sevoflurane (n = 231) or isoflurane (n = 233) administered at a dose of 0.5-2.0 MAC throughout the entire operation. All caregivers were blinded except for the anesthesiologist and perfusionist. The primary outcome was a composite of intensive care unit (ICU) length of stay ≥ 48 hr and all-cause 30-day mortality. We hypothesized that sevoflurane would be non-inferior to isoflurane (non-inferiority margin < 10% based on an expected event rate of 25%). Secondary outcomes included prolonged ICU stay, 30- and 365-day all-cause mortality, inotrope or vasopressor usage, new-onset hemodialysis or atrial fibrillation, stroke, and readmission to the ICU.
Results
No losses to follow-up occurred. The primary outcome occurred in 25% of sevoflurane patients and 30% of isoflurane patients (absolute difference, −5.4%; one-sided 95% confidence interval, 1.4), thus non-inferiority was declared. Sevoflurane was not superior to isoflurane for the primary outcome (P = 0.21) or for any secondary outcomes.
Conclusion
Sevoflurane is non-inferior to isoflurane on a composite outcome of prolonged ICU stay and all-cause 30-day mortality. Sevoflurane is not superior to isoflurane on any other of the clinically important outcomes. This trial was registered at clinicaltrials.gov; NCT01477151.
doi:10.1007/s12630-016-0706-y
PMCID: PMC5023754  PMID: 27465213
10.  Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors 
Nature medicine  2016;22(2):194-201.
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials1. One PARP inhibitor, olaparib (Lynparza™, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with BRCA mutations. BRCA1 and BRCA2 play essential roles in repairing DNA double strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition2,3. Here we show that receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907. Phosphorylation of PARP1 Tyr907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. Combining c-Met and PARP1 inhibitors synergized to suppress growth of breast cancer cells in vitro and xenograft tumor models. Similar synergistic effects were observed in a lung cancer xenograft tumor model. These results suggest that PARP1 pTyr907 abundance may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients bearing tumors with high c-Met expression who do not respond to PARP inhibition alone.
doi:10.1038/nm.4032
PMCID: PMC4754671  PMID: 26779812
11.  CD15 Expression Does Not Identify a Phenotypically or Genetically Distinct Glioblastoma Population 
The data from this study contribute to the ongoing debate about the role of cancer stem cells in gliomagenesis. Results showed that CD15, a marker previously thought to be a cancer stem-like marker in glioblastoma, could not isolate a phenotypically or genetically distinct population. Moreover, isolated CD15-positive and -negative cells were able to generate mixed populations of glioblastoma cells in vitro.
Recent research has focused on the hypothesis that the growth and regeneration of glioblastoma (GB) is sustained by a subpopulation of self-renewing stem-like cells. This has led to the prediction that molecular markers for cancer stem cells in GB may provide a treatment target. One candidate marker is CD15: we wanted to determine if CD15 represented a credible stem cell marker in GB. We first demonstrated that CD15-positive (CD15+) cells were less proliferative than their CD15-negative (CD15−) counterparts in 10 patient GB tumors. Next we compared the proliferative activity of CD15+ and CD15− cells in vitro using tumor-initiating primary GB cell lines (TICs) and found no difference in proliferative behavior. Furthermore, TICs sorted for CD15+ and CD15− were not significantly different cytogenetically or in terms of gene expression profile. Sorted single CD15+ and CD15− cells were equally capable of reconstituting a heterogeneous population containing both CD15+ and CD15− cells over time, and both CD15+ and CD15− cells were able to generate tumors in vivo. No difference was found in the phenotypic or genomic behavior of CD15+ cells compared with CD15− cells from the same patient. Moreover, we found that in vitro, cells were able to interconvert between the CD15+ and CD15− states. Our data challenge the utility of CD15 as a cancer stem cell marker.
