Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

Diffusion tensor brain imaging at 0.55T: A feasibility study.

PURPOSE: To investigate the feasibility of diffusion tensor brain imaging at 0.55T with comparisons against 3T. METHODS: Diffusion tensor imaging data with 2 mm isotropic resolution was acquired on a cohort of five healthy subjects using both 0.55T and 3T scanners. The signal-to-noise ratio (SNR) of the 0.55T data was improved using a previous SNR-enhancing joint reconstruction method that jointly reconstructs the entire set of diffusion weighted images from k-space using shared-edge constraints. Quantitative diffusion tensor parameters were estimated and compared across field strengths. We also performed a test-retest assessment of repeatability at each field strength. RESULTS: After applying SNR-enhancing joint reconstruction, the diffusion tensor parameters obtained from 0.55T data were strongly correlated ( R 2 ≥ 0 . 70 $$ {R}^2\ge 0.70 $$ ) with those obtained from 3T data. Test-retest analysis showed that SNR-enhancing reconstruction improved the repeatability of the 0.55T diffusion tensor parameters. CONCLUSION: High-resolution in vivo diffusion MRI of the human brain is feasible at 0.55T when appropriate noise-mitigation strategies are applied.

Use, variability, and justification of eligibility criteria for phase II and III clinical trials in acute leukemia.

Clinical trial eligibility criteria can unfairly exclude patients or unnecessarily expose them to known risks if criteria are not concordant with drug safety. There are few data evaluating the extent to which acute leukemia eligibility criteria are justified. We analyzed criteria and drug safety data for front-line phase II and/or III acute leukemia trials with start dates 1/1/2010-12/31/2019 registered on clinicaltrials.gov. Multivariable analyses assessed concordance between criteria use and safety data (presence of criteria with a safety signal, or absence of criteria without a signal), and differences between criteria and safety-based limits. Of 250 eligible trials, concordant use of ejection fraction criteria was seen in 34.8%, corrected QT level (QTc) in 22.4%, bilirubin in 68.4%, aspartate transaminase/alanine aminotransferase (AST/ALT) in 58.8%, renal function in 68.4%, human immunodeficiency virus (HIV) in 54.8%, and hepatitis B and C in 42.0% and 41.2%. HIV and hepatitis B and C criteria use was concordant with safety data (adjusted Odds Ratios 2.04 [95%CI: 1.13, 3.66], 2.64 [95%CI: 1.38, 5.04], 2.27 [95%CI: 1.20, 4.32]) but organ function criteria were not (all P>0.05); phase III trials were not more concordant. Bilirubin criteria limits were the same as safety-based limits in 16.0% of trials, AST/ALT in 18.1%, and renal function in 13.9%; in 75.7%, 51.4%, and 56.5% of trials, criteria were more restrictive, respectively, by median differences of 0.2, 0.5, and 0.5 times the upper limits of normal. We found limited drug safety justifications for acute leukemia eligibility criteria. These data define criteria use and limits that can be rationally modified to increase patient inclusion and welfare.

Expedited evaluation of hereditary hematopoietic malignancies in the setting of stem cell transplantation.

Not available.

Transfusion management and hemoglobin-based oxygen carrier treatment in a patient with anti-Rh17 antibody.

BACKGROUND: A 54-year-old Hispanic OPos female with known history of anti-Rh17 antibodies was diagnosed with Philadelphia-Chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Rh17, also known as Hr0, is a high-frequency antigen composed of several epitopes on the RhCE protein. Anti-Rh17 antibodies can be made by individuals with missing or varied C/c, E/e antigens. Anti-Rh17 antibodies are clinically significant given multiple case reports of hemolytic disease of the fetus and newborn (HDFN). Finding compatible units for patients with anti-Rh17 can be particularly difficult given that only 1 in 100,000 people are Rh17 negative. STUDY DESIGN AND METHODS: Search for compatible units was conducted by the American Rare Donor Program (ARDP) with no leads. After chemotherapy induction and despite erythropoiesis stimulating agent administration, the patient's hemoglobin continued to trend down to a nadir of 2.8 g/dL. Here we report transfusion of incompatible pRBC to this patient with critically symptomatic anemia. HBOC-201 (Hemopure) was obtained and administered under an emergency compassionate/expanded access designation from the Food and Drug Administration (FDA) under an emergency Investigational New Drug (IND) application. RESULTS AND DISCUSSION: Overall difficulties in this case included the challenge of finding compatible units, dilemma of transfusing incompatible units in a patient with severe anemia and obtaining alternatives to blood products. This case report demonstrates the successful use of HBOC-21 in treating life-threatening anemia.

