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1.  Results of a multicenter phase II trial of brentuximab vedotin as second-line therapy before autologous transplantation in relapsed/refractory Hodgkin Lymphoma 
This multicenter prospective phase II study examines the activity and tolerability of brentuximab vedotin as second-line therapy in patients with Hodgkin lymphoma that was relapsed or refractory after induction therapy. Brentuximab vedotin (1.8 mg/kg) was administered intravenously on day 1 of a 21-day cycle for a total of 4 cycles. Patients then proceeded to autologous hematopoietic cell transplantation (AHCT), if eligible, with or without additional salvage therapy, based on remission status post brentuximab vedotin. The primary endpoint was overall response rate (ORR). Secondary endpoints were safety, stem cell mobilization/collection, AHCT outcomes and association of CD68+ with outcomes. Of 37 patients, the ORR was 68% (13 complete remission, 12 partial remission). The regimen was well tolerated with few grade 3/4 adverse events including lymphopenia (1), neutropenia (3), rash (2), and hyperuricemia (1). Thirty-three (89%) patients were able to proceed to AHCT, with 24 (65%) in CR at time of AHCT. Thirteen patients in CR, 4 in PR and 1 in SD (49%) received AHCT without salvage combination chemotherapy. CD 68 expression did not correlate with response to brentuximab vedotin. The median number of stem cells mobilized was 6.0 × 106 (2.6–34) and median number of days to obtain minimum collection (2 × 106) was 2 (1–6). Brentuximab vedotin as second-line therapy is active, well tolerated, and allows adequate stem cell collection and engraftment. For Hodgkin lymphoma patients with relapsed/refractory disease post-induction therapy, second-line brentuximab vedotin, followed by combination chemotherapy for residual disease, can effectively bridge patients to AHCT.
doi:10.1016/j.bbmt.2015.07.018
PMCID: PMC4639410  PMID: 26211987
2.  Detecting Staphylococcus aureus Virulence and Resistance Genes: a Comparison of Whole-Genome Sequencing and DNA Microarray Technology 
Journal of Clinical Microbiology  2016;54(4):1008-1016.
Staphylococcus aureus is a major bacterial pathogen causing a variety of diseases ranging from wound infections to severe bacteremia or intoxications. Besides host factors, the course and severity of disease is also widely dependent on the genotype of the bacterium. Whole-genome sequencing (WGS), followed by bioinformatic sequence analysis, is currently the most extensive genotyping method available. To identify clinically relevant staphylococcal virulence and resistance genes in WGS data, we developed an in silico typing scheme for the software SeqSphere+ (Ridom GmbH, Münster, Germany). The implemented target genes (n = 182) correspond to those queried by the Identibac S. aureus Genotyping DNA microarray (Alere Technologies, Jena, Germany). The in silico scheme was evaluated by comparing the typing results of microarray and of WGS for 154 human S. aureus isolates. A total of 96.8% (n = 27,119) of all typing results were equally identified with microarray and WGS (40.6% present and 56.2% absent). Discrepancies (3.2% in total) were caused by WGS errors (1.7%), microarray hybridization failures (1.3%), wrong prediction of ambiguous microarray results (0.1%), or unknown causes (0.1%). Superior to the microarray, WGS enabled the distinction of allelic variants, which may be essential for the prediction of bacterial virulence and resistance phenotypes. Multilocus sequence typing clonal complexes and staphylococcal cassette chromosome mec element types inferred from microarray hybridization patterns were equally determined by WGS. In conclusion, WGS may substitute array-based methods due to its universal methodology, open and expandable nature, and rapid parallel analysis capacity for different characteristics in once-generated sequences.
doi:10.1128/JCM.03022-15
PMCID: PMC4809937  PMID: 26818676
3.  Feedforward consequences of isometric contractions: effort and ventilation 
Physiological Reports  2016;4(15):e12882.
Abstract
The onset of voluntary muscle contractions causes rapid increases in ventilation and is accompanied by a sensation of effort. Both the ventilatory response and perception of effort are proportional to contraction intensity, but these behaviors have been generalized from contractions of a single muscle group. Our aim was to determine how these relationships are affected by simultaneous contractions of multiple muscle groups. We examined the ventilatory response and perceived effort of contraction during separate and simultaneous isometric contractions of the contralateral elbow flexors and of an ipsilateral elbow flexor and knee extensor. Subjects made 10‐sec contractions at 25, 50, and 100% of maximum during normocapnia and hypercapnia. For simultaneous contractions, both muscle groups were activated at the same intensities. Ventilation was measured continuously and subjects rated the effort required to produce each contraction. As expected, ventilation and perceived effort increased proportionally with contraction intensity during individual contractions. However, during simultaneous contractions, neither ventilation nor effort reflected the combined muscle output. Rather, the ventilatory response was similar to when contractions were performed separately, and effort ratings showed a small but significant increase for simultaneous contractions. Hypercapnia at rest doubled baseline ventilation, but did not affect the difference in perceived effort between separate and simultaneous contractions. The ventilatory response and the sense of effort at the onset of muscle activity are not related to the total output of the motor pathways, or the working muscles, but arise from cortical regions upstream from the motor cortex.
doi:10.14814/phy2.12882
PMCID: PMC4985548  PMID: 27482074
Bilateral; central command; force; human; hypercapnia; muscle
4.  Melioidosis: A Rare Cause of Liver Abscess 
Case Reports in Hepatology  2016;2016:5910375.
