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Background: The cumulative, health system‐wide survival benefit of immune checkpoint inhibitors (ICIs) is unclear, particularly among real‐world patients with limited life expectancies and among subgroups poorly represented on clinical trials. We sought to determine the health system‐wide survival impact of ICIs. Methods: We identified all patients receiving PD‐1/PD‐L1 or CTLA‐4 inhibitors from 2010 to 2023 in the national Veterans Health Administration (VHA) system (ICI cohort) and all patients who received non‐ICI systemic therapy in the years before ICI approval (historical control). ICI and historical control cohorts were matched on multiple cancer‐related prognostic factors, comorbidities, and demographics. The effect of ICI on overall survival was quantified with Cox regression incorporating matching weights. Cumulative life‐years gained system‐wide were calculated from the difference in adjusted 5‐year restricted mean survival times. Results: There were 27,322 patients in the ICI cohort and 69,801 patients in the historical control cohort. Among ICI patients, the most common cancer types were NSCLC (46%) and melanoma (10%). ICI demonstrated a large OS benefit in most cancer types with heterogeneity across cancer types (NSCLC: adjusted HR [aHR] 0.56, 95% confidence interval [CI] 0.54–0.58, p < 0.001; urothelial: aHR 0.91, 95% CI 0.83–1.01, p = 0.066). The relative benefit of ICI was stable across patient age, comorbidity, and self‐reported race subgroups. Across VHA, 15,859 life‐years gained were attributable to ICI within 5‐years of treatment, with NSCLC contributing the most life‐years gained. Conclusion: We demonstrated substantial increase in survival due to ICIs across a national health system, including in patient subgroups poorly represented on clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Real world evidence is crucial to understanding the diffusion of new oncologic therapies, monitoring cancer outcomes, and detecting unexpected toxicities. In practice, real world evidence is challenging to collect rapidly and comprehensively, often requiring expensive and time‐consuming manual case‐finding and annotation of clinical text. In this Review, we summarise recent developments in the use of artificial intelligence to collect and analyze real world evidence in oncology. Methods: We performed a narrative review of the major current trends and recent literature in artificial intelligence applications in oncology. Results: Artificial intelligence (AI) approaches are increasingly used to efficiently phenotype patients and tumors at large scale. These tools also may provide novel biological insights and improve risk prediction through multimodal integration of radiographic, pathological, and genomic datasets. Custom language processing pipelines and large language models hold great promise for clinical prediction and phenotyping. Conclusions: Despite rapid advances, continued progress in computation, generalizability, interpretability, and reliability as well as prospective validation are needed to integrate AI approaches into routine clinical care and real‐time monitoring of novel therapies. [ABSTRACT FROM AUTHOR]

This document is a transcript of a presentation by Professor Michael Green on the topic of the American Law Institute (ALI) and the Restatement (Third) of Torts. The presentation discusses the history and development of the Restatement, as well as the various projects undertaken by the ALI to restate different aspects of tort law. The document also mentions the completion of the Third Restatement and the need for a separate project to address remaining doctrines and new developments in tort law. The presentation concludes with praise for Professor Nora Freeman Engstrom, one of the co-reporters involved in the project. [Extracted from the article]

Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker. We performed HLA typing on 85 patients with mNSCLC, on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 genotype was seen in 34/85 (40%) and its presence correlated with improved OS in both univariate (p = 0.022; 26.3 months vs 10.2 months) and multivariate analysis (p = 0.011, HR 0.49, 95% CI [0.29, 0.85]). PFS did not reach significance (univariate, p = 0.12, 8.2 months vs 5.1 months). Eleven patients developed endocrine irAEs. HLA-DRB4 was the predominant genotype among these patients (9/11, 81.8%). Cumulative incidence of endocrine irAEs was higher in patients with HLA-DRB4 (p = 0.0139). Our study is the first to suggest that patients with metastatic NSCLC patients on ICI therapy with HLA-DRB4 genotype experience improved survival outcomes. Patients with HLA-DRB4 had the longest median OS (26.3 months). Additionally, we found a correlation between HLA-DRB4 and the occurrence of endocrine irAEs. [ABSTRACT FROM AUTHOR]

