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1.  Framingham cardiovascular disease risk scores and incident frailty: The English Longitudinal Study of Ageing 
Age (Dordrecht, Netherlands)  2014;36(4):9692.
Cross-sectional studies show that frailty is common in older people with cardiovascular disease. Whether older people at higher risk of developing cardiovascular disease are more likely to become frail is unclear. We used multinomial logistic regression to examine the prospective relation between Framingham cardiovascular disease risk scores and incidence of physical frailty or pre-frailty, defined according to the Fried criteria, in 1726 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing who had no history of cardiovascular disease at baseline. Men and women with higher Framingham cardiovascular risk scores were more likely to become frail over the 4-year follow-up period. For a standard deviation higher score at baseline, the relative risk ratio (95% confidence interval) for incident frailty, adjusted for sex and baseline frailty status, was 2.76 (2.18, 3.49). There was a significant association between Framingham cardiovascular risk score and risk of pre-frailty: 1.69 (1.46, 1.95). After further adjustment for other potential confounding factors the relative risk ratios for frailty and pre-frailty were 2.15 (1.68, 2.75) and 1.50 (1.29, 1.74) respectively. The associations were unchanged after excluding incident cases of cardiovascular disease. Separate adjustment for each component of the risk score suggested that no single component was driving the associations between cardiovascular risk score and incident pre-frailty or frailty. Framingham cardiovascular risk scores may be useful for predicting the development of physical frailty in older people. We now need to understand the biological mechanisms whereby cardiovascular risk increases the risk of frailty.
doi:10.1007/s11357-014-9692-6
PMCID: PMC4129936  PMID: 25085033
frailty; cardiovascular risk; cohort; longitudinal study
2.  Framingham cardiovascular disease risk scores and incident frailty: the English longitudinal study of ageing 
Age  2014;36(4):9692.
Cross-sectional studies show that frailty is common in older people with cardiovascular disease. Whether older people at higher risk of developing cardiovascular disease are more likely to become frail is unclear. We used multinomial logistic regression to examine the prospective relation between Framingham cardiovascular disease risk scores and incidence of physical frailty or pre-frailty, defined according to the Fried criteria, in 1,726 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing who had no history of cardiovascular disease at baseline. Men and women with higher Framingham cardiovascular risk scores were more likely to become frail over the 4-year follow-up period. For a standard deviation higher score at baseline, the relative risk ratio (95 % confidence interval) for incident frailty, adjusted for sex and baseline frailty status, was 2.76 (2.18, 3.49). There was a significant association between Framingham cardiovascular risk score and risk of pre-frailty: 1.69 (1.46, 1.95). After further adjustment for other potential confounding factors, the relative risk ratios for frailty and pre-frailty were 2.15 (1.68, 2.75) and 1.50 (1.29, 1.74), respectively. The associations were unchanged after excluding incident cases of cardiovascular disease. Separate adjustment for each component of the risk score suggested that no single component was driving the associations between cardiovascular risk score and incident pre-frailty or frailty. Framingham cardiovascular risk scores may be useful for predicting the development of physical frailty in older people. We now need to understand the biological mechanisms whereby cardiovascular risk increases the risk of frailty.
doi:10.1007/s11357-014-9692-6
PMCID: PMC4129936  PMID: 25085033
Frailty; Cardiovascular risk; Cohort; Longitudinal study
3.  Physical capability and subsequent positive mental wellbeing in older people: findings from five HALCyon cohorts 
Age (Dordrecht, Netherlands)  2013;36(1):10.1007/s11357-013-9553-8.
Objective measures of physical capability are being used in a growing number of studies as biomarkers of healthy ageing. However, very little research has been done to assess the impact of physical capability on subsequent positive mental wellbeing, the maintenance of which is widely considered to be an essential component of healthy ageing. We aimed to test the associations of grip strength and walking, timed get up and go and chair rise speeds (assessed at ages 53 to 82 years) with positive mental wellbeing assessed using the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) five to ten years later. Data were drawn from five British cohorts participating in the HALCyon research collaboration. Data from each study were analysed separately and then combined using random-effects meta-analyses. Higher levels of physical capability were consistently associated with higher subsequent levels of wellbeing; for example, a 1SD increase in grip strength was associated with an age and sex-adjusted mean difference in WEMWBS score of 0.81 (0.25, 1.37), equivalent to 10% of a standard deviation (3 studies, N=3,096). When adjusted for body size, health status, living alone, socioeconomic position and neuroticism the associations remained albeit attenuated. The finding of these consistent modest associations across five studies, spanning early and later old age, highlights the importance of maintaining physical capability in later life and provides additional justification for using objective measures of physical capability as markers of healthy ageing.
doi:10.1007/s11357-013-9553-8
PMCID: PMC3818137  PMID: 23818103
physical capability; positive mental wellbeing; grip strength; walking speed; chair rise time
4.  Physical capability and subsequent positive mental wellbeing in older people: findings from five HALCyon cohorts 
Age  2013;36(1):445-456.