Case Presentation. This is a case of a 44-year-old male, farmer, known to be diabetic, presenting with two-week history of vague abdominal pain associated with high grade fever. Abdominal CT scan showed localized liver abscess at segment 8 measuring 7.5 × 6.8 × 6.1 cm. Patient subsequently underwent laparoscopic ultrasound guided pigtail insertion for drainage of abscess. Culture studies showed moderate growth of Burkholderia pseudomallei in which the patient completed seven days of IV Meropenem. On follow-up after 12 weeks of oral Sulfamethoxazole/Trimethoprim, taken twice a day, the patient remained asymptomatic with no residual findings based on the abdominal ultrasound. Discussion. Diagnosis of melioidosis, a known “great masquerader,” relies heavily on culture studies. Consensus with regard to the management of liver abscess caused by Burkholderia pseudomallei has not yet been established due to the rarity of cases. Surgical intervention through either a percutaneous or open drainage has shown good outcomes compared to IV antibiotics alone. In Philippines, the possibility of underreporting is highly plausible. This write-up serves not only to report a rare presentation of melioidosis but also to add to the number of cases reported in the country, possibly indicative of disease emergence.
doi:10.1155/2016/5910375
PMCID: PMC4977379  PMID: 27529039
5.  Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients 
Clinical Epigenetics  2016;8:79.
Background
Refractory and/or relapsed diffuse large B cell lymphoma (RR-DLBCL) patients are incurable with conventional chemotherapy due to the aggressiveness and the chemorefractory state of these tumors. DNA hypermethylation and histone deacetylation are two major epigenetic modifications by which aggressive DLBCL maintain their oncogenic state. We have previously reported that DNA methyltransferase inhibitors (DNMTI) affect RR-DLBCL growth and improve chemosensitivity. Here, we hypothesized that the combination of DNMTI with histone deacetylase inhibitor (HDI) would be an active and feasible therapeutic strategy in RR-DLBCL. Thus, we evaluated the anti-lymphoma activity of the HDI vorinostat (VST) in combination with the DNMTI azacitidine (AZA) or decitabine (DAC) in pre-clinical models of RR-DLBCL, and we determined the feasibility of the combination by conducting a phase Ib trial in RR-DLBCL patients.
Results
Concurrent combination of DNMTI and HDI resulted in synergistic anti-lymphoma effect toward RR-DLBCL cells in vitro and in vivo, with no significant toxicity increase. In a phase Ib trial, a total of 18 patients with a median of three prior therapies were treated with four different dose levels of AZA and VST. The most common toxicities were hematological, followed by gastrointestinal and metabolic. The clinical benefit was low as only one subject had a partial response and three subjects had stable disease. Interestingly, two of the seven patients that received additional chemotherapy post-study achieved a complete response and three others had a significant clinical benefit. These observations suggested that the combination might have a delayed chemosensitization effect that we were able to confirm by using in vitro and in vivo models. These studies also demonstrated that the addition of VST does not improve the chemosensitizing effect of DAC alone.
Conclusions
Our data supports the strategy of epigenetic priming by employing DNMTI in RR-DLBCL patients in order to overcome resistance and improve their outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-016-0245-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13148-016-0245-y
PMCID: PMC4957280  PMID: 27453763
Histone deacetylase inhibitors; Demethylating agents; Lymphoma; Chemosensitization; Phase Ib
6.  Phase I study of the anti-CD74 monoclonal antibody milatuzumab (hLL1) in patients with previously treated B-cell lymphomas 
Leukemia & lymphoma  2015;56(11):3065-3070.
Milatuzumab (hLL1), a humanized anti-CD74 monoclonal antibody, has activity in preclinical NHL models. We conducted a phase 1 trial in previously treated B-cell malignancies. Dose escalation included 4 planned dose levels (1.5, 4, 6, and 8 mg/kg) with milatuzumab given twice weekly for 6 weeks. After dose level 1, the schedule was changed to daily (Monday-Friday) for 10 days. Twenty-two patients were treated. The most common possibly-related toxicities were infusion reaction, anemia, lymphopenia, neutropenia, and thrombocytopenia. Three patients experienced dose-limiting toxicity (neutropenia, neutropenia, rash) at dose levels 1, 2, and 4 respectively. Eight patients had stable disease, with no objective responses. The serum half-life of milatuzumab was ~2 hours. In 7 patients, In-111-imaging showed no clear evidence of tumor targeting. The short half-life may reflect CD74 rapid internalization and presence on extratumoral tissues; this antigen sink must be overcome to capitalize on the promising preclinical activity of the drug.
doi:10.3109/10428194.2015.1028052
PMCID: PMC4855286  PMID: 25754579
7.  Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma 
The New England journal of medicine  2015;373(19):1835-1844.
BACKGROUND
Mantle-cell lymphoma is generally incurable. Initial treatment is not standardized but usually includes cytotoxic chemotherapy. Lenalidomide, an immunomodulatory compound, and rituximab, an anti-CD20 antibody, are active in patients with recurrent mantle-cell lymphoma. We evaluated lenalidomide plus rituximab as a first-line therapy.