NCCN Guidelines® Insights: Systemic Mastocytosis, Version 3.2024.

Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.

Treatment of Anemia in Lower-Risk Myelodysplastic Syndrome.

OPINION STATEMENT: A majority of patients with lower-risk myelodysplastic syndrome (MDS) will present with or develop anemia. Anemia in MDS is associated with decreased quality of life and may correlate with decreased progression-free survival and overall survival. In this state of the art review we summarize current risk stratification approaches to identify lower-risk MDS (LR-MDS), the natural history of the disease, and meaningful clinical endpoints. The treatment landscape of LR-MDS with anemia is also rapidly evolving; we review the role of supportive care, erythropoietin stimulating agents, lenalidomide, luspatercept, hypomethylating agents (HMAs), and immunosuppressive therapy (IST) in the management of LR-MDS with anemia. In patients with deletion 5q (del5q) syndrome lenalidomide has both efficacy and durability of response. For patients without del5q who need treatment, the management approach is impacted by serum erythropoietin (EPO) level, SF3B1 mutation status, and ring sideroblast status. Given the data from the Phase III COMMANDS trial, we utilize luspatercept in those with SF3B1 mutation or ring sideroblasts that have an EPO level < 500 U/L; in patients without an SF3B1 mutation or ring sideroblasts there is equipoise between luspatercept and use of an erythropoietin stimulating agent (ESA). For patients who have an EPO level ≥ 500 U/L or have been previously treated there is not a clear standard of care. For those without previous luspatercept exposure it can be considered particularly if there is an SF3B1 mutation or the presence of ring sideroblasts. Other options include HMAs or IST; the Phase III IMERGE trial supports the efficacy of the telomerase inhibitor imetelstat in this setting and this may become a standard option in the future as well.

Molecular detection of Orientia tsutsugamushi in ectoparasites & their small mammal hosts captured from scrub typhus endemic areas in Madurai district, India.

BACKGROUND OBJECTIVES: Scrub typhus, caused by Orientia tsutsugamushi present in small mammals harbouring the ectoparasites. A study was undertaken to detect the pathogen present in small mammals and its ectoparasites in the scrub typhus-reported areas. METHODS: The small mammals (rodents/shrews) and its ectoparasites were screened for O. tsutsugamushi using nested PCR amplification of the groEL gene. Small mammals were collected by trapping and screened for ectoparasites (mites, ticks and fleas) by combing method. RESULTS: All the chigger mites collected were tested negative for O. tsutsugamushi . Interestingly, adult non-trombiculid mites ( Oribatida sp., Dermanyssus gallinae ), fleas ( Xenopsylla astia, X. cheopis, Ctenophalides felis and Ctenophalides sp.) and ticks ( Rhipicephalus sanguineus , R. haemaphysaloides ) screened were found to be positive for O. tsutsugamushi , which the authors believe is the first report on these species globally. Bandicota bengalensis with O. tsutsugamushi infection is reported for the first time in India. The O. tsutsugamushi groEL sequences from the positive samples were similar to the reference strains, Karp and Ikeda and phylogenetically clustered in clade IV with less evolutionary divergence. The blood samples of Rattus rattus , Suncus murinus and B. bengalensis collected from this area were tested positive for O. tsutsugamushi ; interestingly, the sequence similarity was much pronounced with their ectoparasites indicating the transmission of the pathogen to host or vice versa . INTERPRETATION CONCLUSIONS: The outcome of the present investigations widened our scope on the pathogens present in ectoparasites and rodents/shrews from this area. This will help to formulate the required vector control methods to combat zoonotic diseases.

A Systematic Review and Meta-Analysis of Drug Eluting Stents for Safety and Efficacy in Intracranial Atherosclerotic Disease.