This article discusses the American Law Institute's work on the Restatement (Third) of Torts, highlighting the importance of restating various aspects of tort law. The author also explores the connection between positive tort theory and the Restatement, arguing for its incorporation into the project. The text acknowledges the influence of various scholars on the development of tort theory and emphasizes the importance of theoretical explanation and justification in tort law. It discusses the application of positive tort theory in understanding existing tort doctrines and regulating different categories of activities. The author suggests that integrating positive tort theory into the Restatement process would enhance its social value and provide a better understanding of common law rules. [Extracted from the article]

Simple Summary: Uveal melanoma is a rare form of melanoma but is the most common tumor in the eye. Despite having effective treatments for the initial tumor, many patients experience the spread of their cancer to distant body sites. There is no uniform way of treating metastatic disease, but physicians often use therapies that harness the patient's immune system because these same treatments have been very effective in other types of melanoma. Not all patients respond to this therapy though, and some develop toxicity related to the treatment. The goal of this paper was to identify features or blood markers that may help determine response to treatment early. Specifically, we analyzed a molecule called lactate dehydrogenase (LDH) and the ratio of different white blood cells at the start of therapy and 2 months after treatment was started. We found that these non-invasive blood markers could be useful in determining which patients are responding to treatment. Background: There is no standardized treatment for metastatic uveal melanoma (MUM) but immune checkpoint inhibitors (ICI) are increasingly used. While ICI has transformed the survival of metastatic cutaneous melanoma, MUM patients do not equally benefit. Factors known to affect ICI response include the hematologic markers, lactate dehydrogenase (LDH) and neutrophil:lymphocyte ratio (NLR). We evaluated the prognostic value of LDH and NLR at the start of ICI and on treatment in MUM. Methods: MUM patients were treated between August 2006 and May 2022 with combination ipilimumab/nivolumab or ipilimumab/nivolumab/pembrolizumab single-agent therapy. Univariable (UVA) and multivariable (MVA) analyses were used to assess the prognostic value of predefined baseline factors on progression-free (PFS) and overall survival (OS). Results: In forty-six patients with MUM treated with ICI, elevated baseline and on-treatment LDH was prognostic for OS (start of ICI, HR (95% CI): 3.6 (1.9–7.0), p < 0.01; on-treatment, HR (95% CI): 3.7 (1.6–8.8), p < 0.01) and PFS (start of ICI, (HR (95% CI): 2.8 (1.5–5.4), p < 0.0001); on-treatment LDH (HR (95% CI): 2.2 (1.1–4.3), p < 0.01). On-treatment NLR was prognostic for PFS (HR (95% CI): 1.9 (1.0–3.9), p < 0.01). On-treatment LDH remained an important contributor to survival on MVA (OS: HR (95% CI): 1.001 (1.00–1.002), p < 0.05); PFS: HR (95% CI): 1.001 (1.00–1.002), p < 0.01). Conclusions: This study demonstrates that LDH and NLR could be useful in the prognostication of MUM patients treated with ICI. Additional studies are needed to confirm the importance of these and other prognostic biomarkers. [ABSTRACT FROM AUTHOR]

CRISPR screening is a powerful tool that links specific genetic alterations to corresponding phenotypes, thus allowing for high-throughput identification of novel gene functions. Pooled CRISPR screens have enabled discovery of innate and adaptive immune response regulators in the setting of viral infection and cancer. Emerging methods couple pooled CRISPR screens with parallel highcontent readouts at the transcriptomic, epigenetic, proteomic, and optical levels. These approaches are illuminating cancer immune evasion mechanisms as well as nominating novel targets that augment T cell activation, increase T cell infiltration into tumors, and promote enhanced T cell cytotoxicity. This review details recent methodological advances in high-content CRISPR screens and highlights the impact this technology is having on tumor immunology. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent non-skin cancer diagnosed in females and developing novel therapeutic strategies to improve patient outcomes is crucial. The immune system plays an integral role in the body's response to breast cancer and modulating this immune response through immunotherapy is a promising therapeutic option. Although immune checkpoint inhibitors were recently approved for the treatment of breast cancer patients, not all patients respond to immune checkpoint inhibitors as a monotherapy, highlighting the need to better understand the biology underlying patient response. Additionally, as radiotherapy is a critical component of breast cancer treatment, understanding the interplay of radiation and immune checkpoint inhibitors will be vital as recent studies suggest that combined therapies may induce synergistic effects in preclinical models of breast cancer. This review will discuss the mechanisms supporting combined approaches with radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer. Moreover, this review will analyze the current clinical trials examining combined approaches of radiotherapy, immunotherapy, chemotherapy, and targeted therapy. Finally, this review will evaluate data regarding treatment tolerance and potential biomarkers for these emerging therapies aimed at improving breast cancer outcomes. [ABSTRACT FROM AUTHOR]

