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Purpose: The World Health Organization's International Agency on Research for Cancer has determined that glyphosate is "probably carcinogenic to humans." There is a great public interest to investigate whether glyphosate are detected in breast milk. Thus, the goal of this study was to assess the concentration of glyphosate and its main metabolite in breast milk. Materials and Methods: Liquid chromatography was performed at 25°C using a Luna NH 2 , 50 × 2 mm, 3⎛ m (Phenomenex) analytical column. Electrospray ionization mass spectrometry was collected using negative ionization mode. The calibration curve for glyphosate ranged from 10 to 250 ng/mL. The detection limit was 1 ng/mL. Results: Breast milk samples were collected from 74 women, which included vegans ( n = 26), vegetarians ( n = 22), and nonvegetarians ( n = 26). One of the 74 milk samples contained a detectable concentration of glyphosate and an additional 7 were found to contain aminomethylphosphonic acid. Conclusions: In breast milk samples collected mainly from women residing in urban regions of the United States, glyphosate detection was rare. Consistently, breastfed infants have a low or minimal risk of being exposed to glyphosate through ingestion of mother's milk. It is possible that the presence/absence and/or level of concentration of milk glyphosate depend on a place of residency and time of breastfeeding vis-à-vis time of its agricultural application.

Humans and Mycobacterium tuberculosis have co-evolved together for thousands of years. Many individuals are infected with the bacterium, but few show signs and symptoms of tuberculosis (TB). Pharmacotherapy to treat those who develop disease is useful, but drug resistance and non-adherence significantly impact the efficacy of these treatments. Prior to the introduction of antibiotic therapies, public health strategies were used to reduce TB mortality. This work shows how these strategies were able to reduce TB mortality in 19th and 20th century populations, compared with antibiotic treatments. Previously published mortality data from historical records for several populations (Switzerland, Germany, England and Wales, Scotland, USA, Japan, Brazil and South Africa) were used. Curvilinear regression was used to examine the reduction in mortality before and after the introduction of antibiotic treatments (1946). A strong decline in TB mortality was already occurring in Switzerland, Germany, England and Wales, Scotland and the USA prior to the introduction of antibiotic treatment. This occurred following many public health interventions including improved sanitation, compulsory reporting of TB cases, diagnostic techniques and sanatoria treatments. Following the introduction of antibiotics, mortality rates declined further, however, this had a smaller effect than the previously employed strategies. In Japan, Brazil and South Africa, reductions in mortality rates were largely driven by antibiotic treatments that caused rapid decline of mortality, with a smaller contribution from public health strategies. For the development of active disease, immune status is important. Individuals infected with the bacterium are more likely to develop signs and symptoms if their immune function is reduced. Effective strategies against TB can therefore include enhancing immune function of the population by improving nutrition, as well as reducing transmission by improving living conditions and public health. This has been effective in the past. Improving immunity may be an important strategy against drug resistant TB., Competing Interests: Declarations of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Improvised explosive devices pose a threat to the public by way of terrorism and criminal activities. In the United States a commonly used low explosive in improvised explosive devices is smokeless powder (SP), due to its ease of access. Traditionally, forensic examinations are often sufficient in determining the physical and chemical characteristics of SPs. However, these exams are limited in differentiating or associating SPs when comparing two materials which are physically and/or chemically consistent. Stable isotope analysis of carbon and nitrogen has been used for explosives to further forensic chemical comparisons and aid in sample differentiation. In this manuscript we explore the utility of stable isotope analysis of SPs to differentiate manufacturer and geographic origin. Both bulk isotope analysis and component isotope analysis of carbon and nitrogen via an extraction method using dichloromethane were evaluated to compare the overall isotope signature of individual SPs. Through the combination of bulk and component isotope measurements of SPs, we were able to identify geographic relationships; however, the manufacturer origins were not as clearly discriminated. This technique demonstrates a potential improvement to traditional forensic examinations of smokeless powder by adding additional information when explosives are chemically and/or physically consistent.