BACKGROUND: Advancements in arterial stenting technology have challenged prior notions favoring medical management for intracranial atherosclerotic disease (ICAD). Where previous conclusions were drawn from bare metal stent (BMS) technology, recent studies suggest drug-eluting stents (DES) are favorable due to their anti-proliferative effect, which reduces vascular remodeling. METHODS: We conducted a systematic review and meta-analysis of the literature prior to August 2023 reviewing all reports of ICAD treated with DES. Our target outcomes were incidence of any stroke, transient ischemic attack (TIA), or death within 30 days (postprocedural complications), ischemic stroke in the territory of the qualifying artery beyond 30 days (long-term complications), radiographically detected in-stent restenosis rate (ISR), and symptomatic ISR during follow-up. A subgroup analysis further stratified preprocedural mean stenosis above and below 70% into severe and moderate cohorts, respectively. RESULTS: PubMed, Web of Science, Cochrane and EMBASE query identified 527 candidate articles, from which 14 studies met inclusion criteria for a total of 607 patients and 640 ICAD lesions. Incidence of postprocedural complications was 7.3% (95% CI 3.9-11.7%) with subgroup analysis demonstrating significantly higher incidence in the severely stenotic group [9.0% (95% CI 4.7-14.5%)] than the moderately stenotic group [3.0% (95% CI 0.7-6.8%)]. Long-term complications were 1.2% (95% CI 0.4-2.3%). Radiographic ISR was 3.5% (95% CI 1.4-6.3%) and symptomatic ISR was 0.3% (95% CI 0.0-1.5%). CONCLUSIONS: Our systematic review and meta-analysis suggest that DES can effectively reduce the risk of ISR and may be a viable treatment modality to reduce long-term complications in refractory ICAD patients.

Epigenetic Regulation of Inflammatory Mechanisms and a Psychological Symptom Cluster in Patients Receiving Chemotherapy.

BACKGROUND: A psychological symptom cluster is the most common cluster identified in oncology patients. Although inflammatory mechanisms are hypothesized to underlie this cluster, epigenetic contributions are unknown. OBJECTIVES: This study's purpose was to evaluate associations between the occurrence of a psychological symptom cluster and levels of DNA methylation for inflammatory genes in a heterogeneous sample of patients with cancer receiving chemotherapy. METHODS: Prior to their second or third cycle of chemotherapy, 1,071 patients reported the occurrence of 38 symptoms using the Memorial Symptom Assessment Scale. A psychological cluster was identified using exploratory factor analysis. Differential methylation analyses were performed in two independent samples using Illumina Infinium 450K and EPIC microarrays. Expression-associated CpG (eCpG) loci in the promoter region of 114 inflammatory genes on the 450K and 112 genes on the EPIC microarray were evaluated for associations with the psychological cluster. Robust rank aggregation was used to identify differentially methylated genes across both samples. Significance was assessed using a false discovery rate of 0.05 under the Benjamini-Hochberg procedure. RESULTS: Cluster of differentiation 40 ( CD40 ) was differentially methylated across both samples. All six promoter eCpGs for CD40 that were identified across both samples were hypomethylated in the psychological cluster group. CONCLUSIONS: This study is the first to suggest associations between a psychological symptom cluster and differential DNA methylation of a gene involved in tissue inflammation and cell-mediated immunity. Our findings suggest that increased CD40 expression through hypomethylation of promoter eCpG loci is involved in the occurrence of a psychological symptom cluster in patients receiving chemotherapy. These findings suggest a direction for mechanistic studies.

Distribution and concentration pathway of particulate pollution during pandemic-induced lockdown in metropolitan cities in India.

To characterize the pollutant dispersal across major metropolitan cities in India, daily particulate matter (PM10 and PM2.5) data for the study areas were collected from the National Air Quality Monitoring stations database provided by the Central Pollution Control Board (CPCB) of India. The data were analysed for three temporal ranges, i.e. before the pandemic-induced lockdown, during the lockdown, and after the upliftment of lockdown restrictions. For the purpose, the time scale ranged from 1st April to 31st May for the years 2019 (pre), 2020, and 2021 (post). Statistical distributions (lognormal, Weibull, and Gamma), aerosol optical thickness, and back trajectories were assessed for all three time periods. Most cities followed the lognormal distribution for PM2.5 during the lockdown period except Mumbai and Hyderabad. For PM10, all the regions followed the lognormal distribution. Delhi and Kolkata observed a maximum decline in particulate pollution of 41% and 52% for PM2.5 and 49% and 53% for PM10, respectively. Air mass back trajectory suggests local transmission of air mass during the lockdown period, and an undeniable decline in aerosol optical thickness was observed from the MODIS sensor. It can be concluded that statistical distribution analysis coupled with pollution models can be a counterpart in studying the dispersal and developing pollution abatement policies for specific sites. Moreover, incorporating remote sensing in pollution study can enhance the knowledge about the origin and movement of air parcels and can be helpful in taking decisions beforehand.