Background: Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma followed by nivolumab single-agent maintenance therapy. While many patients receive less than 4 doses due to immune-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and assess if fewer doses of I/N can lead to similar survival outcomes. Methods: We performed a retrospective analysis on a cohort of patients with advanced melanoma who w0ere treated with standard I/N. Cox regression of progression-free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 1 or 2 vs 3 or 4 doses of I/N adjusted by known prognostic variables in advanced melanoma. Results: 199 patients were evaluated. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.16, 95% CI 0.08-0.33; p<0.001) and OS (HR: 0.12, 0.05-0.32; p<0.001) compared to progressive disease (PD). Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS (HR: 0.09, 0.05-0.16; p<0.001) and OS (HR: 0.07, 0.03-0.14; p<0.001). There was no survival risk difference comparing 1 or 2 vs 3 or 4 doses of I/N for PFS (HR: 0.95, 0.37-2.48; p=0.921) and OS (HR: 1.04, 0.22-4.78; p=0.965). Conclusions: Early interval imaging with response during induction with I/N may be predictive of long-term survival in advanced stage melanoma. CBR after 1 or 2 doses of I/N is associated with favorable survival outcomes, even in the setting of fewer I/N doses received. Further studies are warranted to evaluate if electively administering fewer combination I/N doses despite tolerance in select patients may balance the benefits of therapy while decreasing toxicities. [ABSTRACT FROM AUTHOR]

Objectives: In 2012, a stratified random survey, using mystery shoppers, was conducted to investigate the availability and quality of antibiotics sold to patients in the private sector in five southern provinces of the Lao People's Democratic Republic (Laos).Methods: A total of 147 outlets were sampled in 10 districts. The active pharmaceutical ingredient (API) content measurements for 909 samples, including nine APIs (amoxicillin, ampicillin, ceftriaxone, ciprofloxacin, doxycycline, ofloxacin, sulfamethoxazole, tetracycline and trimethoprim), were determined using HPLC.Results: All the analysed samples contained the stated API and we found no evidence for falsification. All except one sample had all the units tested with %API values between 75% and 125% of the content stated on the label. However, we identified the presence of substandard antibiotics: 19.6% (201/1025) of samples had their units outside the 90%-110% content of the label claim and 18.3% (188/1025) of the samples had units outside the International Pharmacopoeia/United States Pharmacopoeia assay (percentage of label claim) specifications. Trimethoprim had a high number of samples [51.6% (64)] with units below the limit range, followed by ceftriaxone [42.9% (3)] and sulfamethoxazole [34.7% (43)]. Doxycycline, ofloxacin and ciprofloxacin had the highest number of samples with high API content: 43.7% (38), 14.7% (10) and 11.8% (2), respectively. Significant differences in %API were found between stated countries of manufacture and stated manufacturers.Conclusions: With the global threat of antimicrobial resistance on patient outcomes, greater understanding of the role of poor-quality antibiotics is needed. Substandard antibiotics will have reduced therapeutic efficacy, impacting public health and control of bacterial infections. [ABSTRACT FROM AUTHOR]