Objective measures of physical capability are being used in a growing number of studies as biomarkers of healthy ageing. However, very little research has been done to assess the impact of physical capability on subsequent positive mental wellbeing, the maintenance of which is widely considered to be an essential component of healthy ageing. We aimed to test the associations of grip strength and walking, timed get up and go and chair rise speeds (assessed at ages 53 to 82 years) with positive mental wellbeing assessed using the Warwick–Edinburgh Mental Wellbeing Scale (WEMWBS) 5 to 10 years later. Data were drawn from five British cohorts participating in the Healthy Ageing across the Life Course research collaboration. Data from each study were analysed separately and then combined using random-effects meta-analyses. Higher levels of physical capability were consistently associated with higher subsequent levels of wellbeing; for example, a 1SD increase in grip strength was associated with an age and sex-adjusted mean difference in WEMWBS score of 0.81 (0.25, 1.37), equivalent to 10 % of a standard deviation (three studies, N = 3,096). When adjusted for body size, health status, living alone, socioeconomic position and neuroticism the associations remained albeit attenuated. The finding of these consistent modest associations across five studies, spanning early and later old age, highlights the importance of maintaining physical capability in later life and provides additional justification for using objective measures of physical capability as markers of healthy ageing.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-013-9553-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-013-9553-8
PMCID: PMC3818137  PMID: 23818103
Physical capability; Positive mental wellbeing; Grip strength; Walking speed; Chair rise time
5.  Association of lung function with physical, mental and cognitive function in early old age 
Age  2010;33(3):385-392.
Lung function predicts mortality; whether it is associated with functional status in the general population remains unclear. This study examined the association of lung function with multiple measures of functioning in early old age. Data are drawn from the Whitehall II study; data on lung function (forced expiratory volume in 1 s, height FEV1), walking speed (2.44 m), cognitive function (memory and reasoning) and self-reported physical and mental functioning (SF-36) were available on 4,443 individuals, aged 50–74 years. In models adjusted for age, 1 standard deviation (SD) higher height-adjusted FEV1 was associated with greater walking speed (beta = 0.16, 95% CI: 0.13, 0.19), memory (beta = 0.09, 95% CI: 0.06, 0.12), reasoning (beta = 0.16, 95% CI: 0.13, 0.19) and self-reported physical functioning (beta = 0.13, 95% CI: 0.10, 0.16). Socio-demographic measures, health behaviours (smoking, alcohol, physical activity, fruit/vegetable consumption), body mass index (BMI) and chronic conditions explained two-thirds of the association with walking speed and self-assessed physical functioning and over 80% of the association with cognitive function. Our results suggest that lung function is a good ‘summary’ measure of overall functioning in early old age.
doi:10.1007/s11357-010-9189-x
PMCID: PMC3168608  PMID: 20878489
Ageing; Lung function; Cognitive function; Physical function
6.  Association of lung function with physical, mental and cognitive function in early old age 
Age  2010;33(3):385-392.
Lung function predicts mortality, whether it is associated with functional status in the general population remains unclear. This study examined the association of lung function with multiple measures of functioning in early old age. Data are drawn from the Whitehall II study; data on lung function (forced expiratory volume in one second, height FEV1), walking speed (over 2.44 m), cognitive function (memory and reasoning), and self-reported physical and mental functioning (SF-36) were available on 4443 individuals, aged 50–74 years. In models adjusted for age, one standard deviation (SD) higher height-adjusted FEV1 was associated with greater walking speed (beta=0.16, 95% CI: 0.13, 0.19), memory (beta=0.09, 95% CI: 0.06, 0.12), reasoning (beta=0.16, 95% CI: 0.13, 0.19), and self-reported physical functioning (beta=0.13, 95% CI: 0.10, 0.16). Socio-demographic measures, health behaviours (smoking, alcohol, physical activity, fruit/vegetable consumption), BMI and chronic conditions explained two-thirds of the association with walking speed and self-assessed physical functioning and over 80% of the association with cognitive function. Our results suggest that lung function is a good “summary” measure of overall functioning in early old age.
