Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen ...receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study.
We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee.
A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found.
In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248 .).
To propose Irish CT diagnostic reference levels (DRLs) by collecting radiation doses for the most commonly performed CT examinations.
A pilot study investigated the most frequent CT examinations. 40 ...CT sites were then asked to complete a survey booklet to allow the recording of CT parameters for each of 9 CT examinations during a 12-week period. Dose data CT volume index (CTDI(vol)) and dose-length product (DLP) on a minimum of 10 average-sized patients in each category were recorded to calculate a mean site CTDI(vol) and DLP value. The rounded 75th percentile was used to calculate a DRL for each site and the country by compiling all results.
are compared with international DRL data. Results Data were collected for 3305 patients. 30 sites responded with data for 34 scanners, representing 54% of the national total. All equipment had multislice capability (2-128 slices). DRLs are proposed using CTDI(vol) (mGy) and DLP (mGy cm) for CT head (66/58 and 940, respectively), sinuses (16 and 210, respectively), cervical spine (19 and 420, respectively), thorax (9/11 and 390, respectively), high resolution CT (7 and 280, respectively), CT pulmonary angiography (13 and 430, respectively), multiphase abdomen (13 and 1120, respectively), routine abdomen/pelvis (12 and 600, respectively) and trunk examinations (10/12 and 850, respectively). These values are lower than current DRLs and comparable to other international studies. Wide variations in mean doses are noted across sites.
Baseline figures for Irish CT DRLs are provided on the most frequently performed CT examinations. The variations in dose between CT departments as well as between identical scanners suggest a large potential for optimisation of examinations.
α-Actinins are a major class of actin filament cross-linking proteins expressed in virtually all cells. In muscle, actinins cross-link thin filaments from adjacent sarcomeres. In non-muscle cells, ...different actinin isoforms play analogous roles in cross-linking actin filaments and anchoring them to structures such as cell-cell and cell-matrix junctions. Although actinins have long been known to play roles in cytokinesis, cell adhesion and cell migration, recent studies have provided further mechanistic insights into these functions. Roles for actinins in synaptic plasticity and membrane trafficking events have emerged more recently, as has a 'non-canonical' function for actinins in transcriptional regulation in the nucleus. In the present paper we review recent advances in our understanding of these diverse cell biological functions of actinins in non-muscle cells, as well as their roles in cancer and in genetic disorders affecting platelet and kidney physiology. We also make two proposals with regard to the actinin nomenclature. First, we argue that naming actinin isoforms according to their expression patterns is problematic and we suggest a more precise nomenclature system. Secondly, we suggest that the α in α-actinin is superfluous and can be omitted.
Si-rich Mediterranean type lamproites (48–56 wt.% SiO
2) are olivine-phyric, mantle-derived volcanics, in which both phenocrystic and xenocrystic olivine are present. Here we demonstrate the ...phenocrystic origin of the most extremely NiO–MgO enriched olivine in lamproites with Mg# up to 0.95, that host Cr-rich (Cr# around 0.95) spinels. Our comprehensive study of olivine–spinel pairs from Mediterranean lamproites enables us to constrain the extent of depletion of their mantle source. Olivine–spinel pairs from primitive Mediterranean lamproites plot in the most refractory part of the olivine–spinel mantle array diagram, showing even more refractory character than mineral pairs from boninites and cratonic mantle xenoliths. This indicates involvement of an ultra-depleted mantle component which had previously lost up to 40% basaltic components. These characteristics would fit the involvement of depleted subcratonic lithospheric mantle which underwent komatiite extraction in the Archaean, but mantle of such composition and age is known neither from ultramafic xenolith suites nor in tectonically emplaced ultramafic massifs in western and central Europe. Here, we explore the possibility that the extremely depleted component of the mantle source of Mediterranean lamproites is derived from an island-arc oceanic lithosphere accreted during Alpine collisional processes. This may provide compelling evidence for recent accretion of oceanic lithospheric blocks during Mesozoic subduction–collision processes in the Mediterranean.