METHODS
We conducted a single-group, multicenter, phase 2 study with induction and maintenance phases. During the induction phase, lenalidomide was administered at a dose of 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles; the dose was escalated to 25 mg daily after the first cycle if no dose-limiting adverse events occurred during the first cycle and was reduced to 15 mg daily during the maintenance phase. Rituximab was administered once weekly for the first 4 weeks and then once every other cycle until disease progression. The primary end point was the overall response rate. Secondary end points included outcomes related to safety, survival, and quality of life.
RESULTS
A total of 38 participants were enrolled at four centers from July 2011 through April 2014. The median age was 65 years. On the basis of the Mantle Cell Lymphoma International Prognostic Index scores, the proportions of participants with low-risk, intermediate-risk, and high-risk disease at baseline were similar (34%, 34%, and 32%, respectively). The most common grade 3 or 4 adverse events were neutropenia (in 50% of the patients), rash (in 29%), thrombocytopenia (in 13%), an inflammatory syndrome (“tumor flare”) (in 11%), anemia (in 11%), serum sickness (in 8%), and fatigue (in 8%). At the median follow-up of 30 months (through February 2015), the overall response rate among the participants who could be evaluated was 92% (95% confidence interval [CI], 78 to 98), and the complete response rate was 64% (95% CI, 46 to 79); median progression-free survival had not been reached. The 2-year progression-free survival was estimated to be 85% (95% CI, 67 to 94), and the 2-year overall survival 97% (95% CI, 79 to 99). A response to treatment was associated with improvement in quality of life.
CONCLUSIONS
Combination biologic therapy consisting of lenalidomide plus rituximab was active as initial therapy for mantle-cell lymphoma. (Funded by Celgene and Weill Cornell Medical College; ClinicalTrials.gov number, NCT01472562.)
doi:10.1056/NEJMoa1505237
PMCID: PMC4710541  PMID: 26535512
8.  Prescription Opioid Epidemic and Infant Outcomes 
Pediatrics  2015;135(5):842-850.
BACKGROUND AND OBJECTIVES:
Although opioid pain relievers are commonly prescribed in pregnancy, their association with neonatal outcomes is poorly described. Our objectives were to identify neonatal complications associated with antenatal opioid pain reliever exposure and to establish predictors of neonatal abstinence syndrome (NAS).
METHODS:
We used prescription and administrative data linked to vital statistics for mothers and infants enrolled in the Tennessee Medicaid program between 2009 and 2011. A random sample of NAS cases was validated by medical record review. The association of antenatal exposures with NAS was evaluated by using multivariable logistic regression, controlling for maternal and infant characteristics.
RESULTS:
Of 112 029 pregnant women, 31 354 (28%) filled ≥1 opioid prescription. Women prescribed opioid pain relievers were more likely than those not prescribed opioids (P < .001) to have depression (5.3% vs 2.7%), anxiety disorder (4.3% vs 1.6%) and to smoke tobacco (41.8% vs 25.8%). Infants with NAS and opioid-exposed infants were more likely than unexposed infants to be born at a low birth weight (21.2% vs 11.8% vs 9.9%; P < .001). In a multivariable model, higher cumulative opioid exposure for short-acting preparations (P < .001), opioid type (P < .001), number of daily cigarettes smoked (P < .001), and selective serotonin reuptake inhibitor use (odds ratio: 2.08 [95% confidence interval: 1.67–2.60]) were associated with greater risk of developing NAS.
CONCLUSIONS:
Prescription opioid use in pregnancy is common and strongly associated with neonatal complications. Antenatal cumulative prescription opioid exposure, opioid type, tobacco use, and selective serotonin reuptake inhibitor use increase the risk of NAS.
doi:10.1542/peds.2014-3299
PMCID: PMC4411781  PMID: 25869370
neonatal abstinence syndrome; neonatal drug withdrawal syndrome; neonatal opioid withdrawal syndrome; opioid pain reliever
9.  Effect of Mono and Di-rhamnolipids on Biofilms Pre-formed by Bacillus subtilis BBK006 
Current Microbiology  2016;73:183-189.
Different microbial inhibition strategies based on the planktonic bacterial physiology have been known to have limited efficacy on the growth of biofilms communities. This problem can be exacerbated by the emergence of increasingly resistant clinical strains. Biosurfactants have merited renewed interest in both clinical and hygienic sectors due to their potential to disperse microbial biofilms. In this work, we explore the aspects of Bacillus subtilis BBK006 biofilms and examine the contribution of biologically derived surface-active agents (rhamnolipids) to the disruption or inhibition of microbial biofilms produced by Bacillus subtilis BBK006. The ability of mono-rhamnolipids (Rha–C10–C10) produced by Pseudomonas aeruginosa ATCC 9027 and the di-rhamnolipids (Rha–Rha–C14–C14) produced by Burkholderia thailandensis E264, and phosphate-buffered saline to disrupt biofilm of Bacillus subtilis BBK006 was evaluated. The biofilm produced by Bacillus subtilis BBK006 was more sensitive to the di-rhamnolipids (0.4 g/L) produced by Burkholderia thailandensis than the mono-rhamnolipids (0.4 g/L) produced by Pseudomonas aeruginosa ATCC 9027. Rhamnolipids are biologically produced compounds safe for human use. This makes them ideal candidates for use in new generations of bacterial dispersal agents and useful for use as adjuvants for existing microbial suppression or eradication strategies.
doi:10.1007/s00284-016-1046-4
PMCID: PMC4923089  PMID: 27113589
10.  A QTL on the short arm of wheat (Triticum aestivum L.) chromosome 3B affects the stability of grain weight in plants exposed to a brief heat shock early in grain filling 
BMC Plant Biology  2016;16:100.
