Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS ...lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome.
Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R, and patients who achieved CR received EA consolidation. We performed a prospective analysis of molecular prognostic biomarkers in PCNSL in the setting of a clinical trial.
The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with median follow-up of 4.9 years. The 2-year time to progression was 0.59, and for patients who completed consolidation, it was 0.77. Patients age > 60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. High BCL6 expression correlated with shorter survival.
CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT.
Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death that often goes undetected in the general population. HCM is also prevalent in patients with cardio-facio-cutaneous ...syndrome (CFCS), which is a genetic disorder characterized by aberrant signaling in the RAS/MAPK signaling cascade. Understanding the mechanisms of HCM development in such RASopathies may lead to novel therapeutic strategies, but relevant experimental models of the human condition are lacking. Therefore, the objective of this study was to develop the first 3D human engineered cardiac tissue (hECT) model of HCM. The hECTs were created using human cardiomyocytes obtained by directed differentiation of induced pluripotent stem cells derived from a patient with CFCS due to an activating BRAF mutation. The mutant myocytes were directly conjugated at a 3:1 ratio with a stromal cell population to create a tissue of defined composition. Compared to healthy patient control hECTs, BRAF-hECTs displayed a hypertrophic phenotype by culture day 6, with significantly increased tissue size, twitch force, and atrial natriuretic peptide (ANP) gene expression. Twitch characteristics reflected increased contraction and relaxation rates and shorter twitch duration in BRAF-hECTs, which also had a significantly higher maximum capture rate and lower excitation threshold during electrical pacing, consistent with a more arrhythmogenic substrate. By culture day 11, twitch force was no longer different between BRAF and wild-type hECTs, revealing a temporal aspect of disease modeling with tissue engineering. Principal component analysis identified diastolic force as a key factor that changed from day 6 to day 11, supported by a higher passive stiffness in day 11 BRAF-hECTs. In summary, human engineered cardiac tissues created from BRAF mutant cells recapitulated, for the first time, key aspects of the HCM phenotype, offering a new in vitro model for studying intrinsic mechanisms and screening new therapeutic approaches for this lethal form of heart disease.
Dark side of the tune Johnson, Bruce; Cloonan, Martin
c2008., 2009, 20170705, 2009-09-01, 2017-07-05
eBook
"Written against the academically dominant but simplistic romanticization of popular music as a positive force, this book focuses on the 'dark side' of the subject. It is an examination of the ways ...in which popular music has been deployed in association with violence, ranging from what appears to be an incidental relationship, to one in which music is explicitly applied as an instrument of violence." "A preliminary overview of the physiological and cognitive foundations of sounding/hearing which are distinctive within the sensorium, discloses in particular their potential for organic and psychic violence. The study then elaborates working definitions of key terms (including the vexed idea of the 'popular') for the purposes of this investigation, and provides a historical survey of examples of the nexus between music and violence, from (pre)Biblical times to the late nineteenth century." "The second half of the book concentrates on the modern era, marked in this case by the emergence of technologies by which music can be electronically augmented, generated, and disseminated, beginning with the advent of sound recording from the 1870s, and proceeding to audio-internet and other contemporary audio-technologies. Johnson and Cloonan argue that these technologies have transformed the potential of music to mediate cultural confrontations from the local to the global, particularly through violence. The authors present a taxonomy of case histories in the connection between popular music and violence, through increasingly intense forms of that relationship, culminating in the topical examples of music and torture, including those in Bosnia, Darfur, and by US forces in Iraq and Guantanamo Bay."--BOOK JACKET.
•Advances in understanding the natural history of hepatitis B have led to new definitions of the major phases of infection.•New phases are high replicative, low inflammatory (formerly immune ...tolerant) and non-replicative (formerly inactive carrier).•The new concept of trained immunity may alter future hepatitis B treatment strategies.•The current goal of treatment for chronic hepatitis B is a functional cure.•Experimental therapies now under development target viral and host factors and previously inaccessible pathways.