U. L. Rev. 859, 868 (1996) (suggesting that the move toward apportioning liability - which is seen most clearly in the advent of comparative negligence - is the most "important" development in tort law since "the coming of insurance"); Robert L. Rabin, I Past as Prelude: The Legacy of Five Landmarks of Twentieth-Century Injury Law for the Future of Torts, in i Exploring Tort Law 52, 72 (M. Stuart Madden ed., 2005) (identifying comparative fault, and its "erosion of the all-or-nothing character of the common law tort system", as one of the five "most critical" developments "in restructuring the very foundations of tort law in the twentieth century"). Gary T. Schwartz, I Mixed Theories of Tort Law: Affirming Both Deterrence and Corrective Justice i , 75 Tex. L. Rev. 1801, 1806 (1997); I see also i Jed Handelsman Shugerman, I A Watershed Moment: Reversals of Tort Theory in the Nineteenth Century, i 2 J. Tort L. 1, 6 (2008) (explaining the twists and turns in the use of moral or instrumental theories in the development of tort law and that the experience suggests that "tort law and judges' underlying theories for its rules - including its theories of corrective justice - are contingent upon events and context"). 3 Our View of Tort Law We do not wish to take up arms in the "tort theory wars" in which proponents of one meta-theory of tort law insist that, as a descriptive matter, this or that theory I captures i contemporary tort law and then point out the inadequacies of rivals. [Extracted from the article]

Nearly half of all metastatic melanoma patients possess the BRAF V600 mutation. Several therapies are approved for advanced stage melanoma, but it is unclear if there is a differential outcome to various immunotherapy regimens based on BRAF mutation status. We retrospectively analyzed a cohort of metastatic or unresectable melanoma patients who were treated with combination ipilimumab/nivolumab (ipi/nivo) or anti‐PD‐1 monotherapy, nivolumab, or pembrolizumab, as first‐line treatment. 235 previously untreated patients were identified in our study. Our univariate analysis showed no statistical difference in progression‐free survival (PFS) or overall survival (OS) with ipi/nivo versus anti‐PD‐1 monotherapy in the BRAF V600 mutant cohort, but there was improved PFS [HR: 0.48, 95% CI, 0.28–0.80] and OS [HR: 0.50, 95% CI, 0.26–0.96] with ipi/nivo compared to anti‐PD‐1 monotherapy in the BRAF WT group. After adjusting for known prognostic variables in our multivariable analysis, the BRAF WT cohort continued to show PFS and OS benefit with ipi/nivo compared to anti‐PD‐1 monotherapy. Our single‐institution analysis suggests ipi/nivo should be considered over anti‐PD‐1 monotherapy as the initial immunotherapy regimen for metastatic melanoma patients regardless of BRAF mutation status, but possibly with greater benefit in BRAF WT. [ABSTRACT FROM AUTHOR]

He studies the effects of radiation in combination with targeted therapies, and how radiotherapy can be used to delay resistance development or modulate the patient's immune response. SBRT has already been shown to spare the circulating lymphocytes compared to conventional fractionation in patients.[18] Especially in the context of combining radiation with immunotherapeutic approaches, radiation-induced depletion of lymphocytes can dampen synergistic effects,[19] and it has been shown that the predictive value of lymphocyte counts also holds for metastatic patients on treatment with checkpoint inhibitors receiving RT.[20] SBRT evolved from the success of brain stereotactic radiosurgery (SRS), a treatment technique that stereotactically delivers high doses of radiation to precisely defined cranial lesions.[29] The extension of stereotactic treatments extracranially required tools to ensure patients were appropriately immobilized, the target position was verified directly or through the use of surrogates (e.g., fiducial markers, neighboring anatomy), and target motion was minimized, as well as a delivery system that was capable of precisely delivering radiation to the intended target. [Extracted from the article]

Objectives: In 2012, a stratified random survey, using mystery shoppers, was conducted to investigate the availability and quality of antibiotics sold to patients in the private sector in five southern provinces of the Lao People's Democratic Republic (Laos).Methods: A total of 147 outlets were sampled in 10 districts. The active pharmaceutical ingredient (API) content measurements for 909 samples, including nine APIs (amoxicillin, ampicillin, ceftriaxone, ciprofloxacin, doxycycline, ofloxacin, sulfamethoxazole, tetracycline and trimethoprim), were determined using HPLC.Results: All the analysed samples contained the stated API and we found no evidence for falsification. All except one sample had all the units tested with %API values between 75% and 125% of the content stated on the label. However, we identified the presence of substandard antibiotics: 19.6% (201/1025) of samples had their units outside the 90%-110% content of the label claim and 60.2% (617/1025) of the samples had units outside of the International Pharmacopoeia uniformity of content limit range. Amoxicillin had a high number of samples [67.1% (151)] with units above the limit range, followed by ciprofloxacin [58.8% (10)] and ofloxacin [57.4% (39)]. Ceftriaxone, trimethoprim and sulfamethoxazole had the highest number of samples with low API content: 57.1% (4), 51.6% (64) and 34.7% (43), respectively. Significant differences in %API were found between stated countries of manufacture and stated manufacturers.Conclusions: With the global threat of antimicrobial resistance to patient outcomes, greater understanding of the role of poor-quality antibiotics is needed. Substandard antibiotics will have reduced therapeutic efficacy, impacting public health and control of bacterial infections. [ABSTRACT FROM AUTHOR]

