Miracle-dz/UniFAR-FTUs huggingface dataset:
Blinatumomab for the treatment of B-cell lymphoma

Introduction: Blinatumomab is a bispecific T-cell engager (BiTE) molecule that recruits cytotoxic T cells to target tumor B cells by linking the CD3 and CD19 antigens. Among the various formats of bispecific antibodies developed in the past 50 years, the BiTE class is remarkable for its low effector-to-target ratio, high tissue penetration and singular ability to activate T cells independent of MHC class I presentation or costimulation. Blinatumomab has been studied in patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL) and B-precursor acute lymphoblastic leukemia (B-ALL). Areas covered: This article reviews the current literature on blinatumomab including its pharmacology, preclinical findings, clinical trials in B-cell NHL and, to a lesser extent, Phase II studies in B-ALL. The authors discuss the potential future directions in light of other new competing therapies for NHL and unmet clinical needs in the market. Expert opinion: The recent approval of blinatumomab for B-ALL symbolizes a breakthrough for BiTE technology with prospective application in the targeted therapy of other cancers. Although blinatumomab seems an unlikely option for treating indolent lymphoma due to toxicity, the need for long-term continuous infusion therapy and multiple promising well-tolerated oral agents, it holds promise for aggressive NHL patients whose diseases are refractory to current standard approaches. Larger trials are needed to demonstrate blinatumomab’s curative potential in aggressive histologies.
Failure of highly immunogenic filarial proteins to provide host-protective immunity.

In areas that are endemic for lymphatic filariasis, there are individuals who are parasite free and who appear not to have experienced symptoms attributable to filarial infection. These "putatively immune" individuals may recognize immunogens that could be important in host protection. We have immunoscreened expression libraries expressing epitopes encoded by filarial open reading frames and have identified three antigens that are differentially recognized by the two polar clinical groups-endemic normals and asymptomatic microfilaremics. Pre-immunization of susceptible hosts (Meriones unguiculatus) with these antigens revealed that none was able to elicit consistent host protective immunity. Our data are consistent with Waksman's conjecture that highly immunogenic antigens of parasite origin may be inappropriate candidates for prophylactic immunization.
A methodology for thermal dose model parameter development using perioperative MRI

Abstract Post-treatment imaging is the principal method for evaluating thermal lesions following image-guided thermal ablation procedures. While real-time temperature feedback using magnetic resonance temperature imaging (MRTI) is a complementary tool that can be used to optimise lesion size throughout the procedure, a thermal dose model is needed to convert temperature–time histories to estimates of thermal damage. However, existing models rely on empirical parameters derived from laboratory experiments that are not direct indicators of post-treatment radiologic appearance. In this work, we investigate a technique that uses perioperative MR data to find novel thermal dose model parameters that are tailored to the appearance of the thermal lesion on post-treatment contrast-enhanced imaging. Perioperative MR data were analysed for five patients receiving magnetic resonance-guided laser-induced thermal therapy (MRgLITT) for brain metastases. The characteristic enhancing ring was manually segmented on post-treatment T1-weighted imaging and registered into the MRTI geometry. Post-treatment appearance was modelled using a coupled Arrhenius-logistic model and non-linear optimisation techniques were used to find the maximum-likelihood kinetic parameters and dose thresholds that characterise the inner and outer boundary of the enhancing ring. The parameter values and thresholds were consistent with previous investigations, while the average difference between the predicted and segmented boundaries was on the order of one pixel (1 mm). The areas predicted using the optimised model parameters were also within 1 mm of those predicted by clinically utilised dose models. This technique makes clinically acquired data available for investigating new thermal dose model parameters driven by clinically relevant endpoints.
Improved Contemporary Surgical Management of Insulinomas: A 25-year Experience at the Massachusetts General Hospital