Significance
The data from this study contribute to the ongoing debate about the role of cancer stem cells in gliomagenesis. Results showed that CD15, a marker previously thought to be a cancer stem-like marker in glioblastoma, could not isolate a phenotypically or genetically distinct population. Moreover, isolated CD15-positive and -negative cells were able to generate mixed populations of glioblastoma cells in vitro.
doi:10.5966/sctm.2014-0047
PMCID: PMC4479614  PMID: 26019225
Glioblastoma; CD15; SSEA1; Hierarchy; Stem cell; Cancer
12.  Human Keratinocytes have two interconvertible modes of proliferation 
Nature cell biology  2015;18(2):145-156.
Summary
Single stem cells, including those in human epidermis, have a remarkable ability to reconstitute tissues in vitro, but the cellular mechanisms that enable this are ill defined. We used live imaging to track the outcome of thousands of divisions in clonal cultures of primary human epidermal keratinocytes. Two modes of proliferation were seen. In ‘balanced’ mode, similar proportions of proliferating and differentiating cells were generated, achieving the ‘population asymmetry’ that sustains epidermal homeostasis in vivo. In ‘expanding’ mode, an excess of cycling cells was produced, generating large expanding colonies. Cells in expanding mode switched their behaviour to balanced mode once local confluence was attained. However when a confluent area is wounded in a scratch assay, cells near the scratch switch back to expanding mode until the defect is closed. We conclude that the ability of a single epidermal stem cell to reconstitute an epithelium is explained by two interconvertible modes of proliferation regulated by confluence.
doi:10.1038/ncb3282
PMCID: PMC4872834  PMID: 26641719
13.  Clock-like mutational processes in human somatic cells 
Nature genetics  2015;47(12):1402-1407.
During the course of a lifetime somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell’s genome. Some processes generate mutations throughout life at a constant rate in all individuals and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This study provides the first survey of clock-like mutational processes operative in human somatic cells.
doi:10.1038/ng.3441
PMCID: PMC4783858  PMID: 26551669
14.  Development and Validation of a Short Version of the Kansas City Cardiomyopathy Questionnaire 
Supplemental Digital Content is available in the text.
Background—
There is a growing demand to collect patients’ experiences of their health status (their symptoms, function, and quality of life) in clinical trials, quality assessment initiatives, and in routine clinical care. In heart failure, the 23-item, disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ) has been shown to be valid, reliable, sensitive to clinical change, and prognostic of both clinical events and costs. However, its use has been limited, in part, by its length. We sought to develop a shortened version of the instrument that maintains the psychometric properties of the full KCCQ.
Methods and Results—
Using data from 3 clinical studies incorporating 4168 patients, we derived and validated a 12-item KCCQ, the KCCQ-12, to capture symptom frequency, physical and social limitations, and quality of life impairment as a result of heart failure, as well as an overall summary score. The KCCQ-12 scores had high correlations with the original scales (>0.93 for all scales in all clinical settings), high test–retest reliability (>0.76 for all domains), high responsiveness (16–31 point improvements after discharge from hospitalization; standardized response mean =0.61–1.12), and comparable prognostic significance and interpretation of clinically important differences as compared with the full KCCQ.
Conclusions—
The KCCQ-12 is a shorter version of the original 23-item instrument that should be more feasible to implement while preserving the psychometric properties of the full instrument.
doi:10.1161/CIRCOUTCOMES.115.001958
PMCID: PMC4885562  PMID: 26307129
heart failure; methodology; patient-reported outcomes; quality; quality assessment; quality of life
15.  Longitudinal persistence with secondary prevention therapies relative to patient risk after myocardial infarction 
Heart (British Cardiac Society)  2015;101(10):800-807.
Background
Prior studies have demonstrated that high-risk AMI patients are less likely to receive guideline-directed medications during hospitalization. It is unknown if this paradox persists following discharge. We aimed to assess if persistence with guideline-directed medications post-discharge varies by patients’ risk following acute myocardial infarction (AMI).
Methods
Data were analyzed from two prospective, multicenter U.S. AMI registries. The primary outcome was persistence with all prescribed guideline-directed medications (aspirin, beta-blockers, statins, angiotensin-antagonists) at 1, 6, and 12-months post-discharge. The association between risk and medication persistence post-discharge was assessed using multivariable mixed-effect models.