Proof of Causation addresses many contemporary and classical issues about causation and its proof in tort cases. This review explains the admirable depth, breadth, and scope of the book, along with the author's assessment that would limit instances when the burden and standard of proof of causation are relaxed. In the final section, the review addresses the relative paucity of consideration by Proof of Causation of scientific evidence despite its increased importance in the contemporary toxic tort area. [ABSTRACT FROM AUTHOR]

The prevalence of pediatric antimicrobial stewardship programs (ASPs) is increasing in acute care facilities across the United States. Over the past several years, the evidence base used to inform effective stewardship practices has expanded, and regulatory interest in stewardship programs has increased. Here, we review approaches for established, hospital-based pediatric ASPs to adapt and report standardized metrics, broaden their reach to specialized populations, expand to undertake novel stewardship initiatives, and implement rapid diagnostics to continue their evolution in improving antimicrobial use and patient outcomes. [ABSTRACT FROM AUTHOR]

Pharmaceutical claims are arguably the most significant type of product liability cases in the United States. Failure to warn is the primary theory used against pharmaceutical manufacturers, and it can be brought under strict product liability or negligence; the standard is essentially the same under either doctrine. In this descriptive overview of United States law, the authors discuss theories of recovery, causation, damages, defences, procedure, and alternative regulations and remedies. [ABSTRACT FROM AUTHOR]

The article offers information about Benjamin N. Cardozo, former Associate Justice of the Supreme Court of the U.S., who is known for his opinions about torts and contracts. Topics discussed include different aspect of his jurisprudence along with his opinions on the practice of law; and his opinions in which he had the opportunity to evaluate the conduct of lawyers within the practice of law; and his views on civil jury.

In this review of 200 charts, piperacillin-tazobactam usage was analyzed at a pediatric tertiary hospital, with an assessment of the indications for initiation, and continuation at day 3 of usage. Significant cost savings could be obtained with antibiotic stewardship audit on day 3 of antibiotic administration. [ABSTRACT FROM AUTHOR]

The article discusses the authors' views about how to control the quality of expert witness testimony in America, and it mentions the U.S. Supreme Court's establishment of a method for assessing the admissibility of expert testimony in federal courts in the 1993 case Daubert v. Merrell Dow Pharmaceuticals Inc. The sufficiency of scientific evidence to support a plaintiff verdict is examined, along with expert evidence cases such as Frye v. United States and In re Agent Orange Prod. Liab. Litig.

Background: Malaria infection can cause high oxidative stress, which could lead to the development of severe forms of malaria, such as pulmonary malaria. In recent years, the role of reactive oxygen species in the pathogenesis of the disease has been discussed, as well as the potential benefit of antioxidants supplementation. The aim of this study was to investigate the effects of N-acetyl cysteine (NAC) or mushroom Agaricus sylvaticus supplementation on the pulmonary oxidative changes in an experimental model of malaria caused by Plasmodium berghei strain ANKA. Methods: Swiss male mice were infected with P. berghei and treated with NAC or AS. Samples of lung tissue and whole blood were collected after one, three, five, seven or ten days of infection for the assessment of thiobarbituric acid reactive substances (TBARS), trolox equivalent antioxidant capacity (TEAC), nitrites and nitrates (NN) and to assess the degree of parasitaemia. Results: Although parasitaemia increased progressively with the evolution of the disease in all infected groups, there was a significant decrease from the seventh to the tenth day of infection in both antioxidant-supplemented groups. Results showed significant higher levels of TEAC in both supplemented groups, the highest occurring in the group supplemented with A. sylvaticus. In parallel, TBARS showed similar levels among all groups, while levels of NN were higher in animals supplemented with NAC in relation to the positive control groups and A. sylvaticus, whose levels were similar to the negative control group. Conclusion: Oxidative stress arising from plasmodial infection was attenuated by supplementation of both antioxidants, but A. sylvaticus proved to be more effective and has the potential to become an important tool in the adjuvant therapy of malaria. [ABSTRACT FROM AUTHOR]