Symptom clusters in outpatients with cancer using different dimensions of the symptom experience.

PURPOSE: Relatively few studies have evaluated for symptom clusters across multiple dimensions. It is unknown whether the symptom dimension used to create symptom clusters influences the number and types of clusters that are identified. Study purposes were to describe ratings of occurrence, severity, and distress for 38 symptoms in a heterogeneous sample of oncology patients (n = 1329) undergoing chemotherapy; identify and compare the number and types of symptom clusters based on three dimensions (i.e., occurrence, severity, and distress); and identify common and distinct clusters. METHODS: A modified version of the Memorial Symptom Assessment Scale was used to assess the occurrence, severity, and distress ratings of 38 symptoms in the week prior to patients' next cycle of chemotherapy. Symptom clusters for each dimension were identified using exploratory factor analysis. RESULTS: Patients reported an average of 13.9 (±7.2) concurrent symptoms. Lack of energy was both the most common and severe symptom while "I don't look like myself" was the most distressing. Psychological, gastrointestinal, weight gain, respiratory, and hormonal clusters were identified across all three dimensions. Findings suggest that psychological, gastrointestinal, and weight gain clusters are common while respiratory and hormonal clusters are distinct. CONCLUSIONS: Psychological, gastrointestinal, weight gain, hormonal, and respiratory clusters are stable across occurrence, severity, and distress in oncology patients receiving chemotherapy. Given the stability of these clusters and the consistency of the symptoms across dimensions, the use of a single dimension to identify these clusters may be sufficient. However, comprehensive and disease-specific inventories need to be used to identify distinct clusters.

Word recognition memory and serum levels of Borna disease virus specific circulating immune complexes in obsessive-compulsive disorder.

BACKGROUND: Borna disease virus 1 (BoDV-1) is a non-segmented, negative-strand RNA virus that persistently infects mammals including humans. BoDV-1 worldwide occurring strains display highly conserved genomes with overlapping genetic signatures between those of either human or animal origin. BoDV-1 infection may cause behavioral and cognitive disturbances in animals but has also been found in human major depression and obsessive-compulsive disorder (OCD). However, the impact of BoDV-1 on memory functions in OCD is unknown. METHOD: To evaluate the cognitive impact of BoDV-1 in OCD, event-related brain potentials (ERPs) were recorded in a continuous word recognition paradigm in OCD patients (n = 16) and in healthy controls (n = 12). According to the presence of BoDV-1-specific circulating immune complexes (CIC), they were divided into two groups, namely group H (high) and L (low), n = 8 each. Typically, ERPs to repeated items are characterized by more positive waveforms beginning approximately 250 ms post-stimulus. This "old/new effect" has been shown to be relevant for memory processing. The early old/new effect (ca. 300-500 ms) with a frontal distribution is proposed to be a neural correlate of familiarity-based recognition. The late old/new effect (post-500 ms) is supposed to reflect memory recollection processes. RESULTS: OCD patients were reported to show a normal early old/new effect and a reduced late old/new effect compared to normal controls. In our study, OCD patients with a high virus load (group H) displayed exactly these effects, while patients with a low virus load (group L) did not differ from healthy controls. CONCLUSION: These results confirmed that OCD patients had impaired memory recollection processes compared to the normal controls which may to some extent be related to their BoDV-1 infection.

Acute toxicity studies and protective effects of Cinnamon cassia bark extract in streptozotocin-induced diabetic rats.