Objective:To determine changes in the management strategy of patients with insulinomas and identify critical factors in patient outcome. Background:Pancreatic insulinomas are rare neoplasms that are present in various ways. The optimal approach to localization, operative management, and follow-up of insulinomas is undetermined. Methods:Sixty-one patients with a diagnosis of insulinoma requiring surgery at a tertiary care center between 1983 and 2007 were reviewed. Demographic details, mode of presentation, preoperative localization, operative procedures, and pathology data were assessed. The effect of different factors on survival was determined. Results:Seven of 61 (11%) patients had a diagnosis of multiple endocrine neoplasia-type 1 (MEN-1). Multiple insulinomas were noted in 8% of cases and were more common in MEN-1 patients. The overall rate of malignancy was 8%. Confusion (67%), visual disturbances (42%), and diaphoresis (30%) were the most common presenting symptoms. Weight gain was noted in 44% of patients. The median duration of symptoms before diagnosis was 18 (1–240) months. The sensitivity of preoperative imaging of tumors before 1994 was 75%, compared with 98% after this period, which included use of endoscopic ultrasound scanning (P = 0.012). A combination of palpation and intraoperative ultrasound detected 92% of tumors. Distal pancreatectomy (40%), enucleation (34%), and pancreaticoduodenectomy (16%) were the most common procedures and pancreatic fistula occurred in 18% of patients. Three patients underwent noncurative distal pancreatectomy in the early period. The 10-year disease-specific and disease-free survival was 100% and 90% respectively. There were 5 patients with disease recurrence. Lymph node metastases (P < 0.001), lymphovascular invasion (P < 0.001), and the presence of MEN-1 (P = 0.035) were prognostically significant adverse factors in disease-free survival. Lymphovascular invasion was the only significant factor on multivariate analysis (P = 0.002). Conclusion:Pancreatic insulinomas can be readily localized preoperatively with modern imaging to avoid unsuccessful blind pancreatic resection. Surgical resection is associated with low morbidity and mortality and achieves long-term disease-free survival in the absence of lymphovascular invasion.
The Trump Administration's "Zero Tolerance" Immigration Enforcement Policy

This report briefly reviews the statutory authority for prosecuting persons who enter the United States illegally between U.S. ports of entry, and the policies and procedures for processing apprehended illegal border entrants and any accompanying children. It explains enforcement policies in the past and then discusses the Trump Administration's zero tolerance policy on illegal border crossers and the attendant family separations. The report concludes by presenting varied policy perspectives on the zero-tolerance policy and briefly reviews recent related congressional activity. An appendix examines recent trends in the apprehension of family units at the U.S. southern border.
Reduction in the risk of vertical transmission of HIV-1 associated with treatment of pregnant women with orally administered zidovudine alone.

In a prospective cohort study of 267 children born to mothers infected with HIV-1 in New Haven, Connecticut, an abrupt decline in the risk of mother-to-child transmission occurred in 1990 and persisted at least through December, 1993. A retrospective, observational study was undertaken to identify factors that might be responsible for this decline. Three variables were assessed: the use of orally administered zidovudine during pregnancy, the CD4+ T-lymphocyte count of the mother, and the mode of delivery. The risk of transmission was 18.6% (36/194; 95% CI: 14.1-24.8%) in infants of all women not treated with zidovudine compared with 5.5% (3/55; 95% CI: 1.1-15.1%) in infants of all women who were treated (odds ratio: 0.25; p = 0.02). In a subgroup of women with known CD4+ cell counts, the risk of transmission was 21.1% (20/95; 95% CI: 13.4-30.6%) in untreated women compared with 5.5% (3/55) in those who received zidovudine (odds ratio: 0.22; p = 0.01). In women with CD4+ T-cell counts < 200/microl, the differences remained significant (39.1% in those not treated vs. 4.2% in those treated; p < 0.004). There was an inverse relationship between CD4+ cell count and risk of transmission: among untreated mothers whose T-lymphocyte counts were > or = 500, 200-499, or < 200/microl, HIV-1 was transmitted to the offspring of 8.2, 30.4, and 39.1% of offspring, respectively (p < 0.002 by the exact trend test). There was no significant association between mode of delivery and vertical transmission of HIV. We conclude that treatment with orally administered zidovudine alone (500 mg/day) in the course of routine prenatal care is associated with a significant reduction in the risk of vertical transmission.
Conformational flexibility of the complete catalytic domain of Cdc25B phosphatases