Background: Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs) in Enugu metropolis, Nigeria, and compared the resulting quality estimates. Methods: ACAs were purchased using three sampling approaches - convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified. Results: Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200), mystery (n=1,919) and overt (n=905) approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified) and dihydroartemisinin (n=14) monotherapy tablets, not recommended by WHO, were also identified. Conclusion: Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained. [ABSTRACT FROM AUTHOR]

In this article, the authors respond to the comments of law professors Aaron D. Twerski and Lior Sapir on the relationship between the sufficiency of scientific evidence and the admissibility of expert witness testimony, made in an article within this issue. It discusses the judicial decision of the U.S. Supreme Court's decision in Daubert v. Merrell Dow Pharmaceuticals determining the admissibility of a scientific expert's opinion on causation in a toxic tort case.

The ability to generate lung and airway epithelial cells from human pluripotent stem cells (hPSCs) would have applications in regenerative medicine, modeling of lung disease, drug screening and studies of human lung development. We have established, based on developmental paradigms, a highly efficient method for directed differentiation of hPSCs into lung and airway epithelial cells. Long-term differentiation of hPSCs in vivo and in vitro yielded basal, goblet, Clara, ciliated, type I and type II alveolar epithelial cells. The type II alveolar epithelial cells were capable of surfactant protein-B uptake and stimulated surfactant release, providing evidence of specific function. Inhibiting or removing retinoic acid, Wnt and BMP-agonists to signaling pathways critical for early lung development in the mouse-recapitulated defects in corresponding genetic mouse knockouts. As this protocol generates most cell types of the respiratory system, it may be useful for deriving patient-specific therapeutic cells. [ABSTRACT FROM AUTHOR]

Calcification of the intervertebral disc is a common occurrence in the adult population, but it is rare in children. However, its radiological and clinical fmdings are well described in the pediatric age group, with close to 150 publications on record. In contrast, little information is available regarding the histological features of this entity, which may prove to be challenging to surgical pathologists. Here we provide a detailed description of a young patient with an inflammatory retropharyngeal mass originating in a calcified intervertebral disc. A review of the pathological features described in the literature in English, with pathogenic considerations, is presented. [ABSTRACT FROM AUTHOR]

Background: Malaria morbidity and mortality have been significantly reduced through the proper use of insecticide-treated mosquito nets, but the extra protection afforded by the insecticide diminishes over time. The insecticide depletion rates vary according to location where wash frequency and wear are influenced by cultural habits as well as the availability of water. Monitoring of available insecticides on the net surface is essential for determining the effective life of the net. Therefore, a rapid and inexpensive colorimetric field test for cyanopyrethroids (Cyanopyrethroid Field Test or CFT) was used to measure surface levels of deltamethrin on insecticide-coated polyester nets (PowerNets ™) in rural Lao PDR over a two-year period. Methods: Net surface levels of deltamethrin were measured by wiping the net with filter paper and measuring the adsorbed deltamethrin using the CFT. A relationship between surface levels of deltamethrin and whole net levels was established by comparing results of the CFT with whole levels assayed by high-performance liquid chromatography (HPLC). An effective deltamethrin surface concentration (EC80) was determined by comparing mosquito mortality (WHO Cone Test) with CFT and HPLC results. Five positions (roof to bottom) on each of 23 matched nets were assayed for deltamethrin surface levels at 6, 12, and 24 months. Mosquito mortality assays (WHO Cone Tests) were performed on a subset of eleven 24-month old nets and compared with the proportion of failed nets as predicted by the CFT. Results: At six months, the nets retained about 80% of the baseline (new net) levels of deltamethrin with no significant differences between net positions. At 12 months, ~15-40%, and at 24 months <10% of deltamethrin was retained on the nets, with significant differences appearing between positions. Results from the CFT show that 93% of the nets failed (deltamethrin surface levels 80) at 24 months. This value is in agreement with 91% failure as determined by the WHO Cone Test on a subset of 11 nets. The CFT results show that 50% of the nets from Laos failed at 12 months of normal use. Conclusion: The CFT is a useful and accurate indicator of net efficacy and may be substituted for mosquito bioassays. [ABSTRACT FROM AUTHOR]