Salmonellosis is a worldwide health problem; Salmonella infections are the second leading cause of bacterial foodborne illness in the United States. Approximately 95% of cases of human salmonellosis ...are associated with the consumption of contaminated products such as meat, poultry, eggs, milk, seafood, and fresh produce. Salmonella can cause a number of different disease syndromes including gastroenteritis, bacteremia, and typhoid fever, with the most common being gastroenteritis, which is often characterized by abdominal pain, nausea, vomiting, diarrhea, and headache. Typically the disease is self-limiting; however, with more severe manifestations such as bacteremia, antimicrobial therapy is often administered to treat the infection. Currently, there are over 2,500 identified serotypes of SALMONELLA: A smaller number of these serotypes are significantly associated with animal and human disease including Typhimurium, Enteritidis, Newport, Heidelberg, and Montevideo. Increasingly, isolates from these serotypes are being detected that demonstrate resistance to multiple antimicrobial agents, including third-generation cephalosporins, which are recommended for the treatment of severe infections. Many of the genes that encode resistance are located on transmissible elements such as plasmids that allow for potential transfer of resistance among strains. Plasmids are also known to harbor virulence factors that contribute to Salmonella pathogenicity. Several serotypes of medical importance, including Typhimurium, Enteritidis, Newport, Dublin, and Choleraesuis, are known to harbor virulence plasmids containing genes that code for fimbriae, serum resistance, and other factors. Additionally, many Salmonella contain pathogenicity islands scattered throughout their genomes that encode factors essential for bacterial adhesion, invasion, and infection. Salmonella have evolved several virulence and antimicrobial resistance mechanisms that allow for continued challenges to our public health infrastructure.
Abstract In East Africa, community-based conservation models (CBCMs) have been established to support the conservation of wildlife in fragmented landscapes like the Tarangire Ecosystem, Tanzania. To ...assess how different management approaches maintained large herbivore populations, we conducted line distance surveys and estimated seasonal densities of elephant, giraffe, zebra, and wildebeest in six management units, including three CBCMs, two national parks (positive controls), and one area with little conservation interventions (negative control). Using a Monte-Carlo approach to propagate uncertainties from the density estimates and trend analysis, we analyzed the resulting time series (2011–2019). Densities of the target species were consistently low in the site with little conservation interventions. In contrast, densities of zebra and wildebeest in CBCMs were similar to national parks, providing evidence that CBCMs contributed to the stabilization of these migratory populations in the central part of the ecosystem. CBCMs also supported giraffe and elephant densities similar to those found in national parks. In contrast, the functional connectivity of Lake Manyara National Park has not been augmented by CBCMs. Our analysis suggests that CBCMs can effectively conserve large herbivores, and that maintaining connectivity through CBCMs should be prioritized.
The short GRB 120323A had the highest flux ever detected with the Gamma-Ray Burst Monitor on board the Fermi Gamma-Ray Space Telescope. Here we study its remarkable spectral properties and their ...evolution using two spectral models: (1) a single emission component scenario, where the spectrum is modeled by the empirical Band function (a broken power law), and (2) a two-component scenario, where thermal (a Planck-like function) emission is observed simultaneously with a non-thermal component (a Band function). We conclude that GRB 120323A has a strong photospheric emission contribution, observed for the first time in a short GRB. Magnetic dissipation models are difficult to reconcile with these results, which instead favor photospheric thermal emission and fast cooling synchrotron radiation from internal shocks.
Abstract
Background
Lesbian, gay and bisexual (LGB) young people’s increased risk of self-harm, suicidal attempts and suicide compared with heterosexual youth is well established. The current study ...sought to examine whether these findings also apply to the trans (T) population and which factors act as additional risk or protective factors.
Methods
In a national cross-sectional survey, 3713 LGBT adolescents, aged 11–19 years, reported on their own history of self-harm, suicidal ideation and suicide attempts, as well as their experiences of school and homophobic, biphobic and transphobic bullying. Logistic regressions tested the association between risk and protective factors on self-harm, suicidal ideation and suicide attempts.