doi:10.1007/s11357-010-9189-x
PMCID: PMC3168608  PMID: 20878489
Aged; Aging; physiology; psychology; Cognition; physiology; Female; Health Status; Humans; Lung; physiology; Male; Middle Aged; Spirometry; Walking; physiology; ageing; lung function; cognitive function; physical function
7.  Dehydroepiandrosterone and age-related cognitive decline 
Age  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
8.  Dehydroepiandrosterone and age-related cognitive decline 
Age (Dordrecht, Netherlands)  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
9.  EN FACE IMAGING OF THE CHOROID IN POLYPOIDAL CHOROIDAL VASCULOPATHY USING SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY 
American journal of ophthalmology  2014;159(4):634-643.e2.
Objective
To define morphological features of polypoidal choroidal vasculopathy (PCV) using en face images from swept source optical coherence tomography (SS-OCT).
Design
Prospective cross-sectional study.
Methods
Ten eyes from 6 patients with PCV and 10 eyes from 5 age-matched normal subjects. All subjects were prospectively scanned with a prototype SS-OCT system. A motion correction algorithm was applied to correct and merge scans into a single volumetric dataset. En face images were generated at intervals of 4.13 μm (1 pixel) relative to the Bruch’s membrane.
Results
Age ± standard deviation for the normal group was 62.4 (±12.1) years and for the PCV group was 68.3 (±5.2) years. En face SS-OCT imaging of PCV eyes demonstrated the relationship between larger pigment epithelial detachments (PEDs) and small adjoining PEDs which correlated with the polypoidal lesions seen on indocyanine green angiography in all PCV eyes. En face SS-OCT demonstrated choroidal vascular abnormalities in 7 out of 7 eyes with PCV, and in 2 out of 3 enrolled fellow eyes in patients with unilateral PCV. Out of 7 PCV eyes, focal choroidal vascular dilatation was noted in 3 eyes and diffuse choroidal vascular dilatation was noted in 1 eye. In addition, a branching vascular network was noted above Bruch’s membrane in 1 eye, below Bruch’s membrane within the choriocapillaris in 1 eye, and in the larger choroidal vascular layer in 1 eye.
Conclusions
En face SS-OCT provides an in vivo tool to visualize the pathological features and the choroidal vasculature in PCV.
doi:10.1016/j.ajo.2014.12.012
PMCID: PMC4387278  PMID: 25528955
10.  Serodiagnosis for Tumor Viruses 
Seminars in oncology  2014;42(2):191-206.
The known human tumor viruses include the DNA viruses Epstein-Barr virus, Kaposi sarcoma herpesvirus, Merkel cell polyomavirus, human papillomavirus, and hepatitis B virus. RNA tumor viruses include Human T-cell lymphotrophic virus type-1 and hepatitis C virus. The serological identification of antigens/antibodies in plasma serum is a rapidly progressing field with utility for both scientists and clinicians. Serology is useful for conducting seroepidemiology studies and to inform on the pathogenesis and host immune response to a particular viral agent. Clinically, serology is useful for diagnosing current or past infection and for aiding in clinical management decisions. Serology is useful for screening blood donations for infectious agents and for monitoring the outcome of vaccination against these viruses. Serodiagnosis of human tumor viruses has improved in recent years with increased specificity and sensitivity of the assays, as well as reductions in cost and the ability to assess multiple antibody/antigens in single assays. Serodiagnosis of tumor viruses plays an important role in our understanding of the prevalence and transmission of these viruses and ultimately in the ability to develop treatments/preventions for these globally important diseases.
doi:10.1053/j.seminoncol.2014.12.024
PMCID: PMC4387312  PMID: 25843726
11.  Biomarker-based Asthma Phenotypes of Corticosteroid Response 
Background
Asthma is a heterogeneous disease with different phenotypes. Inhaled corticosteroid (ICS) therapy is a mainstay of treatment for asthma but the clinical response to ICS is variable.
Objective
We hypothesized that a panel of inflammatory biomarkers i.e. FENO, sputum eosinophils and urinary BromoTyrosine (BrTyr) might predict steroid responsiveness.