Background
Molecular markers and knowledge of traits associated with heat tolerance are likely to provide breeders with a more efficient means of selecting wheat varieties able to maintain grain size after heat waves during early grain filling.
Results
A population of 144 doubled haploids derived from a cross between the Australian wheat varieties Drysdale and Waagan was mapped using the wheat Illumina iSelect 9,000 feature single nucleotide polymorphism marker array and used to detect quantitative trait loci for heat tolerance of final single grain weight and related traits. Plants were subjected to a 3 d heat treatment (37 °C/27 °C day/night) in a growth chamber at 10 d after anthesis and trait responses calculated by comparison to untreated control plants. A locus for single grain weight stability was detected on the short arm of chromosome 3B in both winter- and autumn-sown experiments, determining up to 2.5 mg difference in heat-induced single grain weight loss. In one of the experiments, a locus with a weaker effect on grain weight stability was detected on chromosome 6B. Among the traits measured, the rate of flag leaf chlorophyll loss over the course of the heat treatment and reduction in shoot weight due to heat were indicators of loci with significant grain weight tolerance effects, with alleles for grain weight stability also conferring stability of chlorophyll (‘stay-green’) and shoot weight. Chlorophyll loss during the treatment, requiring only two non-destructive readings to be taken, directly before and after a heat event, may prove convenient for identifying heat tolerant germplasm. These results were consistent with grain filling being limited by assimilate supply from the heat-damaged photosynthetic apparatus, or alternatively, accelerated maturation in the grains that was correlated with leaf senescence responses merely due to common genetic control of senescence responses in the two organs. There was no evidence for a role of mobilized stem reserves (water soluble carbohydrates) in determining grain weight responses.
Conclusions
Molecular markers for the 3B or 6B loci, or the facile measurement of chlorophyll loss over the heat treatment, could be used to assist identification of heat tolerant genotypes for breeding.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-016-0784-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-016-0784-6
PMCID: PMC4841048  PMID: 27101979
Heat tolerance; Wheat; Triticum aestivum; Quantitative trait loci; QTL; Stay-green; Senescence; Grain size; Grain filling
11.  ICC-dementia (International Centenarian Consortium - dementia): an international consortium to determine the prevalence and incidence of dementia in centenarians across diverse ethnoracial and sociocultural groups 
BMC Neurology  2016;16:52.
Background
Considerable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium – Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population. The primary goal of the ICC-Dementia is to establish a large and thorough heterogeneous sample that has the power to answer epidemiological questions that small, separate studies cannot. A secondary aim is to examine cohort-specific effects and differential survivorship into very old age. We hope to lay the foundation for further investigation into risk and protective factors for dementia and healthy exceptional brain ageing in centenarians across diverse ethnoracial and sociocultural groups.
Methods
Studies focusing on individuals aged ≥95 years (approximately the oldest 1 percentile for men, oldest 5th percentile for women), with a minimum sample of 80 individuals, including assessment of cognition and functional status, are invited to participate. There are currently seventeen member or potential member studies from Asia, Europe, the Americas, and Oceania. Initial attempts at harmonising key variables are in progress.
Discussion
General challenges facing large, international consortia like ICC-Dementia include timely and effective communication among member studies, ethical and practical issues relating to human subject studies and data sharing, and the challenges related to data harmonisation. A specific challenge for ICC-Dementia relates to the concept and definition of’abnormal’ in this exceptional group of individuals who are rarely free of physical, sensory and/or cognitive impairments.
doi:10.1186/s12883-016-0569-4
PMCID: PMC4839126  PMID: 27098177
Centenarians; Dementia; International; Prevalence; Incidence; Risk factors
12.  Personality Structure among Centenarians: The Georgia Centenarian Study 
Experimental aging research  2015;41(4):361-385.