Opioids are not universally effective for treating neuropathic pain following spinal cord injury (SCI), a finding that we previously demonstrated in a rat model of SCI. The aim of this study was to determine analgesic response of morphine-responsive and nonresponsive SCI rats to adjunct treatment with dopamine modulators and to establish if the animal groups expressed distinct metabolomic profiles. Thermal thresholds were tested in female Long Evans rats (N = 45) prior to contusion SCI, after SCI and following injection of morphine, morphine combined with dopamine modulators, or dopamine modulators alone. Spinal cord and striatum samples were processed for metabolomics and targeted mass spectrometry. Morphine provided analgesia in 1 of 3 of SCI animals. All animals showed improved analgesia with morphine + pramipexole (D3 receptor agonist). Only morphine nonresponsive animals showed improved analgesia with the addition of SCH 39166 (D1 receptor antagonist). Metabolomic analysis identified 3 distinct clusters related to the tyrosine pathway that corresponded to uninjured, SCI morphine-responsive and SCI morphine-nonresponsive groups. Mass spectrometry showed matching differences in dopamine levels in striatum and spinal cord between these groups. The data suggest an overall benefit of the D3 receptor system in improving analgesia, and an association between morphine responsiveness and metabolomic changes in the tyrosine/dopamine pathways in striatum and spinal cord. PERSPECTIVE: Spinal cord injury (SCI) leads to opioid-resistant neuropathic pain that is associated with changes in dopamine metabolomics in the spinal cord and striatum of rats. We present evidence that adjuvant targeting of the dopamine system may be a novel pain treatment approach to overcome opioid desensitization and tolerance after SCI., (Copyright © 2021 United States Association for the Study of Pain, Inc. All rights reserved.)

The emergence of targeted and precision therapies has increased treatment options for people living with cancer. Of particular note is the development and approval of chimeric antigen receptor (CAR) T-cell therapies that involve the use of a patient's own immune system to treat cancers that have proven resistant to other approaches. Keeping abreast of treatment changes and practice guidelines is a challenge for all healthcare professionals, and the pressure of doing so becomes most acute with innovations in cancer therapeutics that have the potential to extend or save lives. Though uncommon, step changes like CAR T-cell therapy pose a challenge, often requiring completely new ways of thinking about efficacy evidence, basic science, ethics and service delivery. At a time when patients are able and empowered to readily access information about novel and exploratory treatments, healthcare professionals need to feel informed enough to help patients with life-changing or life-limiting cancers who approach them for advice. This article gives an overview of the basic principles of CAR T-cell therapy including how it is delivered, who is eligible to receive it in the UK, and a brief outline of current evidence of its efficacy and safety. The information is intended to provide healthcare professionals with an introduction to CAR T-cell therapy to help them advise potentially eligible patients or those already undergoing treatment about what to expect., Competing Interests: Competing interests: None declared. Refer to the online supplementary files to view the ICMJE form(s)., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The key to evolution is reproduction. Pathogens can either kill the human host or can invade the host without causing death, thus ensuring their own survival, reproduction and spread. Tuberculosis, treponematoses and leprosy are widespread chronic infectious diseases whereby the host is not immediately killed. These diseases are examples of the co-evolution of host and pathogen. They can be well studied as the paleopathological record is extensive, spanning over 200 human generations. The paleopathology of each disease has been well documented in the form of published synthetic analyses recording each known case and case frequencies in the samples they were derived from. Here the data from these synthetic analyses were re-analysed to show changes in the prevalence of each disease over time. A total of 69,379 skeletons are included in this study. There was ultimately a decline in the prevalence of each disease over time, this decline was statistically significant (Chi-squared, p<0.001). A trend may start with the increase in the disease's prevalence before the prevalence declines, in tuberculosis the decline is monotonic. Increase in skeletal changes resulting from the respective diseases appears in the initial period of host-disease contact, followed by a decline resulting from co-adaptation that is mutually beneficial for the disease (spread and maintenance of pathogen) and host (less pathological reactions to the infection). Eventually either the host may become immune or tolerant, or the pathogen tends to be commensalic rather than parasitic., Competing Interests: The Authors have declared that no competing interests exist.