Methods
The original study, from which this analysis originates, comprised 2 phases: a steroid naïve phase 1 and a 28-day trial of ICS (phase 2) during which times, FENO, sputum eosinophils, and urinary BrTyr were measured. Response to ICS was based on clinical improvements including: ≥12% increase in FEV1; ≥0.5 point decrease in Asthma Control Questionnaire; and ≥2 doubling dose increase in provocation concentration of adenosine 5′-monophosphate causing a 20% fall in FEV1 (PC20 AMP). Healthy controls were also evaluated in this study for comparison of biomarkers to asthmatics.
Results
Asthmatics had higher than normal FENO, sputum eosinophils and urinary BrTyr at steroid naïve phase and after ICS. After 28-day trial of ICS, FENO decreased in 82% of asthmatics, sputum eosinophils decreased in 60% and urinary BrTyr decreased in 58%. Each of the biomarkers at steroid naïve phase had utility for predicting steroid- responsiveness, but the combination of high FENO and high urinary BrTyr had the best power (13.3 fold; p<0.01) to predict a favorable response to ICS. However, the magnitude of decrease of biomarkers was unrelated to the magnitude of clinical response to ICS.
Conclusion
A noninvasive panel of biomarkers in steroid naïve asthmatics predicts clinical responsiveness to ICS.
doi:10.1016/j.jaci.2014.10.026
PMCID: PMC4388771  PMID: 25488689
Asthma; Inhaled Corticosteroids; Biomarker; Clinical outcome; Sputum eosinophils; Urinary Bromotyrosine and fractional exhaled NO
12.  The Cost of Learning: Interference Effects in Memory Development 
Learning often affects future learning and memory for previously learned information by exerting either facilitation or interference effects. Several theoretical accounts of interference effects have been proposed, each making different developmental predictions. This research examines interference effects across development, with the goal of better understanding mechanisms of interference and of memory development. Preschool-aged children and adults participated in a three-phased associative learning paradigm containing stimuli that were either unique or repeated across phases. Both age groups demonstrated interference effects, but only for repeated items. Whereas proactive interference effects were comparable across age groups, retroactive interference reached catastrophic-like levels in children. Additionally, retroactive interference increased in adults when contextual differences between phases were minimized (Experiment 2), and decreased in adults who were more successful at encoding repeated pairs of stimuli during a training phase (Experiment 3). These results are discussed with respect to theories of memory and memory development.
doi:10.1037/xge0000051
PMCID: PMC4388774  PMID: 25688907
13.  Oxygen Saturation Target Range for Extremely Preterm Infants 
JAMA pediatrics  2015;169(4):332-340.
IMPORTANCE
The optimal oxygen saturation (SpO2) target for extremely preterm infants is unknown.
OBJECTIVE
To systematically review evidence evaluating the effect of restricted vs liberal oxygen exposure on morbidity and mortality in extremely preterm infants.
DATA SOURCES
MEDLINE, PubMed, CENTRAL, and CINAHL databases from their inception to March 31, 2014, and abstracts submitted to Pediatric Academic Societies from 2000 to 2014.
STUDY SELECTION
All published randomized trials evaluating the effect of restricted (SpO2, 85%–89%) vs liberal (SpO2, 91%–95%) oxygen exposure in preterm infants (<28 weeks’ gestation at birth).
DATA EXTRACTION AND SYNTHESIS
All meta-analyses were performed using Review Manager 5.2. The Cochrane risk-of-bias tool was used to assess study quality. The summary of the findings and the level of confidence in the estimate of effect were assessed using GRADEpro. Treatment effect was analyzed using a random-effects model.
MAIN OUTCOMES AND MEASURES
Death before hospital discharge, death or severe disability before 24 months, death before 24months, neurodevelopmental outcomes, hearing loss, bronchopulmonary dysplasia, necrotizing enterocolitis, and severe retinopathy of prematurity.
RESULTS
Five trials were included in the final synthesis. These studies had a similar design with a prespecified composite outcome of death/disability at 18 to 24 months corrected for prematurity; however, this outcome has not been reported for 2 of the 5 trials. There was no difference in the outcome of death/disability before 24 months (risk ratio [RR], 1.02 [95% CI, 0.92–1.14]). Mortality before 24 months was not different (RR, 1.13 [95% CI, 0.97–1.33]); however, a significant increase in mortality before hospital discharge was found in the restricted oxygen group (RR, 1.18 [95% CI, 1.03–1.36]). The rates of bronchopulmonary dysplasia, neurodevelopmental outcomes, hearing loss, and retinopathy of prematurity were similar between the 2 groups. Necrotizing enterocolitis occurred more frequently in infants on restricted oxygen (RR, 1.24 [95% CI, 1.05–1.47]). Using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria, we found that the quality of evidence for these outcomes was moderate to low.