We demonstrate that observer-rated factor structure of personality in centenarians is congruent with the normative structure. Prevalence of cognitive impairment, which has previously been linked to changes in personality in younger samples, is high in this age group, requiring observer ratings to obtain valid data in a population-based context. Likewise, the broad range of cognitive functioning necessitates synthesis of results across multiple measures of cognitive performance. Data from 161 participants in the Georgia Centenarian Study (GCS, MAge = 100.3 years, 84% women, 20% African American, 40% community-dwelling, 30% low cognitive functioning) support strong overall correspondence with reference structure (full sample: .94; higher cognitive functioning: .94; lower cognitive functioning: .90). Centenarians with lower cognitive functioning are higher on neuroticism and lower on openness to experience, agreeableness, and conscientiousness. Facet-level differences (higher N1–N6: anxiety, hostility, depression, self-consciousness, impulsiveness, vulnerability to stress; lower E1: warmth, lower O4–O6: actions, ideas, values; lower A1, A3, A4: trust, altruism, compliance; C1, C5: competence, self-discipline) are also observed. Multivariate factor-level models indicate only neuroticism of the five broad factors predicts membership in cognitively impaired group; facet-level models showed that lower-order scales from three of the five domains were significant. Centenarians with: higher self-consciousness (N4), impulsiveness (N5), and deliberation (C6), but lower ideas (O5), compliance (A4), and self-discipline (C5) were more likely to be in the lower cognitive functioning category. Results present first normative population-based data for personality structure in centenarians and offer intriguing possibilities for the role of personality in cognitive impairment centered on neuroticism.
doi:10.1080/0361073X.2015.1053752
PMCID: PMC4778554  PMID: 26214097
Five factor model; Personality; Procrustes Rotation; Centenarians; Cognitive Impairment; NEO PI-R
13.  Successful Aging and Subjective Well-Being Among Oldest-Old Adults 
The Gerontologist  2014;55(1):132-143.
Purpose of the Study:
This research integrates successful aging and developmental adaptation models to empirically define the direct and indirect effects of 2 distal (i.e., education and past life experiences) and 5 proximal influences (i.e., physical functioning, cognitive functioning, physical health impairment, social resources, and perceived economic status) on subjective well-being. The proximal influences involved predictors outlined in most extant models of successful aging (e.g., Rowe & Kahn, 1998 [Rowe, J. W., & Kahn, R. L. (1998). Successful aging. New York: Pantheon Books.]). Our model extends such models by including distal impact as well as interactions between distal and proximal impacts.
Design and Methods:
Data were obtained from 234 centenarians and 72 octogenarians in the Georgia Centenarian Study. Structural equation modeling was conducted with Mplus 6.1.
Results:
Results showed significant direct effects of physical health impairment and social resources on positive aspects of subjective well-being among oldest-old adults. We also found significant indirect effects of cognitive functioning and education on positive affect among oldest-old adults. Social resources mediated the relationship between cognitive functioning and positive affect; and cognitive functioning and social resources mediated the relationship between education and positive affect. In addition, physical health impairment mediated the relationship between cognitive functioning and positive affect; and cognitive functioning and physical health impairment mediated the relationship between education and positive affect.
Implications:
Integrating 2 different models (i.e., successful aging and developmental adaptation) provided a comprehensive view of adaptation from a developmental perspective.
doi:10.1093/geront/gnu074
PMCID: PMC4542895  PMID: 25112594
Georgia Centenarian Study; Successful aging; Subjective well-being; Oldest-old adults; Developmental adaptation model
14.  Defining Successful Aging: A Tangible or Elusive Concept? 
The Gerontologist  2014;55(1):14-25.
Purpose of the Study:
Everyone wants to age successfully; however, the definition and criteria of successful aging remain vague for laypersons, researchers, and policymakers in spite of decades of research on the topic. This paper highlights work of scholars who made significant theoretical contributions to the topic.
Design and Methods:
A thorough review and evaluation of the literature on successful aging was undertaken.
Results:
Our review includes early gerontological definitions of successful aging and related concepts. Historical perspectives reach back to philosophical and religious texts, and more recent approaches have focused on both process- and outcome-oriented models of successful aging. We elaborate on Baltes and Baltes’ theory of selective optimization with compensation [Baltes, P. B., & Baltes, M. M. (1990a). Psychological perspectives on successful aging: The model of selective optimization with compensation. In P. B. Baltes & M. M. Baltes (Eds.), Successful aging: Perspectives from the behavioral sciences (pp. 1–34). United Kingdom: Cambridge University Press], Kahana and Kahana’s preventive and corrective proactivity model [Kahana, E., & Kahana, B. (1996). Conceptual and empirical advances in understanding aging well through proactive adaptation. In V. Bengtson (Ed.), Adulthood and aging: Research on continuities and discontinuities (pp. 18–40). New York: Springer], and Rowe and Kahn’s model of successful aging [Rowe, J. W., & Kahn, R. L. (1998). Successful aging. New York: Pantheon Books], outlining their commonalities and differences. Additional views on successful aging emphasize subjective versus objective perceptions of successful aging and relate successful aging to studies on healthy and exceptional longevity.
Implications:
Additional theoretical work is needed to better understand successful aging, including the way it can encompass disability and death and dying. The extent of rapid social and technological change influencing views on successful aging also deserves more consideration.
doi:10.1093/geront/gnu044
PMCID: PMC4542894  PMID: 24840916
Successful aging; Longevity; Centenarians
15.  Tracing the Origins of Success: Implications for Successful Aging 
The Gerontologist  2014;55(1):5-13.
Purpose of the Study:
This paper addresses the debate about the use of the term “successful aging” from a humanistic, rather than behavioral, perspective. It attempts to uncover what success, a term frequently associated with aging, is: how can it be defined and when did it first come into use? In this paper, we draw from a number of humanistic perspectives, including the historical and linguistic, in order to explore the evolution of the term “success.” We believe that words and concepts have deep implications for how concepts (such as aging) are culturally and historically perceived.