Cdc25B phosphatases are involved in cell cycle checkpoints and have become a possible target for developing new anticancer drugs. A more rational design of Cdc25B ligands would benefit from detailed knowledge of its tertiary structure. The conformational flexibility of the C‐terminal region of the Cdc25B catalytic domain has been debated recently and suggested to play an important structural role. Here, a combination of experimental NMR measurements and molecular dynamics simulations for the complete catalytic domain of the Cdc25B phosphatase is presented. The stability of the C‐terminal α‐helix is confirmed, but the last 20 residues in the complete catalytic domain are very flexible, partially occlude the active site and may establish transient contacts with the protein core. This flexibility in the C‐terminal tail may modulate the molecular recognition of natural substrates and competitive inhibitors by Cdc25B. Proteins 2016; 84:1567–1575. © 2016 Wiley Periodicals, Inc.
Low Blood Levels of Long-Chain n–3 Polyunsaturated Fatty Acids in US Hemodialysis Patients: Clinical Implications

Background: Cardioprotective and other clinical benefits of long-chain n–3 polyunsaturated fatty acids (PUFA) are inversely related to dietary intake and hence blood content. We therefore investigated, in the first study of its kind, the blood content and distribution of these fatty acids in a large representative population of US hemodialysis patients. Methods: Frozen sera were obtained from 400 individuals who were part of a large, contemporary, representative cohort of US incident hemodialysis patients. Long-chain n–3 PUFA were measured in total serum lipids and in the neutral and polar serum fractions using gas chromatography and solid phase extraction techniques. Mean long-chain n–3 PUFA levels were compared to levels in other dialysis and nondialysis populations from published reports. Results: The study population was qualitatively similar to the overall US hemodialysis population in terms of major clinical characteristics. Long-chain n–3 PUFA were present in the serum polar fraction, with essentially none being detected in the neutral fraction (p < 0.0001 for polar vs. neutral fractions for all three long-chain n–3 PUFA). Mean serum long-chain n–3 PUFA levels (weight percent (±SD): total 1.55 ± 0.95, polar 3.99 ± 1.45) were low compared to nondialysis and most other non-US hemodialysis cohorts. Conclusions: While US hemodialysis patients have a blood distribution of long-chain n–3 PUFA that is similar to that in the general population, blood content is among the lowest recorded in the medical literature. This has implications for renal dietary recommendations and makes US patients an ideal group for testing the clinical effects of long-chain n–3 PUFA supplementation.
Option Writing: Using VIX to Improve Returns

Buy-write and put-write strategies have been shown to match market returns with lower volatility, resulting in higher risk-adjusted performance. The strategies benefit from the fact that the implied volatility of options is generally higher than actual realized volatility. In this article, we show that this premium is higher at elevated levels of implied volatility (as represented by the VIX index level). Based on this finding, we propose a simple conditional strategy in which one sells options at elevated levels of the VIX. Using data from 1990 through 2018, we find that this conditional strategy outperforms both the market and continuous option-selling strategies on an absolute and risk-adjusted basis.
Quantitative ex vivo analysis of functional virus-specific CD8 T lymphocytes in the blood and genital tract of HIV-infected women

Background: CD8 T lymphocytes are important in HIV-1 control and mediate virus-specific immunity in the blood and genital tract. The induction and monitoring of mucosal CD8 cell responses will be an important component of HIV-1 vaccine trials, but information regarding the frequency, phenotype and function of genital tract CD8 cell responses is lacking. Methods: Simultaneous blood and cervical cytobrush samples were obtained from 16 HIV-1-infected Kenyan sex workers. Epitope-specific CD8 T lymphocyte frequencies in the blood and genital tract were analysed after short-term peptide incubation and intracellular cytokine staining for interferon-γ (IFNγ). Results: Cervical sampling resulted in adequate cell numbers for analysis in 10/16 women. Background IFNγ production was higher in CD3+/CD8+ lymphocytes from the genital tract than from blood (0.48% versus 0.1%; P < 0.01). Responses to staphylococcal enterotoxin B were detected in cervical CD8 lymphocytes from 10/10 women, at a similar frequency to blood (16.7% in cervix and 13.3% in blood; P = 0.4). HIV-1-specific responses were detected the cervix of 8/10 women, with a trend to higher response frequencies in the genital tract than blood (2.1% versus 0.8%; P = 0.09). Co-expression of integrin CD103 (αEβ7), a mucosal marker, was used to confirm the mucosal origin of cervical responses. Conclusions: Cytobrush sampling and intracellular cytokine staining is well suited to the analysis of cervical CD8 cell responses. The frequency of functional virus-specific CD3+/CD8+ T cells is similar in the genital tract and blood of HIV-1-infected women. The role of genital tract CD8 cell responses in HIV-1 control warrants further investigation.
The determinants and longitudinal course of post-stroke mild cognitive impairment