Background: Metastasis and mortality remain high among breast cancer patients with the claudin-low subtype because these tumors are aggressive, chemoresistant, and lack targeted therapies. Our objective was to utilize discovery-based proteomics to identify proteins associated with claudin-low primary and metastatic tumors to gain insight into pathways and mechanisms of tumor progression., Methods: We used nano-LC-MS/MS proteomics to analyze orthotopic and metastatic tumors from the syngeneic murine T11 tumor model, which displays gene expression profiles mirroring human claudin-low tumors. Galectin-1 identity, expression and spatial distribution were investigated by biochemical and immunochemical methods and MALDI/IMS. RNA seq data from mouse and human tumors in our study and publicly available microarray data were analyzed for differential galectin-1 expression across breast cancer subtypes., Results: Galectin-1, an N-acetyllactosamine-binding protein, exhibited the highest sequence coverage and high abundance rank order among nano-LC-MS/MS-identified proteins shared by T11 claudin-low tumors but not normal tissue. Label-free quantitation, Western immunoblot and ELISA confirmed galectin-1 identity and significant differential expression. MALDI/IMS spatial mapping and immunohistochemistry detected galectin-1 in T11 metastatic lung foci. Immunohistochemistry of human claudin-low tumors demonstrated intermediate-to-high intensity galectin-1 staining of tumor and stroma. Gene expression analysis of mouse and human tumors found the highest galectin-1 levels in the claudin-low breast cancer subtype., Conclusions: Proteomics and genomics reveal high expression of galectin-1 protein and RNA in primary and metastatic claudin-low breast cancer., General Significance: This work endorses proteomic approaches in cancer research and supports further investigations of the function and significance of galectin-1 overexpression in claudin-low tumor progression., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Neonatal abstinence syndrome is an array of signs and symptoms experienced by a newborn due to abrupt discontinuation of intrauterine exposure to certain drugs, primarily opioids. In the United States, the incidence of neonatal abstinence syndrome has tripled over the past decade. The current standard of care for drug testing includes the analysis of infant urine and meconium. Sample collection is associated with several limitations, including diaper media interferences, limited sample amount, sample heterogeneity, and the need for professional staff for collection. Umbilical cord tissue has emerged as a convenient sample matrix for testing owing to its universal availability. The purpose of this study was to examine umbilical cords using an untargeted metabolomics approach to determine the detected drugs and validate an analytical method to confirm and quantify the identified drugs., Methods: A metabolomics analysis was performed with 21 umbilical cords to screen for drugs and drug metabolites by liquid chromatography-mass spectrometry. Drugs were identified using the National Institute of Standards and Technology database, and an analytical method was developed and validated using secondary liquid chromatography-mass spectrometry instrument for positive confirmation and quantitative analysis., Results: Twenty-one random umbilical cords from women were tested: 4 were positive for cocaine and the primary and secondary metabolites; one was positive for methadone, the primary metabolite; 3 were positive for cotinine, the metabolite of nicotine; and 5 were positive for acetyl norfentanyl., Conclusions: Our research is a prospective method development study using untargeted and targeted approaches to characterize steady-state drug metabolite levels in the umbilical cord matrix at the time of delivery. By characterizing drug type and concentration, this methodology can be used to develop a reliable complementary testing method for meconium toxicology screens.

Background: This study investigated if implementation of a 20-min rounding intervention can reduce falls in aged care settings., Methods: Participants (aged 66-99 years) from five aged care facilities were randomly allocated to intervention (n = 20) or control groups (n = 21). The intervention consisted of 20-min rounding observations over a six month period. The number of falls for all residents of each aged care facility was also collected., Results: For participants of the intervention study, there were no differences for number of falls in the intervention compared to the control group (mean(95%CI) control:2.3(0.8-3.7), intervention:4.0(2.5-5.5), p = 0.108). There was a trend for a decreased average number of falls across all aged care sites (mean±SD, 60.4 ± 35.7 falls occurred prior vs. 53.4 ± 37.4 during the intervention, p = 0.056). There were no fall related fractures in the intervention group during the study., Conclusions: This study suggests that 20-min rounding may decrease falls for all residents of aged care sites., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Two new species of Aglaia from Indonesia are described, Aglaia monocaula restricted to West Papua, and Aglaia nyaruensis occurring on Borneo (Kalimantan, Brunei, Sabah and Sarawak). A phylogenetic analysis using nuclear ITS and ETS, and plastid rps15-ycf1 sequence data indicates that the two new species of Aglaia are also genetically distinct. Aglaia monocaula belongs to sectionAmoora, while A. nyaruensis is included in section Aglaia. A dichotomous key, drawings and three-locus DNA barcodes are provided as aids for the identification of the two new species of Aglaia . In addition, the geographic range of Aglaia mackiana (section Amoora) is expanded from a single previously known site in Papua New Guinea to West Papua, Indonesia., (Caroline M. Pannell, Jan Schnitzler, Alexandra N. Muellner-Riehl.)