Design and Methods:
We take a comparative approach, turning to the etymological roots of this term in British, French, and German literature. According to the earliest entries of the term in the Oxford English Dictionary, events can have good or bad success. Another definition marks success as outcome oriented.
Results:
Often used in the context of war, religion, and medicine, the neutral, but often negative, use of “success” in literature of the Renaissance demonstrates the tensions that surround the word, and suggests that success is something to be approached carefully.
Implications:
Ignoring the ambiguous origins of success erases the fact that aging in earlier centuries echoes much of the same ambivalence with which many people discuss it today. Attending to the origins of success can help gerontologists understand the humanistic tradition behind their inquiry into what successful aging means today.
doi:10.1093/geront/gnu054
PMCID: PMC4986587  PMID: 24997595
Successful aging; Longevity; Literature
16.  Selective targeting of BCL6 induces oncogene addiction switching to BCL2 in B-cell lymphoma 
Oncotarget  2015;7(3):3520-3532.
The BCL6 oncogene plays a crucial role in sustaining diffuse large B-cell lymphomas (DLBCL) through transcriptional repression of key checkpoint genes. BCL6-targeted therapy kills lymphoma cells by releasing these checkpoints. However BCL6 also directly represses several DLBCL oncogenes such as BCL2 and BCL-XL that promote lymphoma survival. Herein we show that DLBCL cells that survive BCL6-targeted therapy induce a phenomenon of “oncogene-addiction switching” by reactivating BCL2-family dependent anti-apoptotic pathways. Thus, most DLBCL cells require concomitant inhibition of BCL6 and BCL2-family members for effective lymphoma killing. Moreover, in DLBCL cells initially resistant to BH3 mimetic drugs, BCL6 inhibition induces a newly developed reliance on anti-apoptotic BCL2-family members for survival that translates in acquired susceptibility to BH3 mimetic drugs ABT-737 and obatoclax. In germinal center B cell-like (GCB)-DLBCL cells, the proteasome inhibitor bortezomib and the NEDD inhibitor MLN4924 post-transcriptionally activated the BH3-only sensitizer NOXA thus counteracting the oncogenic switch to BCL2 induced by BCL6-targeting. Hence our study indicates that BCL6 inhibition induces an on-target feedback mechanism based on the activation of anti-apoptotic BH3 members. This oncogene-addition switching mechanism was harnessed to develop rational combinatorial therapies for GCB-DLBCL.
doi:10.18632/oncotarget.6513
PMCID: PMC4823124  PMID: 26657288
lymphoma; BCL6; BCL2; targeting; resistance
17.  A Comparative Assessment of the Risks of Introduction and Spread of Foot-and-Mouth Disease among Different Pig Sectors in Australia 
Small-scale pig producers are believed to pose higher biosecurity risks for the introduction and spread of exotic diseases than commercial pig producers. However, the magnitude of these risks is poorly understood. This study is a comparative assessment of the risk of introduction and spread of foot-and-mouth disease (FMD) through different sectors of the pig industry: (1) large-scale pig producers; (2) small-scale producers (<100 sows) selling at saleyards and abattoirs; and (3) small-scale producers selling through informal means. An exposure and consequence assessments were conducted using the World Organization for Animal Health methodology for risk analysis, assuming FMD virus was introduced into Australia through illegal importation of infected meat. A quantitative assessment, using scenario trees and Monte Carlo stochastic simulation, was used to calculate the probabilities of exposure and spread. Input data for these assessments were obtained from a series of data gathering exercises among pig producers, industry statistics, and literature. Findings of this study suggest there is an Extremely low probability of exposure (8.69 × 10−6 to 3.81 × 10−5) for the three sectors of the pig industry, with exposure through direct swill feeding being 10–100 times more likely to occur than through contact with infected feral pigs. Spread of FMD from the index farm is most likely to occur through movement of contaminated fomites, pigs, and ruminants. The virus is more likely to spread from small-scale piggeries selling at saleyards and abattoirs than from other piggeries. The most influential factors on the spread of FMD from the index farm is the ability of the farmer to detect FMD, the probability of FMD spread through contaminated fomites and the presence of ruminants on the farm. Although small-scale producers selling informally move animals less frequently and do not use external staff, movement of pigs to non-commercial pathways could jeopardize animal traceability in the event of a disease outbreak. This study suggests that producers’ awareness on and engagement with legislative and industry requirements in relation to biosecurity and emergency animal disease management needs to be improved. Results from this study could be used by decision-makers to prioritize resource allocation for improving animal biosecurity in the pig industry.
doi:10.3389/fvets.2016.00085
PMCID: PMC5031773  PMID: 27713881
biosecurity; surveillance; emergency animal disease management; risk assessment; foot-and-mouth disease
19.  Factors Associated with Retention to Care in an HIV Clinic in Gabon, Central Africa 
PLoS ONE  2015;10(10):e0140746.
Background
Retention to HIV care is vital for patients’ survival, to prevent onward transmission and emergence of drug resistance. Travelling to receive care might influence adherence. Data on the functioning of and retention to HIV care in the Central African region are limited.