The host immune system plays an important role in chronic hepatitis B (CHB), both in viral clearance and hepatocellular damage. Advances in our understanding of the natural history of the disease have led to redefining the major phases of infection, with the “high replicative, low inflammatory” phase now replacing what was formerly termed the “immune tolerant” phase, and the “nonreplicative phase” replacing what was formerly termed the “inactive carrier” phase. As opposed to the earlier view that HBV establishes chronic infection by exploiting the immaturity of the neonate’s immune system, new findings on trained immunity show that the host is already somewhat “matured” following birth, and is actually very capable of responding immunologically, potentially altering future hepatitis B treatment strategies. While existing therapies are effective in reducing viral load and necroinflammation, often restoring the patient to near-normal health, they do not lead to a cure except in very rare cases and, in many patients, viremia rebounds after cessation of treatment. Researchers are now challenged to devise therapies that will eliminate infection, with a particular focus on eliminating the persistence of viral cccDNA in the nuclei of hepatocytes. In the context of chronic hepatitis B, new definitions of ‘cure’ are emerging, such as ‘functional’ and ‘virological’ cure, defined by stable off-therapy suppression of viremia and antigenemia, and the normalization of serum ALT and other liver-related laboratory tests. Continued advances in the understanding of the complex biology of chronic hepatitis B have resulted in the development of new, experimental therapies targeting viral and host factors and pathways previously not accessible to therapy, approaches which may lead to virological cures in the near term and functional cures upon long term follow-up. This article forms part of a symposium in Antiviral Research on “An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.”
Data from 38,105 wells were used to characterize fluoride (F) occurrence in untreated United States (U.S.) groundwater. For domestic wells (n = 11,032), water from which is generally not purposely ...fluoridated or monitored for quality, 10.9% of the samples have F concentrations >0.7 mg/L (U.S. Public Health Service recommended optimal F concentration in drinking water for preventing tooth decay) (87% are <0.7 mg/L); 2.6% have F > 2 mg/L (EPA Secondary Maximum Contaminant Level, SMCL); and 0.6% have F > 4 mg/L (EPA MCL). The data indicate the biggest concern with F in domestic wells at the national scale could be one of under consumption of F with respect to the oral-health benchmark (0.7 mg/L). Elevated F concentrations relative to the SMCL and MCL are regionally important, particularly in the western U.S. Statistical comparisons of potentially important controlling factors in four F-concentration categories (<0.1–0.7 mg/L; >0.7–2 mg/L; >2–4 mg/L; >4 mg/L) at the national scale indicate the highest F-concentration category is associated with groundwater that has significantly greater pH values, TDS and alkalinity concentrations, and well depths, and lower Ca/Na ratios and mean annual precipitation, than the lowest F-concentration category. The relative importance of the controlling factors appears to be regionally variable. Three case studies illustrate the spatial variability in controlling factors using groundwater-age (groundwater residence time), water-isotope (evaporative concentration), and water-temperature (geothermal processes) data. Populations potentially served by domestic wells with F concentrations <0.7, >0.7, >2, and >4 mg/L are estimated to be ~28,200,000, ~3,110,000; ~522,000; and ~172,000 people, respectively, in 40 principal aquifers with at least 25 F analyses per aquifer.
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•Data from 38,105 wells used to characterize F occurrence in U.S. groundwater.•85–87% of F concentrations are below the 0.7 mg/L oral-health benchmark.•Multiple factors control F concentrations in groundwater.•Three case studies illustrate processes that produce elevated F concentrations.•~28,200,000 people potentially served by domestic wells with F < 0.7 mg/L.
Objectives The purpose of this study was to comprehensively examine cardiovascular reserve function with exercise in patients with heart failure and preserved ejection fraction (HFpEF). Background ...Optimal exercise performance requires an integrated physiologic response, with coordinated increases in heart rate, contractility, lusitropy, arterial vasodilation, endothelial function, and venous return. Cardiac and vascular responses are coupled, and abnormalities in several components may interact to promote exertional intolerance in HFpEF. Methods Subjects with HFpEF (n = 21), hypertension without heart failure (n = 19), and no cardiovascular disease (control, n = 10) were studied before and during exercise with characterization of cardiovascular reserve function by Doppler echocardiography, peripheral arterial tonometry, and gas exchange. Results Exercise capacity and tolerance were reduced in HFpEF compared with hypertensive subjects and controls, with lower VO2 and cardiac index at peak, and more severe dyspnea and fatigue at matched low-level workloads. Endothelial function was impaired in HFpEF and in hypertensive subjects as compared with controls. However, blunted exercise-induced increases in chronotropy, contractility, and vasodilation were unique to HFpEF and resulted in impaired dynamic ventricular-arterial coupling responses during exercise. Exercise capacity and symptoms of exertional intolerance were correlated with abnormalities in each component of cardiovascular reserve function, and HFpEF subjects were more likely to display multiple abnormalities in reserve. Conclusions HFpEF is characterized by depressed reserve capacity involving multiple domains of cardiovascular function, which contribute in an integrated fashion to produce exercise limitation. Appreciation of the global nature of reserve dysfunction in HFpEF will better inform optimal design for future diagnostic and therapeutic strategies.