Results
Among 6434 AMI patients discharged home, 2824 were considered low-risk, 2014 intermediate-risk and 1596 high-risk for death based upon their GRACE 6-month risk score. High-risk was associated with a lower likelihood of receiving all appropriate therapies at discharge compared with low-risk patients (RR 0.90; 95% CI 0.87–0.94). At 12-months, the rate of persistence with all prescribed therapies was 61.5%, 57.9% and 45.9% among low-, intermediate- and high-risk patients respectively. After multivariable adjustment, high-risk was associated with lower persistence with all prescribed medications (RR 0.87; 95% CI 0.82–0.92) over follow-up. Similar associations were seen for individual medications. Over the 5 years of the study, persistence with prescribed therapies post-discharge improved modestly among high-risk patients (RR 1.05; 95% CI 1.03–1.08 per year).
Conclusion
High-risk AMI patients have a lower likelihood of persistently taking prescribed medications post-discharge as compared with low-risk patients. Continued efforts are needed to improve the use of guideline-directed medications in high-risk patients.
doi:10.1136/heartjnl-2014-306754
PMCID: PMC4871817  PMID: 25801001
myocardial infarction; medication persistence; secondary prevention therapy
16.  Telomere dysfunction drives aberrant hematopoietic differentiation and Myelodysplastic Syndrome 
Cancer cell  2015;27(5):644-657.
SUMMARY
Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including srsf2. RNA-Seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling and histone modification, which are also enriched in mouse CMP haploinsufficient for srsf2 and in CD34+ CMML patient cells harboring srsf2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing and myeloid progenitor differentiation.
doi:10.1016/j.ccell.2015.04.007
PMCID: PMC4596059  PMID: 25965571
17.  Switching roles: the functional plasticity of adult tissue stem cells 
The EMBO Journal  2015;34(9):1164-1179.
Adult organisms have to adapt to survive, and the same is true for their tissues. Rates and types of cell production must be rapidly and reversibly adjusted to meet tissue demands in response to both local and systemic challenges. Recent work reveals how stem cell (SC) populations meet these requirements by switching between functional states tuned to homoeostasis or regeneration. This plasticity extends to differentiating cells, which are capable of reverting to SCs after injury. The concept of the niche, the micro-environment that sustains and regulates stem cells, is broadening, with a new appreciation of the role of physical factors and hormonal signals. Here, we review different functions of SCs, the cellular mechanisms that underlie them and the signals that bias the fate of SCs as they switch between roles.
doi:10.15252/embj.201490386
PMCID: PMC4426478  PMID: 25812989
differentiation; niche; regeneration; signal transduction; stem cells
18.  Insights into the Angoff method: results from a simulation study 
BMC Medical Education  2016;16:134.
Background
In standard setting techniques involving panels of judges, the attributes of judges may affect the cut-scores. This simulation study modelled the effect of the number of judges and test items, as well as the impact of judges’ attributes such as accuracy, stringency and influence on others on the precision of the cut-scores.
Methods
Forty nine combinations of Angoff panels (N = 5, 10, 15, 20, 30, 50, and 80) and test items (n = 5, 10, 15, 20, 30, 50, and 80) were simulated. Each combination was simulated 100 times (in total 4,900 simulations). The simulation was of judges attributes: stringency, accuracy and leadership. Impact of judges attributes, number of judges, number of test items and Angoff’s second (compared to the first) round on the precision of a panel’s cut-score was measured by the deviation of the panel’s cut-score from the cut-score’s true value.
Results
Findings from 4900 simulated panels supported Angoff being both reliable and valid. Unless the number of test items is small, panels of around 15 judges with mixed levels of expertise provide the most precise estimates. Furthermore, if test data were not presented, a second round of decision-making, as used in the modified Angoff, adds little to precision. A panel which has only experts or only non-experts yields a cut-score which is less precise than a cut-score yielded by a mixed-expertise panel, suggesting that optimal composition of an Angoff panel should include a range of judges with diverse expertise and stringency.