Methods
This retrospective study reports outcomes and factors associated with retention to HIV care at a primary HIV clinic in Lambaréné, Gabon. Adult patients who presented to this clinic between January 2010 and January 2012 were included. Outcomes were retention in care (defined as documented show-up for clinical visits, regardless of delay) or LTFU (defined as a patient not retained in care; on ART or ART naïve, not returning to care during the study period with a patient delay for scheduled visits of more than 6 months), and mortality. Cox regression analysis was used to assess factors associated with respective outcomes. Qualitative data on reasons for LTFU were obtained from focus-group discussions.
Results
Of 223 patients included, 67.3% were female. The mean age was 40.5 (standard deviation 11.4) years and the median CD4 count 275 (interquartile range 100.5–449.5) cells/μL. In total, 34.1% were lost to follow up and 8.1% died. Documented tuberculosis was associated with increased risk of being LTFU (adjusted hazard ratio (aHR) 1.80, 95% confidence interval (95% CI) 1.05–3.11, P = 0.03), whereas early starting anti-retroviral therapy (ART) was associated with a decreased risk of LTFU (aHR 0.43, 95%CI 0.24–0.76, P = 0.004), as was confirmed by qualitative data.
Conclusions
Retention to HIV care in a primary clinic in Gabon is relatively poor and interventions to address this should be prioritized in the HIV program. Early initiation of ART might improve retention in care.
doi:10.1371/journal.pone.0140746
PMCID: PMC4608719  PMID: 26473965
20.  Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma 
The New England journal of medicine  2013;369(6):507-516.
BACKGROUND
Bruton's tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.
METHODS
In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.
RESULTS
The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.
CONCLUSIONS
Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)
doi:10.1056/NEJMoa1306220
PMCID: PMC4513941  PMID: 23782157
21.  Buprenorphine Treatment of Opioid-Dependent Pregnant Women: A Comprehensive Review 
Addiction (Abingdon, England)  2012;107(0 1):5-27.
Aims
This paper reviews the published literature regarding outcomes following maternal treatment with buprenorphine in five areas: maternal efficacy, fetal effects, neonatal effects, effects on breast milk, and longer-term developmental effects.
Methods
Within each outcome area, findings are summarized first for the 3 randomized controlled trials and then for the 44 non-randomized studies (i.e., prospective studies, case reports and series, and retrospective chart reviews), only 28 of which involve independent samples.
Results
Results indicate that maternal treatment with buprenorphine has comparable efficacy to methadone, although difficulties may exist with current buprenorphine induction methods. The available fetal data suggest buprenorphine results in less physiologic suppression of fetal heart rate and movements than methadone. Regarding neonatal effects, perhaps the single definitive conclusion is that prenatal buprenorphine treatment results in a clinically significant less severe neonatal abstinence syndrome (NAS) than treatment with methadone. The limited research suggests that, like methadone, buprenorphine is compatible with breastfeeding. Data available thus far suggest that there are no deleterious effects of in utero buprenorphine exposure on infant development.
Conclusions
Buprenorphine produces a less severe neonatal abstinence syndrome than methadone, but there is still a role for methadone in the treatment of opioid dependence during pregnancy.
doi:10.1111/j.1360-0443.2012.04035.x
PMCID: PMC4506646  PMID: 23106923
pregnancy; opioid dependence; pharmacologic treatment; buprenorphine
22.  Maternal Opioid Treatment: Human Experimental Research (MOTHER) – Approach, Issues, and Lessons Learned 
Addiction (Abingdon, England)  2012;107(0 1):28-35.
Aims
The Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, an eight-site randomized, double-blind, double-dummy, flexible-dosing, parallel-group clinical trial is described. This study is the most current – and single most comprehensive – research effort to investigate the safety and efficacy of maternal and prenatal exposure to methadone and buprenorphine.
Methods
The MOTHER study design is outlined, and its basic features are presented.
Conclusions
At least seven important lessons have been learned from the MOTHER study: (1) an interdisciplinary focus improves the design and methods of a randomized clinical trial; (2) multiple sites in a clinical trial present continuing challenges to the investigative team due to variations in recruitment goals, patient populations, and hospital practices that in turn differentially impact recruitment rates, treatment compliance, and attrition; (3) study design and protocols must be flexible in order to meet the unforeseen demands of both research and clinical management; (4) staff turnover needs to be addressed with a proactive focus on both hiring and training; (5) the implementation of a protocol for the treatment of a particular disorder may identify important ancillary clinical issues worthy of investigation; (6) timely tracking of data in a multi-site trial is both demanding and unforgiving; and, (7) complex multi-site trials pose unanticipated challenges that complicate the choice of statistical methods, thereby placing added demands on investigators to effectively communicate their results.
doi:10.1111/j.1360-0443.2012.04036.x
PMCID: PMC4497510  PMID: 23106924
pregnancy; alcohol and other drug use; pharmacologic treatment; opioid dependence
23.  Development and characterization of a novel human Waldenström Macroglobulinemia cell line (RPCI-WM1; Roswell Park Cancer Institute-Waldenström Macroglobulinemia 1) 
Leukemia & lymphoma  2012;54(2):387-396.