Abstract While post-stroke dementia has been extensively investigated, the large number of patients with mild cognitive impairment (MCI) following stroke has received less attention, and reports on the longitudinal course of such impairment are inconsistent in their findings. We examined patients with MCI (n = 45) or no cognitive impairment (NCI) (n = 59), based on consensus criteria following detailed neuropsychological assessments and magnetic resonance imaging (MRI) scans, and compared them with healthy control subjects (n = 84), all of whom were assessed at two time points, 3 years apart. The MCI at baseline in this group was judged to be vascular in etiology (vaMCI). Incident dementia was diagnosed in 24.4% of vaMCI and 8.5% of NCI subjects and no control subjects over 3 years, giving a rate of conversion of approximately 8% per year in post-stroke vaMCI. The vaMCI group showed greater decline in logical memory than the NCI group. Within the vaMCI group, those who developed dementia had great decline in language and executive function. Compared with NCI patients, those with vaMCI had more vascular risk factors and more white matter hyperintensities on MRI at baseline, but did not differ in their brain or hippocampal volumes. Neither MRI volumetric measures nor interval cerebrovascular events predicted decline in function. The major determinant of decline and categorical transition was impaired performance at baseline, suggesting that those with mild impairment post-stroke are more vulnerable to subsequent decline. (JINS, 2009, 15, 915–923.)
Use of Virtual Surgery and Stereolithography-Guided Osteotomy for Mandibular Reconstruction with the Free Fibula

Summary: Fibular osteotomy remains a challenging aspect of mandibular microsurgical reconstruction, dependent largely on surgeon experience, intraoperative judgment, and technical speed. Virtual surgical planning and stereolithographic modeling is a relatively new technique that can allow for reduction in the learning curve associated with neomandible contouring, enhanced levels of accuracy, and acceleration of a time-consuming intraoperative step. The authors present a video (narrated and edited from planning sessions and intraoperative use of technique to illustrate the technology) and describe their favorable results. Five patients underwent composite resection of the mandible and free fibula osteocutaneous reconstruction over a 6-month period (December of 2009 to June of 2010) at a single institution using a virtual planning session and stereolithographic modeling. Outcomes assessed included technical accuracy, aesthetic contour, and functional outcomes. All patients achieved negative margins with cutting guide–directed resection. Use of this technique eliminated the need for intraoperative measurement and yielded fibular segments with excellent apposition and faithful duplication of the preoperative plan. Minimal adjustments were needed for inset. Flap survival was 100 percent. All patients have maintained preoperative occlusion and a symmetric mandibular contour on Panorex study, three-dimensional computed tomography, and clinical examination. Accuracy of the reconstructed contour was confirmed using computed tomographic image overlay. This virtual surgical planning technique combined with stereolithographic model–guided osteotomy is the mainstay of the authors' approach to fibular osteotomy when dealing with patients requiring mandibular reconstruction. The authors feel this technology facilitates realization of technical accuracy, aesthetic contour, and functional outcomes and may be particularly useful if free fibular mandibular reconstruction is performed less frequently. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
Applying Merton’s Valuation Adjustment for Incomplete Information...and Do You Need To?