Conclusions
Simulations aim to improve our understanding of the models assessed but they do not describe natural phenomena as they do not use observed data. While the simulations undertaken in this study help clarify how to set cut-scores defensibly, it is essential to confirm these theories in practice.
doi:10.1186/s12909-016-0656-7
PMCID: PMC4855704  PMID: 27142788
19.  Incidence and Predictors of Cognitive Declinein Patients with Left Ventricular Assist Devices 
Background
Following left ventricular assist device (LVAD) for advanced heart failure, increased cerebral perfusion should result in improved cognitive function. However, stroke (a well-known LVAD complication) and subclinical cerebral ischemia may result in transient or permanent cognitive decline. We sought to describe the incidence and predictors of cognitive decline after LVAD using a valid, sensitive assessment tool.
Methods and Results
Among 4419 patients in the INTERMACS registry who underwent LVAD implantation between May 2012 and December 2013, cognitive function was assessed in 1173 patients with the Trailmaking B Test before LVAD and at 3, 6, and 12 months. The test detects several forms of cognitive impairment, including subclinical stroke. Cognitive decline was defined as a clinically important increase during follow-up using a moderate Cohen’s d effect size of 0.5×baseline standard deviation (32 seconds). The cumulative incidence of cognitive decline in the year after LVAD implantation, treating death and transplantation as competing risks, was 29.2%. In adjusted analysis, older age (≥70 vs. <50: HR 2.24, 95% CI 1.46–3.44; ptrend<0.001) and destination therapy (HR 1.42, 95% CI 1.05–1.92) were significantly associated with greater risk of cognitive decline.
Conclusions
Cognitive decline occurs commonly in patients in the year after LVAD and is associated with older age and destination therapy. These results could have important implications for patient selection and improved communication of risks prior to LVAD implantation. Future studies are needed to explore the association between cognitive decline and subsequent stroke, health status, and mortality in patients after LVAD.
doi:10.1161/CIRCOUTCOMES.115.001856
PMCID: PMC4418227  PMID: 25925372
left ventricular assist device; mechanical circulatory support; cognitive impairment; cerebral ischemia
20.  Association of Smoking Status with Health-Related Outcomes After Percutaneous Coronary Intervention 
Circulation. Cardiovascular interventions  2015;8(5):10.1161/CIRCINTERVENTIONS.114.002226 e002226.
Background
Patients who smoke at the time of percutaneous coronary intervention (PCI) would ideally have a strong incentive to quit, but most do not. We sought to compare the health status outcomes of those who did and did not quit smoking after PCI with those who were not smoking prior to PCI.
Methods and Results
A cohort of 2,765 PCI patients from 10 US centers were categorized into never, past (smoked in the past, but had quit prior to PCI), quitters (smoked at time of PCI, but then quit), and persistent smokers. Health status was measured with the disease-specific Seattle Angina Questionnaire (SAQ) and the EuroQol 5 Dimensions (EQ-5D), adjusted for baseline characteristics. In unadjusted analyses, persistent smokers had worse disease-specific and overall health status as compared with other groups. In fully-adjusted analyses, persistent smokers showed significantly worse health-related quality of life as compared with never smokers. Importantly, of those who smoked at the time of PCI, quitters had significantly better adjusted SAQ angina frequency scores (mean difference=2.73; 95% CI, 0.13 to 5.33) and trends towards higher disease specific (SAQ quality of life mean difference=1.97; 95% CI, -1.24 to 5.18), and overall (EQ-5D VAS scores mean difference=2.45; 95% CI, -0.58 to 5.49) quality of life as compared with persistent smokers at 12 months.
Conclusions
While smokers at the time of PCI have worse health status at 1 year than those who never smoked, smokers who quit after PCI have less angina at 1 year than those who continue smoking.
doi:10.1161/CIRCINTERVENTIONS.114.002226
PMCID: PMC4435805  PMID: 25969546
percutaneous coronary intervention; smoking; quality of life
21.  Recognition of Incident Diabetes Mellitus during an Acute Myocardial Infarction 
Background
Diabetes mellitus (DM) is common in patients hospitalized with an acute myocardial infarction (AMI), representing in some cases the first opportunity to recognize and treat DM. We report the incidence of new DM and its recognition among AMI patients.