Understanding the biology of Waldenström Macroglobulinemia is hindered by a lack of preclinical models. We report a novel cell line, RPCI-WM1, from a patient treated for WM. The cell line secreted human IgM (hIgM) with k-light chain restriction identical to the primary tumor. The cell line has a modal chromosomal number of 46 and harbors chromosomal changes such as deletion of 6q21, monoallelic deletion of 9p21 (CDKN2A), 13q14 (RB1) and 18q21 (BCL-2) with a consistent amplification of 14q32 (IgH) identical to its founding tumor sample. Clonal relationship was confirmed by identical CDR3 length and single nucleotide polymorphisms as well as a matching IgH sequence of the cell line and founding tumor. Both also harbor a heterozygous, non-synonymous mutation at amino acid 265 in MYD88 gene (L265P). The cell line expresses most of the cell surface markers present on the parent cells. Over all, RPCI-WM1 represents a valuable model to study WM.
doi:10.3109/10428194.2012.713481
PMCID: PMC4406272  PMID: 22812491
Waldenström Macroglobulinemia; cell line; preclinical; model
24.  Comparison of Two Informant Questionnaire Screening Tools for Dementia and Mild Cognitive Impairment: AD8 and IQCODE 
Background
Dementia and mild cognitive impairment (MCI) are under-recognized in community settings. This may be due in part to the lack of brief dementia screening tools available to clinicians. We compared two brief, informant-based screening tests: the AD8 and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) in a community-based neurology practice in the Midwestern United States
Methods
We examined 186 consecutive patients (44 controls, 13 with MCI, and 129 with dementia). Receiver operator characteristic curves were used to examine the ability of AD8 and IQCODE to discriminate between controls and MCI or dementia. Sensitivity, specificity, predictive values, and likelihood ratios were reported.
Results
AD8 differentiated healthy controls from MCI (p<.001) or dementia (p<.001), as well as MCI from dementia (p=.008). The IQCODE differentiated controls and MCI from dementia (both p<.001), and between controls and MCI (p=.002). Both AD8 (AUC = 0.953, 95% CI: 0.92–0.99) and IQCODE (AUC = 0.930, 95% CI: 0.88–0.97) provided discrimination between controls and patients with dementia; however the AD8 had superior sensitivity detecting dementia (99.2%) and MCI (100%) compared to the IQCODE (79.1% for dementia, 46.1% for MCI) with non-overlapping confidence intervals. Using published cut-offs (AD8 ≥ 2, IQCODE ≥ 3.4), only one case of dementia was missed with the AD8 while the IQCODE failed to detect dementia in 27 individuals. The AD8 detected MCI in all 13 individuals while the IQCODE misclassified 7 individuals.
Conclusion
Both the AD8 and IQCODE were able to detect dementia in a community setting. The AD8, however, was more successful than IQCODE in detecting MCI. If simple and efficient screening for early cognitive impairment is the goal, particularly in the early stages (e.g., for prevention trials or public screening), the combination of an informant interview (the AD8) and a brief performance measure could be considered as they meet the basic requirements of the Personalized Prevention Plan for Medicare beneficiaries.
doi:10.1097/WAD.0000000000000008
PMCID: PMC3981951  PMID: 24113559
Dementia; Screening; AD8; IQCODE; Mild Cognitive Impairment
25.  Assessing the Consequences of Stigma for Tuberculosis Patients in Urban Zambia 
PLoS ONE  2015;10(3):e0119861.
Background
Stigma is one of the many factors hindering tuberculosis (TB) control by negatively affecting hospital delay and treatment compliance. In Zambia, the morbidity and mortality due to TB remains high, despite extended public health attempts to control the epidemic and to diminish stigma.
Study Aim
To enhance understanding of TB-related stigmatizing perceptions and to describe TB patients’ experiences of stigma in order to point out recommendations to improve TB policy.
Methods
We conducted a mixed method study at Kanyama clinic and surrounding areas, in Lusaka, Zambia; structured interviews with 300 TB patients, multiple in-depth interviews with 30 TB patients and 10 biomedical health workers, 3 focus group discussions with TB patients and treatment supporters, complemented by participant observation and policy analysis of the TB control program. Predictors of stigma were identified by use of multivariate regression analyses; qualitative analysis of the in-depth interviews, focus group discussions and participant observation was used for triangulation of the study findings.
Results
We focused on the 138/300 patients that described TB-related perceptions and attitudes, of whom 113 (82%) reported stigma. Stigma provoking TB conceptions were associated with human immunodeficiency virus (HIV)-infection, alleged immoral behaviour, (perceived) incurability, and (traditional) myths about TB aetiology. Consequences of stigma prevailed both among children and adults and included low self-esteem, insults, ridicule, discrimination, social exclusion, and isolation leading to a decreased quality of life and social status, non-disclosure, and/or difficulties with treatment compliance and adherence. Women had significantly more stigma-related problems than men.
Conclusions
The findings illustrate that many TB patients faced stigma-related issues, often hindering effective TB control and suggesting that current efforts to reduce stigma are not yet optimal. The content and implementation of sensitization programs should be improved and more emphasis needs to be placed on women and children.
doi:10.1371/journal.pone.0119861
PMCID: PMC4373828  PMID: 25806955

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