CONCLUSIONS AND RELEVANCE
Although infants cared for with a liberal oxygen target had significantly lower mortality before hospital discharge than infants cared for with a restricted oxygen target, the quality of evidence for this estimate of effect is low. Necrotizing enterocolitis occurred less frequently in the liberal oxygen group. We found no significant differences in death or disability at 24 months, bronchopulmonary dysplasia, retinopathy of prematurity, neurodevelopmental outcomes, or hearing loss at 24 months.
doi:10.1001/jamapediatrics.2014.3307
PMCID: PMC4388792  PMID: 25664703
14.  Anti-CD138-Targeted Interferon Is a Potent Therapeutic Against Multiple Myeloma 
Multiple myeloma (MM), a plasma cell malignancy, is the second most prevalent hematologic malignancy in the US. Although much effort has been made trying to understand the etiology and the complexities of this disease with the hope of developing effective therapies, MM remains incurable at this time. Because of their antiproliferative and proapoptotic activities, interferons (IFNs) have been used to treat various malignancies, including MM. Although some success has been observed, the inherent toxicities of IFNs limit their efficacy. To address this problem, we produced anti-CD138 antibody fusion proteins containing either IFNα2 or a mutant IFNα2 (IFNα2YNS) with the goal of targeting IFN to CD138-expressing cells, thereby achieving effective IFN concentrations at the site of the tumor in the absence of toxicity. The fusion proteins inhibited the proliferation and induced apoptosis of U266, ANBL-6, NCI-H929, and MM1-144 MM cell lines. The fusion proteins decreased the expression of IFN regulatory factor 4 (IRF4) in U266. In addition, the fusion proteins were effective against primary cells from MM patients, and treatment with fusion proteins prolonged survival in the U266 murine model of MM. These studies show that IFNα antibody fusion proteins can be effective novel therapeutics for the treatment of MM.
doi:10.1089/jir.2014.0125
PMCID: PMC4390003  PMID: 25353626
15.  Association of inpatient and outpatient glucose management with inpatient mortality among patients with and without diabetes at a major academic medical center 
Journal of hospital medicine  2015;10(4):228-235.
Background
Hospitalized patients with diabetes have experienced a disproportionate reduction in mortality over the past decade.
Objective
To examine whether this differential decrease affected all patients with diabetes, and to identify explanatory factors.
Design
Serial, cross-sectional observational study
Setting
Academic medical center
Patients
All adult, non-obstetric patients with an inpatient discharge between Jan 1, 2000 and Dec 31, 2010
Measurement
We assessed in-hospital mortality; inpatient glycemic control (percentage of hospital days with glucose below 70, above 299, and between 70-179 mg/dl, and standard deviation of glucose measurements); and outpatient glycemic control (hemoglobin A1c).
Results
We analyzed 322,938 admissions, including 76,758 (23.8%) with diabetes. Among 54,645 ICU admissions, there was a 7.8% relative reduction in the odds of mortality in each successive year for patients with diabetes, adjusted for age, race, payer, length of stay, discharge diagnosis, comorbidities, and service (OR=0.923, 95% CI: 0.906, 0.940). This was significantly greater than the 2.6% yearly reduction for those without diabetes (OR=0.974, CI: 0.963, 0.985; p<0.001 for interaction). In contrast, the greater decrease in mortality among non-ICU patients with diabetes did not reach significance. Results were similar among medical and surgical patients. Among ICU patients with diabetes, the significant decline in mortality persisted after adjustment for inpatient and outpatient glucose control (OR=0.953, 95% CI: 0.914, 0.994).
Conclusions
Patients with diabetes in the ICU have experienced a disproportionate reduction in mortality that is not explained by glucose control. Potential explanations include improved cardiovascular risk management or advances in therapies for diseases commonly affecting patients with diabetes.
doi:10.1002/jhm.2321
PMCID: PMC4390436  PMID: 25627860
Diabetes; Glucose Management; Mortality; Inpatient Mortality; Outcomes; Hospital Medicine
16.  PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer 
Cancer immunology research  2014;3(4):326-332.