We review recent progress in the stem cell biology of the respiratory system, and discuss its scientific and translational ramifications. Several studies have defined novel stem cells in postnatal lung and airways and implicated their roles in tissue homeostasis and repair. In addition, significant advances in the generation of respiratory epithelium from pluripotent stem cells (PSCs) now provide a novel and powerful platform for understanding lung development, modeling pulmonary diseases, and implementing drug screening. Finally, breakthroughs have been made in the generation of decellularized lung matrices that can serve as a scaffold for repopulation with respiratory cells derived from either postnatal or PSCs. These studies are a critical step forward towards the still distant goal of stem cell-based regenerative medicine for diseases of lung and airways. [ABSTRACT FROM AUTHOR]

Malaria is a significant public health problem in more than 100 countries and causes an estimated 200 million new infections every year. Despite the significant effort to eradicate this dangerous disease, lack of complete knowledge of its physiopathology compromises the success in this enterprise. In this paper we review oxidative stress mechanisms involved in the disease and discuss the potential benefits of antioxidant supplementation as an adjuvant antimalarial strategy. [ABSTRACT FROM AUTHOR]

This paper compares restating tort law in the United States with a recent similar effort in Europe. The authors are affiliated with both the American Law Institute, which prepares US Restatements, and the European Group on Tort Law, which has prepared a similar product entitled Principles of European Tort Law. They compare the different institutions that have engaged in restating work, addressing their founding, history, processes, style, content, and the purposes of the documents that have been drafted. Substantive similarities and differences are explained, as well as the cross-fertilisation that occurred as a result of having several individuals who were involved in both projects. Finally, the paper contrasts the difference in the influence of American Restatements and European harmonisation efforts, explaining differences between the two environments that facilitate or impede the role of these documents in contributing to progressive law reform. [ABSTRACT FROM AUTHOR]

The widespread use of primaquine (PQ) and chloroquine (CQ), together, may be responsible for the relatively few, isolated cases of chloroquine-resistant P. vivax (CQRPV) that have been reported from South America. We report here a case of P. vivax from the Amazon Basin of Peru that recurred against normally therapeutic blood levels of CQ. Four out of 540 patients treated with combination CQ and PQ had a symptomatic recurrence of P. vivax parasitemia within 35 days of treatment initiation, possibly indicating CQ failure. Whole blood total CQ level for one of these four subjects was 95 ng/ml on the day of recurrence. Based on published criteria that delineate CQRPV as a P. vivax parasitemia, either recrudescence or relapse, that appears against CQ blood levels >100 ng/mL, we document the occurrence of a P. vivax strain in Peru that had unusually high tolerance to the synergistic combination therapy of CQ + PQ that normally works quite well. [ABSTRACT FROM AUTHOR]

Information about several topics discussed at the symposium titled "Flying Trampolines and Falling Bookcases: Understanding the Third Restatement of Torts" held in the spring of 2010 in the U.S. is presented. It explores the Third Restatement of Torts developed by the American Law Institute (ALI). It highlights the panelist of the symposium which include law professors Michael Green, David Prince and Justice Daryl Hecht.

The article discusses various reports published within the issue including one by Ken Oliphant on issues involving the legal systems in Vienna, Austria, one by Larry Stewart on the controversial aspect of the Third Restatement and another one by Geoffret Rapps on the need to overhaul the treatment of causation in tort restatements.