Osteoporosis and sarcopenia share risk profiles, so we tested a fracture risk assessment tool (FRAX) as a screening tool for sarcopenia. FRAX probabilities without bone mineral density predicted sarcopenia with high sensitivity and reasonable specificity. There is potential to use this FRAX as a screening tool for sarcopenia., Purpose: There is a need for simple screening tools for sarcopenia. As osteoporosis and sarcopenia share risk profiles, we tested the performance of a fracture risk assessment tool for discriminating individuals at risk for sarcopenia., Methods: In this longitudinal study, FRAX (Australia) probabilities were calculated for 354 women (ages 40-90 years) in the Geelong Osteoporosis Study. Sarcopenia was assessed a decade later using DXA-derived low appendicular lean mass (Lunar; ALM/height 2  < 5.5 kg/m 2 ) and low handgrip strength (Jamar; HGS < 16 kg), according to EWGSOP2. We determined FRAX probabilities (%) for hip fracture (HF-FRAX) and major osteoporotic fracture (MOF-FRAX), with and without BMD. Area under the receiver operator characteristic (AUROC) curves quantified the performance of FRAX for predicting sarcopenia., Results: Baseline median (IQR) values for HF-FRAX without BMD were 0.4 (0.1-1.3) and for MOF-FRAX without BMD, 2.4 (1.2-5.2); comparable figures for HF-FRAX with BMD were 0.2 (0.0-0.7) and for MOF-FRAX with BMD, 2.1 (1.1-4.4). At follow-up, sarcopenia was identified for 11 (3.1%) women. When FRAX was calculated without BMD, the AUROC was 0.90 for HF-FRAX and 0.88 for MOF-FRAX. Optimal thresholds were 0.9 for HF-FRAX (sensitivity 90.9%, specificity 62.4%) and 5.3 for MOF-FRAX (sensitivity 81.8%, specificity 71.7%). Calculating FRAX with BMD did not improve the predictive performance of FRAX for sarcopenia., Conclusion: Here we provide preliminary evidence to suggest that FRAX probabilities without BMD might predict sarcopenia with high sensitivity and reasonable specificity. Given that FRAX clinical risk factors are identified without equipment, there is potential to use this or a modified version of the FRAX tool to screen for individuals at risk of sarcopenia.

We established a murine model of multiwall carbon nanotube (MWCNT)-elicited chronic granulomatous disease that bears similarities to human sarcoidosis pathology, including alveolar macrophage deficiency of peroxisome proliferator-activated receptor γ (PPARγ). Because lymphocyte reactivity to mycobacterial antigens has been reported in sarcoidosis, we hypothesized that addition of mycobacterial ESAT-6 (early secreted antigenic target protein 6) to MWCNT might exacerbate pulmonary granulomatous pathology. MWCNTs with or without ESAT-6 peptide 14 were instilled by the oropharyngeal route into macrophage-specific PPARγ-knockout (KO) or wild-type mice. Control animals received PBS or ESAT-6. Lung tissues, BAL cells, and BAL fluid were evaluated 60 days after instillation. PPARγ-KO mice receiving MWCNT + ESAT-6 had increased granulomas and significantly elevated fibrosis (trichrome staining) compared with wild-type mice or PPARγ-KO mice that received only MWCNT. Immunostaining of lung tissues revealed elevated fibronectin and Siglec F expression on CD11c + infiltrating alveolar macrophages in the presence of MWCNT + ESAT-6 compared with MWCNT alone. Analyses of BAL fluid proteins indicated increased levels of transforming growth factor (TGF)-β and the TGF-β pathway mediator IL-13 in PPARγ-KO mice that received MWCNT + ESAT-6 compared with wild-type or PPARγ-KO mice that received MWCNT. Similarly, mRNA levels of matrix metalloproteinase 9, another requisite factor for TGF-β production, was elevated in PPARγ-KO mice by MWCNT + ESAT-6. Analysis of ESAT-6 in lung tissues by mass spectrometry revealed ESAT-6 retention in lung tissues of PPARγ-KO but not wild-type mice. These data indicate that PPARγ deficiency promotes pulmonary ESAT-6 retention, exacerbates macrophage responses to MWCNT + ESAT-6, and intensifies pulmonary fibrosis. The present findings suggest that the model may facilitate understanding of the effects of environmental factors on sarcoidosis-associated pulmonary fibrosis.