Programmed death 1 ligand 1 (PD-L1) is an immune regulatory molecule that limits antitumor immune activity. Targeting of PD-L1 and other immune checkpoint proteins has shown therapeutic activity in various tumor types. The expression of PD-L1 and its correlation with response to neoadjuvant chemotherapy in breast cancer has not been studied extensively. Our goal was to assess PD-L1 expression in a cohort of breast cancer patients treated with neoadjuvant chemotherapy. Pre-treatment biopsies from 105 breast cancer patients from Yale New Haven Hospital that subsequently received neoadjuvant chemotherapy were assessed for PD-L1 protein expression by automated quantitative analysis (AQUA) with a rabbit monoclonal antibody (E1L3N) to the cytoplasmic domain of PD-L1. Additionally, tumor-infiltrating lymphocytes (TIL) were assessed on H&E slides.PD-L1 expression was observed in 30% of patients and it was positively associated with hormone-receptor negative and triple-negative status and high levels of TILs. Both TILs and PD-L1 measured in the epithelium or stroma predicted pathologic complete response (pCR) to neoadjuvant chemotherapy in univariate and multivariate analysis. However, since they are strongly associated, TILs and PD-L1 cannot both be included in a significant multivariate model.PD-L1 expression is prevalent in breast cancer, particularly hormone-receptor negative and triple-negative patients, indicating a subset of patients that may benefit from immune therapy. Furthermore, PD-L1 and TILs correlate with pCR and high PD-L1 predicts pCR in multivariate analysis.
doi:10.1158/2326-6066.CIR-14-0133
PMCID: PMC4390454  PMID: 25527356
PD-L1; neoadjuvant chemotherapy; breast cancer; predictive biomarkers; tumor-infiltrating lymphocytes
17.  IKKβ in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5 
Cell Death and Differentiation  2014;22(5):852-861.
IκB kinase β (IKKβ) is a catalytic subunit of the IKK complex, which activates nuclear factor-κB (NF-κB). Although its role in osteoclastogenesis is well established, the role of IKKβ in bone formation is poorly understood. Here, we report that conditional knockout of Ikkβ in limb bud mesenchymal cells results in the upregulation of monocyte chemoattractant protein-5 (MCP-5) in the perichondrium, which in turn inhibits the growth of longitudinal bone by compromising chondrocyte hypertrophy and increasing the apoptosis of chondrocytes within the growth plate. Contrary to expectations, IKKβ in cells of chondrocyte or osteoblast lineage was dispensable for bone growth. On the other hand, ex vivo experiments confirmed the role of MCP-5 in the growth of longitudinal bone. Furthermore, an in vitro study demonstrated that the action of IKKβ on MCP-5 is cell autonomous. Collectively, our results provide evidence for a previously unrecognized role of IKKβ in the regulation of the growth plate that is mediated through stimulation-independent downregulation of MCP-5 in the perichondrium.
doi:10.1038/cdd.2014.192
PMCID: PMC4392083  PMID: 25526093
18.  Preoperative Carcinoembryonic Antigen and Prognosis of Colorectal Cancer. An Independent Prognostic Factor Still Reliable 
International Surgery  2015;100(4):617-625.
To evaluate whether, in a sample of patients radically treated for colorectal carcinoma, the preoperative determination of the carcinoembryonic antigen (p-CEA) may have a prognostic value and constitute an independent risk factor in relation to disease-free survival. The preoperative CEA seems to be related both to the staging of colorectal neoplasia and to the patient's prognosis, although this—to date—has not been conclusively demonstrated and is still a matter of intense debate in the scientific community. This is a retrospective analysis of prospectively collected data. A total of 395 patients were radically treated for colorectal carcinoma. The preoperative CEA was statistically compared with the 2010 American Joint Committee on Cancer (AJCC) staging, the T and N parameters, and grading. All parameters recorded in our database were tested for an association with disease-free survival (DFS). Only factors significantly associated (P < 0.05) with the DFS were used to build multivariate stepwise forward logistic regression models to establish their independent predictors. A statistically significant relationship was found between p-CEA and tumor staging (P < 0.001), T (P < 0.001) and N parameters (P = 0.006). In a multivariate analysis, the independent prognostic factors found were: p-CEA, stages N1 and N2 according to AJCC, and G3 grading (grade). A statistically significant difference (P < 0.001) was evident between the DFS of patients with normal and high p-CEA levels. Preoperative CEA makes a pre-operative selection possible of those patients for whom it is likely to be able to predict a more advanced staging.
doi:10.9738/INTSURG-D-14-00100.1
PMCID: PMC4400928  PMID: 25875542
Colorectal carcinoma; Preoperative carcinoembryonic antigen; Disease-free survival; Independent prognostic factor
19.  The impact of executive capacity and age on mechanisms underlying multidimensional feature selection 
Neuropsychologia  2015;70:30-42.