Methods and Results
Patients in a 24-site U.S. AMI registry (2005–08) had HbA1c assessed at a core lab, with results blinded to clinicians and local clinical measurements left to the discretion of the treating providers. Among 2854 AMI patients without known DM on admission, 287 patients (10%) met criteria for previously unknown DM, defined by core lab HbA1c≥6.5%. Among these, 186 (65%) were unrecognized by treating clinicians, receiving neither DM education, glucose-lowering medications at discharge nor documentation of DM in the chart (median HbA1c of unrecognized patients: 6.7%, range 6.5–12.3%). Six months after discharge, only 5% of those not recognized as having DM during hospitalization had been initiated on glucose-lowering medications vs. 66% of those recognized (p<0.001).
Conclusions
Underlying DM that has not been previously diagnosed is common among AMI patients, affecting 1 in 10 patients, yet is recognized by the care team only one-third of the time. Given its frequency and therapeutic implications, including but extending beyond the initiation of glucose-lowering treatment, consideration should be given to screening all AMI patients for DM during hospitalization. Inexpensive, ubiquitous, and endorsed as an acceptable screen for DM, HbA1c testing should be considered for this purpose.
doi:10.1161/CIRCOUTCOMES.114.001452
PMCID: PMC4439264  PMID: 25901045
diabetes mellitus; acute myocardial infarction; quality of care; hemoglobin A1c
22.  Excess Mortality Attributable to Clostridium difficile and Risk Factors for Infection in an Historic Cohort of Hospitalised Patients Followed Up in the United Kingdom Death Register 
PLoS ONE  2016;11(3):e0149983.
Methods
We compared time from hospital admission to death in a probability sample of 100 Clostridium difficile infected cases and a probability sample of 98 non-cases admitted to an English teaching hospital between 2005 and 2007 with follow up in the UK national death register using survival analysis.
Results
Clostridium difficile infection was associated with a 50% increased risk of death (Hazard Ratio 1.51 (95% CI: 1.05–2.19 p = 0.03) at between five to eight years in Cox Regression analysis adjusting for age, sex, Charlson comorbidity index, diagnosis of a malignant condition and insertion of a nasogastric tube during admission. Acquisition of Clostridium difficile infection was independently associated with an almost six fold higher odds of being admitted with a diagnosis of infection of any other type (OR 5.79 (2.19, 15.25) p<0.001).
Conclusions
Our results strongly support continued priority being given to improve prevention and treatment of Clostridium difficile infection in the English National Health Service particularly in patients admitted with an infection. Our results may be applicable to other health systems.
doi:10.1371/journal.pone.0149983
PMCID: PMC4801172  PMID: 26999613
23.  Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer 
Cancer research  2015;75(6):1091-1101.
Mutated KRAS (KRAS*) is a fundamental driver in the majority of pancreatic ductal adenocarcinomas (PDAC). Using an inducible mouse model of KRAS*-driven PDAC, we compared KRAS* genetic extinction to pharmacological inhibition of MEK1 in tumor spheres and in vivo. KRAS* ablation blocked proliferation and induced apoptosis while MEK1 inhibition exerted cytostatic effects. Proteomic analysis evidenced that MEK1 inhibition was accompanied by a sustained activation of the PI3K-AKT-MTOR pathway and by the activation of AXL, PDGFRa, and HER1-2 receptor tyrosine kinases (RTKs) expressed in a large proportion of human PDAC samples analyzed. While single inhibition of each RTK alone or plus MEK1 inhibitors was ineffective, a combination of inhibitors targeting all three co-activated RTKs and MEK1 was needed to inhibit proliferation and induce apoptosis in both mouse and human low-passage PDAC cultures. Importantly, constitutive AKT activation, which may mimic the fraction of AKT2-amplified PDAC, was able to bypass the induction of apoptosis caused by KRAS* ablation, highlighting a potential inherent resistance mechanism that may inform the clinical application of MEK inhibitor therapy. This study suggests that combinatorial targeted therapies for pancreatic cancer must be informed by the activation state of each putative driver in a given treatment context. Additionally, our work may offer explanative and predictive power in understanding why inhibitors of EGFR signaling fail in PDAC treatment and how drug resistance mechanisms may arise in strategies to directly target KRAS.