In 2019, 254 samples were collected from five aquifer systems to evaluate perfluoroalkyl and polyfluoroalkyl substance (PFAS) occurrence in groundwater used as a source of drinking water in the ...eastern United States. The samples were analyzed for 24 PFAS, major ions, nutrients, trace elements, dissolved organic carbon (DOC), volatile organic compounds (VOCs), pharmaceuticals, and tritium. Fourteen of the 24 PFAS were detected in groundwater, with 60 and 20% of public-supply and domestic wells, respectively, containing at least one PFAS detection. Concentrations of tritium, chloride, sulfate, DOC, and manganese + iron; percent urban land use within 500 m of the wells; and VOC and pharmaceutical detection frequencies were significantly higher in samples containing PFAS detections than in samples with no detections. Boosted regression tree models that consider 57 chemical and land-use variables show that tritium concentration, distance to the nearest fire-training area, percentage of urban land use, and DOC and VOC concentrations are the top five predictors of PFAS detections, consistent with the hydrologic position, geochemistry, and land use being important controls on PFAS occurrence in groundwater. Model results indicate that it may be possible to predict PFAS detections in groundwater using existing data sources.
Vaccines are among the greatest successes in the history of public health. However, past strategies for vaccine development are unlikely to succeed in the future against major global diseases such as ...AIDS, tuberculosis, and malaria. For such diseases, the correlates of protection are poorly defined and the pathogens evade immune detection and/or exhibit extensive genetic variability. Recent advances have heralded in a new era of vaccine discovery. However, translation of these advances into vaccines remains impeded by lack of understanding of key vaccinology principles in humans. We review these advances toward vaccine discovery and suggest that for accelerating successful vaccine development, new human immunology-based clinical research initiatives be implemented with the goal of elucidating and more effectively generating vaccine-induced protective immune responses.
Background:
Anterior cruciate ligament (ACL) injuries are disabling and are associated with the early onset of posttraumatic osteoarthritis. Little is known regarding the incidence rate of first-time ...noncontact ACL injuries sustained during athletic events and how they are independently influenced by level of competition, type of sport, and the participant’s sex.
Hypothesis:
Level of competition (college or high school), type of sport (soccer, basketball, lacrosse, field hockey, football, rugby, volleyball), and the athlete’s sex independently influence the incidence rate of first-time noncontact ACL injuries.
Study Design:
Cohort study; Level of evidence, 2.
Methods:
Between fall 2008 and spring 2012, first-time noncontact ACL injury data were collected from 8 colleges and 18 high schools across 7 sports. Athlete exposure was computed retrospectively using team rosters and numbers of scheduled practices and games. Injury incidence rates (IRs) were computed per 1000 athlete exposures. The independent effects of level of competition, sport, and sex on ACL injury risk were estimated by Poisson regression.
Results:
Colleges reported 48 ACL injuries with 320,719 athlete exposures across all sports studied (IR = 0.150 per 1000 person-days), while high schools reported 53 injuries with 873,057 athlete exposures (IR = 0.061). After adjustment for differences in sport and sex, college athletes had a significantly higher injury risk than did high school athletes (adjusted relative risk RR, 2.38; 95% CI, 1.55-3.54). The overall IR for female athletes was 0.112 compared with 0.063 for males. After adjustment for sport and level of play, females were more than twice as likely to have a first-time ACL injury compared with males (RR, 2.10; 95% CI, 1.34-3.27). With lacrosse as the reference group, risk of first-time noncontact ACL injury was significantly higher for soccer players (RR, 1.77) and for rugby players (RR, 2.23), independent of level of play and sex.
Conclusion:
An athlete’s risk of having a first-time noncontact ACL injury is independently influenced by level of competition, the participant’s sex, and type of sport, and there are no interactions between their effects. Female college athletes have the highest risk of having a first-time noncontact ACL injury among the groups studied.
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