The medicinal properties of Cinnamon cassia (C. cassia) bark have been reported for their clinical importance for many diseases including diabetes. However, there is no clear evidence so far regarding dose selection for its hepato- and nephroprotective effect in diabetic condition. Hence, the present study aims at evaluating in vitro antioxidant activity, the acute toxicity, and dose fixation of C. cassia bark for their effective medicinal values in streptozotocin (STZ)-induced rats. All the extracts exhibited potential in vitro antioxidant activity and showed a dose-dependent (1000, 2000, 3000, 4000, and 5000 mg/kg BW) acute toxicity by in vivo model. The levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), urea, and creatinine showed a significant elevation in animals treated with the highest dose. In further studies along with histopathological studies, animals treated with STZ (60 mg/kg BW) followed by a different dose (300, 400, and 500 mg/kg BW) of ethanolic extract of the C. cassia bark and glibenclamide (3 mg/kg BW) revealed that the altered level of mitochondrial enzymes, hepatic, and renal marker in STZ-induced animals were restored in C. cassia bark extract-treated group as of control. These results could be of scientific support for the use of the ethanolic extract of the C. cassia bark in folk medicine for the management of diabetes and its associated complications.

Unexpected Wear of a Uniquely Designed Moderately Cross-Linked Polyethylene in Total Hip Arthroplasty.

BACKGROUND: A uniquely designed, non-heat-treated moderately cross-linked acetabular polyethylene liner used in total hip arthroplasty (THA) demonstrated excessive wear during routine follow-up, prompting an evaluation of the linear wear rate. METHODS: All THAs were performed by the senior author. The study group included 38 THAs using the uniquely designed polyethylene in question, compared to a control group of 21 THAs using another moderately cross-linked polyethylene with good 10-year outcomes. Two-dimensional linear head penetration wear measurements were obtained using the Martell Hip Analysis Suite, and retrieval analysis was performed on two liners. RESULTS: The study group had a significantly higher average penetration rate of 0.089 mm/y than the control group average rate of 0.047 mm/y (P = .04). Forty-five percent of the study group had a wear rate above the osteolysis threshold (0.1 mm/y), compared to 24% in the control group. Macroscopic analysis of two retrieved liners validated the radiographic findings. CONCLUSION: The data suggest unexpectedly higher wear rates for a moderately cross-linked polyethylene design, with nearly half of the study group at risk for osteolysis. Further registry or database analyses of this particular moderately cross-linked polyethylene are warranted.

A robust variational autoencoder using beta divergence.

The presence of outliers can severely degrade learned representations and performance of deep learning methods and hence disproportionately affect the training process, leading to incorrect conclusions about the data. For example, anomaly detection using deep generative models is typically only possible when similar anomalies (or outliers) are not present in the training data. Here we focus on variational autoencoders (VAEs). While the VAE is a popular framework for anomaly detection tasks, we observe that the VAE is unable to detect outliers when the training data contains anomalies that have the same distribution as those in test data. In this paper we focus on robustness to outliers in training data in VAE settings using concepts from robust statistics. We propose a variational lower bound that leads to a robust VAE model that has the same computational complexity as the standard VAE and contains a single automatically-adjusted tuning parameter to control the degree of robustness. We present mathematical formulations for robust variational autoencoders (RVAEs) for Bernoulli, Gaussian and categorical variables. The RVAE model is based on beta-divergence rather than the standard Kullback-Leibler (KL) divergence. We demonstrate the performance of our proposed ß-divergence-based autoencoder for a variety of image and categorical datasets showing improved robustness to outliers both qualitatively and quantitatively. We also illustrate the use of our robust VAE for detection of lesions in brain images, formulated as an anomaly detection task. Finally, we suggest a method to tune the hyperparameter of RVAE which makes our model completely unsupervised.

Robust brain network identification from multi-subject asynchronous fMRI data.

We describe a novel method for robust identification of common brain networks and their corresponding temporal dynamics across subjects from asynchronous functional MRI (fMRI) using tensor decomposition. We first temporally align asynchronous fMRI data using the orthogonal BrainSync transform, allowing us to study common brain networks across sessions and subjects. We then map the synchronized fMRI data into a 3D tensor (vertices × time × subject/session). Finally, we apply Nesterov-accelerated adaptive moment estimation (Nadam) within a scalable and robust sequential Canonical Polyadic (CP) decomposition framework to identify a low rank tensor approximation to the data. As a result of CP tensor decomposition, we successfully identified twelve known brain networks with their corresponding temporal dynamics from 40 subjects using the Human Connectome Project's language task fMRI data without any prior information regarding the specific task designs. Seven of these networks show distinct subjects' responses to the language task with differing temporal dynamics; two show sub-components of the default mode network that exhibit deactivation during the tasks; the remaining three components reflect non-task-related activities. We compare results to those found using group independent component analysis (ICA) and canonical ICA. Bootstrap analysis demonstrates increased robustness of networks found using the CP tensor approach relative to ICA-based methods.