This study examined the role of executive capacity (EC) and aging in multidimensional feature selection. ERPs were recorded from healthy young and old adults of either high or average EC based on neuropsychological testing. Participants completed a color selective attention task in which they responded to target letter-forms in a specified color (attend condition) while ignoring letter-forms in a different color (ignore condition). Two selection negativity (SN) components were computed: the SNColor (attend – ignore), indexing early color selection, and the SNLetter (targets – standards), indexing early letter-form selection. High EC subjects exhibited self-terminating feature selection; the processing of one feature type was reduced if information from the other feature type suggested the stimulus did not contain the task-relevant feature. In contrast, average EC subjects exhaustively selected all features of a stimulus. The self-terminating approach was associated with better task accuracy. Higher EC was also linked to stronger early selection of target letter-forms, but did not modulate the seemingly less demanding task of color selection. Mechanisms utilized for multidimensional feature selection appear to be consistent across the lifespan, although there was age-related slowing of processing speed for early selection of letter features. We conclude that EC is a critical determinant of how multidimensional feature processing is carried out.
doi:10.1016/j.neuropsychologia.2015.02.003
PMCID: PMC4402256  PMID: 25660207
Multidimensional Feature Selection; Selective Attention; ERPs; Selection Negativity; Executive Control; Aging
20.  Hydrogen/Deuterium Exchange Mass Spectrometry Applied to IL-23 Interaction Characteristics: Potential Impact for Therapeutics 
Expert review of proteomics  2015;12(2):159-169.
Interleukin-23 (IL-23) is an important therapeutic target for the treatment of inflammatory diseases. Adnectins are targeted protein therapeutics that are derived from domain III of human fibronectin, and have similar protein scaffold to antibodies. A specific adnectin (Adnectin 2) was identified to bind to IL-23 and compete with IL-23/IL-23R interaction, being a potential protein therapeutic. Hydrogen/deuterium exchange mass spectrometry (HDX MS) and computational methods were applied to probe the binding interactions between IL-23 and Adnectin2 and to determine the correlation between the two orthogonal methods. This review article summarizes the current structural knowledge about Il-23 and it focuses on the applicability of HDX MS to investigate the higher order structure of proteins, which plays an important role for the discovery of new and improved biotherapeutics.
doi:10.1586/14789450.2015.1018897
PMCID: PMC4409866  PMID: 25711416
Interleukins; structure; protein-protein interactions; hydrogen/deuterium exchange; mass spectrometry; protein binding; biotherapeutics
21.  Hepatitis C Surveillance among Youth and Young Adults in New York City, 2009–2013 
Increases in prescription opioid misuse, injection drug use, and hepatitis C infections have been reported among youth and young adults in the USA, particularly in rural and suburban areas. To better understand these trends in New York City and to characterize demographics and risk factors among a population who, by virtue of their age, are more likely to be recently infected with hepatitis C, we analyzed routine hepatitis C surveillance data from 2009 to 2013 and investigated a sample of persons 30 and younger newly reported with hepatitis C in 2013. Between 2009 and 2013, 4811 persons 30 and younger were newly reported to the New York City Department of Health and Mental Hygiene with hepatitis C. There were high rates of hepatitis C among persons 30 and younger in several neighborhoods that did not have high rates of hepatitis C among older people. Among 402 hepatitis C cases 30 and younger investigated in 2013, the largest proportion (44 %) were white, non-Hispanic, and the most commonly reported risk factor for hepatitis C was injection drug use, mostly heroin. Hepatitis C prevention and harm reduction efforts in NYC focused on young people should target these populations, and surveillance for hepatitis C among young people should be a priority in urban as well as rural and suburban settings.
doi:10.1007/s11524-014-9920-5
PMCID: PMC4411323  PMID: 25450518
Hepatitis C; Surveillance; Youth; Young adults; Adolescents; Public health
22.  Choice Impulsivity: Definitions, Measurement Issues, and Clinical Implications 
Personality disorders  2015;6(2):182-198.