Objective: To compare the effectiveness and safety of treatments for advanced or metastatic renal cell carcinoma (amRCC) after treatment with vascular endothelial growth factor (VEGF)-targeted treatment., Design: Systematic review and network meta-analysis of randomised controlled trials (RCTs) and comparative observational studies. MEDLINE, EMBASE and Cochrane Library were searched up to January 2018., Participants: People with amRCC requiring treatment after VEGF-targeted treatment., Interventions: Axitinib, cabozantinib, everolimus, lenvatinib with everolimus, nivolumab, sorafenib and best supportive care (BSC)., Outcomes: Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were objective response rate (ORR), adverse events, and health-related quality of life (HRQoL)., Results: Twelve studies were included (n=5144): five RCTs and seven observational studies. Lenvatinib with everolimus significantly increased OS and PFS over everolimus (HR 0.61, 95% Credible Interval [95%CrI]: 0.36 to 0.96 and 0.47, 95%CrI: 0.26 to 0.77, respectively) as did cabozantinib (HR 0.66, 95%CrI: 0.53 to 0.82 and 0.51, 95%CrI: 0.41 to 0.63, respectively). This remained the case when observational evidence was included. Nivolumab also significantly improved OS versus everolimus (HR 0.74, 95%CrI: 0.57 to 0.93). OS sensitivity analysis, including observational studies, indicates everolimus being more effective than axitinib and sorafenib. However, inconsistency was identified in the OS sensitivity analysis. PFS sensitivity analysis suggests axitinib is more effective than everolimus, which may be more effective than sorafenib. The results for ORR supported the OS and PFS analyses. Nivolumab is associated with fewer grade 3 or grade 4 adverse events than lenvatinib with everolimus or cabozantinib. HRQoL could not be analysed due to differences in tools used., Conclusions: Lenvatinib with everolimus, cabozantinib and nivolumab are effective in prolonging the survival for people with amRCC subsequent to VEGF-targeted treatment, but there is considerable uncertainty about how they compare to each other and how much better they are than axitinib and sorafenib., Prospero Registration Number: CRD42017071540., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

EphrinA1 is a tyrosine kinase receptor localized in the cellular membrane of healthy cardiomyocytes, the expression of which is lost upon myocardial infarction (MI). Intra-cardiac injection of the recombinant form of ephrinA1 (ephrinA1-Fc) at the time of ligation in mice has shown beneficial effects by reducing infarct size and myocardial necrosis post-MI. To date, immunohistochemistry and Western blotting comprise the only experimental approaches utilized to localize and quantify relative changes of ephrinA1 in sections and homogenates of whole left ventricle, respectively. Herein, we used matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) coupled with a time-of-flight mass spectrometer (MALDI/TOF MS) to identify intact as well as tryptic fragments of ephrinA1 in healthy controls and acutely infarcted murine hearts. The purpose of the present study was 3-fold: (1) to spatially resolve the molecular distribution of endogenous ephrinA1, (2) to determine the anatomical expression profile of endogenous ephrinA1 after acute MI, and (3) to identify molecular targets of ephrinA1-Fc action post-MI. The tryptic fragments detected were identified as the ephrinA1-isoform with 38% and 34% sequence coverage and Mascot scores of 25 for the control and MI hearts, respectively. By using MALDI-MSI, we have been able to simultaneously measure the distribution and spatial localization of ephrinA1, as well as additional cardiac proteins, thus offering valuable information for the elucidation of molecular partners, mediators, and targets of ephrinA1 action in cardiac muscle. Graphical Abstract ᅟ.