doi:10.1158/0008-5472.CAN-14-1854
PMCID: PMC4446709  PMID: 25736685
KRAS; receptor tyrosine kinases; pancreatic ductal adenocarcinoma; MEK inhibitor; AKT2 amplification; targeted therapy
24.  Switching roles: the functional plasticity of adult tissue stem cells 
The EMBO Journal  2015;34(9):1164-1179.
Abstract
Adult organisms have to adapt to survive, and the same is true for their tissues. Rates and types of cell production must be rapidly and reversibly adjusted to meet tissue demands in response to both local and systemic challenges. Recent work reveals how stem cell (SC) populations meet these requirements by switching between functional states tuned to homoeostasis or regeneration. This plasticity extends to differentiating cells, which are capable of reverting to SCs after injury. The concept of the niche, the micro‐environment that sustains and regulates stem cells, is broadening, with a new appreciation of the role of physical factors and hormonal signals. Here, we review different functions of SCs, the cellular mechanisms that underlie them and the signals that bias the fate of SCs as they switch between roles.
doi:10.15252/embj.201490386
PMCID: PMC4426478  PMID: 25812989
differentiation; niche; regeneration; signal transduction; stem cells; Development & Differentiation; Molecular Biology of Disease; Stem Cells
25.  Finding big shots: small-area mapping and spatial modelling of obesity among Swiss male conscripts 
BMC obesity  2016;3:10.
Background
In Switzerland, as in other developed countries, the prevalence of overweight and obesity has increased substantially since the early 1990s. Most of the analyses so far have been based on sporadic surveys or self-reported data and did not offer potential for small-area analyses. The goal of this study was to investigate spatial variation and determinants of obesity among young Swiss men using recent conscription data.
Methods
A complete, anonymized dataset of conscription records for the 2010–2012 period were provided by Swiss Armed Forces. We used a series of Bayesian hierarchical logistic regression models to investigate the spatial pattern of obesity across 3,187 postcodes, varying them by type of random effects (spatially unstructured and structured), level of adjustment by individual (age and professional status) and area-based [urbanicity and index of socio-economic position (SEP)] characteristics.
Results
The analysed dataset consisted of 100,919 conscripts, out of which 5,892 (5.8 %) were obese. Crude obesity prevalence increased with age among conscripts of lower individual and area-based SEP and varied greatly over postcodes. Best model’s estimates of adjusted odds ratios of obesity on postcode level ranged from 0.61 to 1.93 and showed a strong spatial pattern of obesity risk across the country. Odds ratios above 1 concentrated in central and north Switzerland. Smaller pockets of elevated obesity risk also emerged around cities of Geneva, Fribourg and Lausanne. Lower estimates were observed in North-East and East as well as south of the Alps. Importantly, small regional outliers were observed and patterning did not follow administrative boundaries. Similarly as with crude obesity prevalence, the best fitting model confirmed increasing risk of obesity with age and among conscripts of lower professional status. The risk decreased with higher area-based SEP and, to a lesser degree – in rural areas.
Conclusion
In Switzerland, there is a substantial spatial variation in obesity risk among young Swiss men. Small-area estimates of obesity risk derived from conscripts records contribute to its understanding and could be used to design further studies and interventions.
Electronic supplementary material
The online version of this article (doi:10.1186/s40608-016-0092-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s40608-016-0092-6
PMCID: PMC4758017  PMID: 26918194
Obesity; Switzerland; Conscripts; Disease mapping; Spatial hierarchical Bayesian analysis; Integrated nested Laplace approximation

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