Background
Impulsivity critically relates to many psychiatric disorders. Given the multi-faceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity.
Method
The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species.
Results
Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings.
Conclusions
The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures.
doi:10.1037/per0000099
PMCID: PMC4535726  PMID: 25867841
impulsivity; response; attention; behavioral control; personality; delay discounting; delay of gratification; self-control
23.  Pivotal Role for Decorin in Angiogenesis 
Angiogenesis, the formation of new blood vessels from preexisting vessels, is a highly complex process. It is regulated in a finely-tuned manner by numerous molecules including not only soluble growth factors such as vascular endothelial growth factor and several other growth factors, but also a diverse set of insoluble molecules, particularly collagenous and non-collagenous matrix constituents. In this review we have focused on the role and potential mechanisms of a multifunctional small leucine-rich proteoglycan decorin in angiogenesis. Depending on the cellular and molecular microenvironment where angiogenesis occurs, decorin can exhibit either a proangiogenic or an antiangiogenic activity. Nevertheless, in tumorigenesis-associated angiogenesis and in various inflammatory processes, particularly foreign body reactions and scarring, decorin exhibits an antiangiogenic activity, thus providing a potential basis for the development of decorin-based therapies in these pathological situations.
doi:10.1016/j.matbio.2015.01.023
PMCID: PMC4560244  PMID: 25661523
Angiogenesis; extracellular matrix; proteoglycan; decorin; mechanism; therapy
24.  HERITABILITY OF BRAIN NETWORK TOPOLOGY IN 853 TWINS AND SIBLINGS 
Anatomical brain networks change throughout life and with diseases. Genetic analysis of these networks may help identify processes giving rise to heritable brain disorders, but we do not yet know which network measures are promising for genetic analyses. Many factors affect the downstream results, such as the tractography algorithm used to define structural connectivity. We tested nine different tractography algorithms and four normalization methods to compute brain networks for 853 young healthy adults (twins and their siblings). We fitted genetic structural equation models to all nine network measures, after a normalization step to increase network consistency across tractography algorithms. Probabilistic tractography algorithms with global optimization (such as Probtrackx and Hough) yielded higher heritability statistics than “greedy” algorithms (such as FACT) which process small neighborhoods at each step. Some global network measures (probtrackx-derived GLOB and ST) showed significant genetic effects, making them attractive targets for genome-wide association studies.
doi:10.1109/ISBI.2015.7163908
PMCID: PMC4578220  PMID: 26413204
diffusion MRI; Brain Network; Tractography; ICC; Normalization
25.  Onlay Tibial Implants Appear to Provide Superior Clinical Results in Robotic Unicompartmental Knee Arthroplasty 
HSS Journal  2014;11(1):43-49.
Background
Unicompartmental knee arthroplasty (UKA) is an increasingly popular option for the treatment of single-compartment knee osteoarthritis (OA) in adults. Two options for tibial resurfacing during UKA are (1) all-polyethylene inlays and (2) metal-backed onlays.
Questions/Purposes
The aim of this study was to determine whether there are any differences in clinical outcomes with inlay versus onlay tibial components.
Patients and Methods
We identified 39 inlays and 45 onlays, with average 2.7- and 2.3-year follow-up, respectively, from a prospective robotic-assisted surgery database. The primary outcome was the Western Ontario and McMaster University Arthritis Index (WOMAC), subcategorized by the pain, stiffness, and function subscores, at 2 years postoperatively. The secondary outcome was the need for secondary or revision surgery.
Results
Postoperative WOMAC pain score was 3.1 for inlays and 1.6 for onlays (p = 0.03). For 25 inlays and 30 onlays with both preoperative and postoperative WOMAC data, pain score improved from 8.3 to 4.0 for inlays versus from 9.2 to 1.7 for onlays (p = 0.01). Function score improved from 27.5 to 12.5 for inlays versus from 32.1 to 7.3 for onlays (p = 0.03). Four inlays and one onlay required a secondary or revision procedure (p = 0.18).
Conclusions
We advise using metal-backed onlays during UKA to improve postoperative clinical outcomes.
Electronic supplementary material
The online version of this article (doi:10.1007/s11420-014-9421-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s11420-014-9421-9
PMCID: PMC4342394  PMID: 25737668
unicompartmental knee arthroplasty; tibial resurfacing; inlay; onlay; robotic surgery

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