Phase 2 study of anastrozole in patients with estrogen receptor/progesterone receptor positive recurrent low-grade endometrial stromal sarcomas: The PARAGON trial (ANZGOG 0903).

BACKGROUND: Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers. METHOD: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER ± PR + ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. RESULTS: 15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48-89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2-29.8%), partial response in three (20%, 95% CI 7.1-45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2-NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5-63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects. CONCLUSION: The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers.

Impact of Effective Global Tuberculosis Control on Health and Economic Outcomes in the United States.

Rationale: Most U.S. residents who develop tuberculosis (TB) were born abroad, and U.S. TB incidence is increasingly driven by infection risks in other countries.Objectives: To estimate the potential impact of effective global TB control on health and economic outcomes in the United States.Methods: We estimated outcomes using linked mathematical models of TB epidemiology in the United States and migrants' birth countries. A base-case scenario extrapolated country-specific TB incidence trends. We compared this with scenarios in which countries achieve 90% TB incidence reductions between 2015 and 2035, as targeted by the World Health Organization's End TB Strategy ("effective global TB control"). We also considered pessimistic scenarios of flat TB incidence trends in individual countries.Measurements and Main Results: We estimated TB cases, deaths, and costs and the total economic burden of TB in the United States. Compared with the base-case scenario, effective global TB control would avert 40,000 (95% uncertainty interval, 29,000-55,000) TB cases in the United States in 2020-2035. TB incidence rates in 2035 would be 43% (95% uncertainty interval, 34-54%) lower than in the base-case scenario, and 49% (95% uncertainty interval, 44-55%) lower than in 2020. Summed over 2020-2035, this represents 0.8 billion dollars (95% uncertainty interval, 0.6-1.0 billion dollars) in averted healthcare costs and $2.5 billion dollars (95% uncertainty interval, 1.7-3.6 billion dollars) in productivity gains. The total U.S. economic burden of TB (including the value of averted TB deaths) would be 21% (95% uncertainty interval, 16-28%) lower (18 billion dollars [95% uncertainty level, 8-32 billion dollars]).Conclusions: In addition to producing major health benefits for high-burden countries, strengthened efforts to achieve effective global TB control could produce substantial health and economic benefits for the United States.

Development and characterization of stabilized omega-3 fatty acid and micronutrient emulsion formulation for food fortification.

We report a novel stabilized emulsified formulation containing omega-3 fatty acid (ω-3 FA) and micronutrient that can be readily used for food fortification. The emulsification methodology for producing a stabilized formulation containing both ω-3 FA and micronutrients is described. The formulation was developed considering the human requirement of ω-3 FA and recommended daily allowance of important micronutrients. This formulation was characterized for physical appearance, pH, specific gravity, color measurement etc. Fatty acid analysis revealed formulations (2, 4 and 5 g/serve) were able to provide 500-1300 mg of alpha linoleic acid. Oxidative stability assessment (peroxide value, free fatty acid content) of the formulations showed, stability of the formulation as non-significant alterations were noted in these parameters when the formulations were compared with raw flaxseed oil. Rheological evaluation indicated formulation followed Non-Newtonian system with shear thickening behavior. Particle size was found to be between 673.83 to 798.76 nm and poly-dispersity index was between 0.438 to 0.681. Microscopic analysis by Cryo-SEM analysis of the formulation showed stable homogeneous nature of formulation. Stability of the formulations was confirmed by freeze-thawing, dilution test and emulsion stability index. Acute oral toxicity study as per OECD guideline showed safety of the formulations. Most importantly, in vivo bioavailability study of ω-3 FA confirmed better bioavailability of the metabolites of ω-3 FA i.e. eicosapentaenoic and docosahexaenoic acids in formulation treated group as compared to flax oil and comparable bioavailability to that of fish oil.