Results
A high proportion of the sample reported self-harm (65.3%), suicidal ideation (73.8%) and suicide attempts (25.7%). Demographic risk factors included identifying as female, non-binary or trans and being from a low-income background. Bullying and online bullying were associated with an increased risk for each outcome, and positive school experience was associated with a reduced risk for each outcome.
Conclusions
Consistent with minority stress theory, the study found high rates of mental health problems within LGBT youth. Interventions focused on improving young people’s experiences in schools appear useful targets to help improve mental health outcomes.
Summary
Thinness is a risk factor for fractures, but the effect of obesity on fracture risk is less clear. We found an association between measures of obesity and prevalence and number of vertebral ...deformities in women but not in men, in a cross-sectional study of 1,011 participants aged 50–80 years.
Introduction
Low body weight is well recognised as a risk factor for fractures, but the association between overweight and fracture risk is less well described. This cross-sectional study describes the association between measures of obesity and vertebral deformities in 1,011 male and female participants in the Tasmanian Older Adult Cohort study.
Methods
Vertebral deformities (anterior wedging) of T4–L4 were determined by morphometric dual-emission X-ray absorptiometry. Body fat was assessed as weight, body mass index (BMI), waist–hip ratio (WHR), waist circumference and DXA measures of trunk fat (in percent) and total fat mass.
Results
The mean age of participants was 63 ± 7 years, and mean BMI was 28 ± 5. Prevalent thoracic vertebral deformities were associated with increasing weight standardised β (Sβ) 0.29,
p
= 0.003, BMI (Sβ 0.33,
p
< 0.001), trunk fat (Sβ 0.20,
p
= 0.03), waist circumference (Sβ 0.19,
p
= 0.03) and fat mass (Sβ 0.23,
p
= 0.03), but not the WHR in women, and only with decreasing total fat mass in men. In addition, the number of vertebral deformities increased as weight, BMI or fat mass increased in women (all
p
< 0.05) but decreased with increasing total fat mass in men. Associations between fat mass and vertebral deformities were mainly linear, but there was some evidence of a threshold effect in women with a BMI ≥35.
Conclusions
There is a deleterious association between increasing amounts of body fat in women but not in men and the prevalence and number of vertebral deformities, which may reflect loading of the thoracic spine.
Salmonellosis is the second leading cause of bacterial foodborne illness in the United States, and the great majority of these infections are associated with the consumption of products such as meat, ...poultry, eggs, milk, seafood, and fresh produce contaminated with Salmonella. The per capita consumption of meat and poultry in United States has increased significantly over the past century. This increase is especially evident with poultry products, where there has been a nearly 6-fold increase in chicken consumption and 17-fold increase in turkey consumption since 1909. The per capita consumption of pork has also increased over this time from 18.7 to 21.7 kg/yr. With this increase in meat and poultry consumption, the dynamics of animal production and consumer exposure have changed leading to new challenges in limiting salmonellosis. To meet the demands of consumers, more intensive agricultural practices have been adopted, which has likely changed the population characteristics of Salmonella present among poultry flocks and swine populations. In Salmonella isolated from swine in the United States, S. Typhimurium has replaced S. Choleraesuis as the predominant serovar in recent years. Among isolates from turkeys collected in 2004, serovars S. Senftenberg and S. Hadar were most common overall; however, S. Heidelberg was most common from clinical diagnostic sources, potentially indicating increased virulence. Salmonella Heidelberg was also the most commonly detected serovar among chicken isolates from clinically ill birds and Salmonella surveillance samples. Overall among the 10 serovars most commonly associated with human infections, 6 are also found in the top serovars of swine and poultry. These include S. Typhimurium, S. Enteritidis, S. Heidelberg, S. Montevideo, S. Saintpaul, and S. I 4,5,12:i:-.
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