BACKGROUND: Although the literature reports a low incidence of Burkitt lymphoma (BL) as a post-transplant lymphoproliferative disorder (PTLD), this entity appears to be different from other monomorphic PTLDs (M-PTLDs), both in its aggressive clinical presentation and its distinct pathologic profile. METHODS: Patients with BL, diagnosed in the post-transplant setting, (patients aged ≤18 years) were retrieved from the pathology archives at Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center from 1982 to 2010. Clinical outcomes were obtained along with pathologic review. RESULTS: Twelve patients with pediatric BL in the post-transplant setting (9 boys, 3 girls) were retrieved. The patients displayed a monomorphic population of small to intermediate-sized, noncleaved, lymphoid elements with a 'starry-sky' pattern. The immunophenotype for patients available to the study was CD20+ (n = 9/10), CD10+ (n = 8/8), bcl-6+ (n = 11/11), with a near 100% Ki-67/MIB-1 proliferation index (n = 7/7), and negative for TdT (n = 7/7). Most pretransplant Epstein-Barr virus titers were negative (n = 8/10), with post-transplant titers positive in all tested patients (n = 11), and with positive Epstein-Barr-encoded RNA in situ hybridization in most cases (n = 9/11). The median time from transplantation to diagnosis was 52 months (range, 6-107 months). Nine patients were currently alive after immediate antineoplastic chemotherapy, with median disease-free time of 93 months from diagnosis (range, 2-199 months). CONCLUSIONS: BL-PTLD had a higher Epstein-Barr virus incidence compared with sporadic and immunodeficiency-associated BL and represented a distinct monomorphic PTLD. Although some M-PTLDs can be managed less aggressively with decreased immunosuppression alone, immediate lymphoma-specific chemotherapy was associated with a favorable outcome and was strongly recommended. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Directed differentiation of human embryonic stem (hES) cells and human induced pluripotent stem (hiPS) cells captures in vivo developmental pathways for specifying lineages in vitro, thus avoiding perturbation of the genome with exogenous genetic material. Thus far, derivation of endodermal lineages has focused predominantly on hepatocytes, pancreatic endocrine cells and intestinal cells. The ability to differentiate pluripotent cells into anterior foregut endoderm (AFE) derivatives would expand their utility for cell therapy and basic research to tissues important for immune function, such as the thymus; for metabolism, such as thyroid and parathyroid; and for respiratory function, such as trachea and lung. We find that dual inhibition of transforming growth factor (TGF)-β and bone morphogenic protein (BMP) signaling after specification of definitive endoderm from pluripotent cells results in a highly enriched AFE population that is competent to be patterned along dorsoventral and anteroposterior axes. These findings provide an approach for the generation of AFE derivatives. [ABSTRACT FROM AUTHOR]

Pluripotent stem cells have the capacity to generate all cell lineages, and substantial progress has been made in realizing this potential. One fascinating but as yet unrealized possibility is the differentiation of pluripotent stem cells into thymic epithelial cells. The thymus is a primary lymphoid organ essential for naïve T-cell generation. T cells play an important role in adaptive immunity, and their loss or dysfunction underlies in a wide range of autoimmune and infectious diseases. T cells are generated and selected through interaction with thymic epithelial cells, the functionally essential element of thymus. The ability to generate functional thymic epithelial cells from pluripotent stem cells would have applications in modeling human immune responses in mice, in tissue transplantation, and in modulating autoimmune and infectious disease. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment (TME). However, the relationship between the phenotype and metabolic pattern of TAMs remains poorly understood. We performed single-cell transcriptome profiling on hepatic TAMs from mice bearing liver metastatic tumors. We find that TAMs manifest high heterogeneity at the levels of transcription, development, metabolism, and function. Integrative analyses and validation experiments indicate that increased purine metabolism is a feature of TAMs with pro-tumor and terminal differentiation phenotypes. Like mouse TAMs, human TAMs are highly heterogeneous. Human TAMs with increased purine metabolism exhibit a pro-tumor phenotype and correlate with poor therapeutic efficacy to immune checkpoint blockade. Altogether, our work demonstrates that TAMs are developmentally, metabolically, and functionally heterogeneous and purine metabolism may be a key metabolic feature of a pro-tumor macrophage population. [Display omitted] • Single-cell RNA-seq reveals metabolic heterogeneity of TAMs • TAM metabolic patterns correlate with their functional features • Purine metabolism marks TAMs with pro-tumor and terminal phenotype • Purine metabolism signature correlates with patient outcome and response to ICB Li et al. examine the metabolic heterogeneity of tumor-associated macrophages (TAMs). They demonstrate metabolic patterns of TAMs correlate with their functional characteristics, and increased purine metabolism is a feature of TAMs with pro-tumor and terminal differentiation phenotype. They confirm these observations in patients with multiple types of cancer. [ABSTRACT FROM AUTHOR]

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Paul Newton and colleagues propose guidelines for conducting and reporting field surveys of the quality of medicines. [ABSTRACT FROM AUTHOR]