Bodnaruk and Ostberg (2009) introduced a simple formula for applying Merton’s (1987) incomplete-information adjustment to a stock’s required rate of return. The adjustment, which is based on market capitalization, idiosyncratic risk, and extent of investor ownership, should in principle improve discount rate estimates used in valuation. This article helps bridge the gap between theory and practice by explaining the application of the adjustment formula and providing adjustment estimates for some example U.S. stocks. The adjustment estimates tend to be material for volatile stocks with a relatively low percentage of shares held by institutional funds.
Gender disparities in the receipt of home care for elderly people with disability in the United States.

CONTEXT Projected demographic shifts in the US population over the next 50 years will cause families, health care practitioners, and policymakers to confront a marked increase in the number of people with disabilities living in the community. Concerns about the adequacy of community support are particularly salient to women, who make up a disproportionate number of disabled elderly people and who may be particularly vulnerable because they are more likely to live alone with limited financial resources. OBJECTIVE To address gender differences in receipt of informal and formal home care. DESIGN, SETTING, AND PARTICIPANTS Nationally representative survey conducted in 1993 among 7443 noninstitutionalized people (4538 women and 2905 men) aged 70 years or older. MAIN OUTCOME MEASURE Number of hours per week of informal (generally unpaid) and formal (generally paid) home care received by survey participants who reported any activity of daily living (ADL) or instrumental activity of daily living (IADL) impairment (n = 3109) compared by gender and living arrangement and controlling for other factors. RESULTS Compared with disabled men, disabled women were much more likely to be living alone (45.4% vs 16.8%, P<.001) and much less likely to be living with a spouse (27.8% vs 73.6%, P<.001). Overall, women received fewer hours of informal care per week than men (15.7 hours; 95% confidence interval [CI], 14.5-16.9 vs 21.2 hours; 95% CI, 19. 7-22.8). Married disabled women received many fewer hours per week of informal home care than married disabled men (14.8 hours; 95% CI, 13.7-15.8 vs 26.2 hours; 95% CI, 24.6-27.9). Children (>80% women) were the dominant caregivers for disabled women while wives were the dominant caregivers of disabled men. Gender differences in formal home care were small (2.8 hours for women; 95% CI, 2.5-3.1 vs 2.1 hours for men; 95% CI, 1.7-2.4). CONCLUSION Large gender disparities appear to exist in the receipt of informal home care for disabled elderly people in the United States, even within married households. Programs providing home care support for disabled elderly people need to consider these large gender disparities and the burden they impose on families when developing intervention strategies in the community.
Biologic effects after a single dose of poly(I):poly(C12U) in healthy volunteers

Poly(I):poly(C12U) (mismatched double-stranded RNA; atvogen), an interferon inducer, is active against human immunodeficiency virus in vitro. To determine the extent and duration of the biologic effects of poly(I):poly(C12U), we administered a single dose of the drug to healthy volunteers in a randomized, double-blind, placebo-controlled 2-week crossover study. We analyzed blood for alpha and gamma interferons, neopterin, 2',5'-oligoadenylate synthetase, lymphocyte surface markers, lymphocyte proliferation after exposure to soluble antigens and mitogens, and natural killer cell activity. Minimal biologic effects were observed after administration of a single 200-mg dose to four volunteers; therefore, the dose was increased to 600 mg in 10 subjects. Only neopterin levels and symptoms were greater after administration of 600 mg of poly(I):poly(C12U) than after administration of placebo (Wilcoxon signed rank sum test, P = 0.06). A definite response in 2',5'-oligoadenylate synthetase activity, however, was seen in a few subjects. Neither alpha nor gamma interferon was detectable in serum after poly(I):poly(C12U) dosing. The neopterin changes after administration of poly(I):poly(C12U) were similar at both poly(I):poly(C12U) dose levels, with an early decrease at 6 h, a peak at 1 day, and a gradual decrease toward the baseline over the following 3 days. A mild flu-like syndrome occurred in one-half of the subjects following administration of poly(I):poly(C12U) and in only one subject following administration of placebo. This syndrome resolved within 16 h after poly(I):poly(C12U) dosing. We conclude that poly(I):poly(C12U) does not induce measurable levels of interferon and causes only minimal biologic or toxic effects among those parameters measured after administration of a single dose in the 200- to 600-mg dose range in health volunteers.