Background: Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative evidence to guide decisions between them., Objective: To evaluate the clinical effectiveness and cost-effectiveness of axitinib (Inlyta ® , Pfizer Inc., NY, USA), cabozantinib (Cabometyx ® , Ipsen, Slough, UK), everolimus (Afinitor ® , Novartis, Basel, Switzerland), nivolumab (Opdivo ® , Bristol-Myers Squibb, NY, USA), sunitinib (Sutent ® , Pfizer, Inc., NY, USA) and best supportive care (BSC) for people with amRCC who were previously treated with vascular endothelial growth factor (VEGF)-targeted therapy., Data Sources: A systematic review and mixed-treatment comparison (MTC) of randomised controlled trials (RCTs) and non-RCTs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were objective response rates (ORRs), adverse events (AEs) and health-related quality of life (HRQoL). MEDLINE, EMBASE and The Cochrane Library were searched from inception to January and June 2016 for RCTs and non-RCTs, respectively. Two reviewers abstracted data and performed critical appraisals., Review Methods: A fixed-effects MTC was conducted for OS, PFS [hazard ratios (HRs)] and ORR (odds ratios), and all were presented with 95% credible intervals (CrIs). The RCT data formed the primary analyses, with non-RCTs and studies rated as being at a high risk of bias included in sensitivity analyses (SAs). HRQoL and AE data were summarised narratively. A partitioned survival model with health states for pre progression, post progression and death was developed to perform a cost-utility analysis. Survival curves were fitted to the PFS and OS results from the MTC. A systematic review of HRQoL was undertaken to identify sources of health state utility values., Results: Four RCTs ( n  = 2618) and eight non-RCTs ( n  = 1526) were included. The results show that cabozantinib has longer PFS than everolimus (HR 0.51, 95% CrI 0.41 to 0.63) and both treatments are better than BSC. Both cabozantinib (HR 0.66, 95% CrI 0.53 to 0.82) and nivolumab (HR 0.73, 95% CrI 0.60 to 0.89) have longer OS than everolimus. SAs were consistent with the primary analyses. The economic analysis, using drug list prices, shows that everolimus may be more cost-effective than BSC with an incremental cost-effectiveness ratio (ICER) of £45,000 per quality-adjusted life-year (QALY), as it is likely to be considered an end-of-life treatment. Cabozantinib has an ICER of £126,000 per QALY compared with everolimus and is unlikely to be cost-effective. Nivolumab was dominated by cabozantinib (i.e. more costly and less effective) and axitinib was dominated by everolimus., Limitations: Treatment comparisons were limited by the small number of RCTs. However, the key limitation of the analysis is the absence of the drug prices paid by the NHS, which was a limitation that could not be avoided owing to the confidentiality of discounts given to the NHS., Conclusions: The RCT evidence suggests that cabozantinib is likely to be the most effective for PFS and OS, closely followed by nivolumab. All treatments appear to delay disease progression and prolong survival compared with BSC, although the results are heterogeneous. The economic analysis shows that at list price everolimus could be recommended as the other drugs are much more expensive with insufficient incremental benefit. The applicability of these findings to the NHS is somewhat limited because existing confidential patient access schemes could not be used in the analysis. Future work using the discounted prices at which these drugs are provided to the NHS would better inform estimates of their relative cost-effectiveness., Study Registration: This study is registered as PROSPERO CRD42016042384., Funding: The National Institute for Health Research Health Technology Assessment programme.

The lungs are a complex organ that fulfill multiple life-sustaining roles including transfer of oxygen and carbon dioxide between the ambient environment and the bloodstream, host defense, and immune homeostasis. As in any biological system, an understanding of the underlying anatomy is prerequisite for successful experimental design and appropriate interpretation of data, regardless of the precise experimental model or procedure in use. This chapter provides an overview of human lung anatomy focused on the airways, the ultrastructure or parenchyma of the lung, the pulmonary vasculature, the innervation of the lungs, and the pulmonary lymphatic system. We will also discuss notable anatomic differences between mouse and human lungs.

A commercial liquid chromatography/drift tube ion mobility-mass spectrometer (LC/IM-MS) was evaluated for its utility in global metabolomics analysis. Performance was assessed using 12 targeted metabolite standards where the limit of detection (LOD), linear dynamic range, resolving power, and collision cross section (Ω) are reported for each standard. Data were collected in three different instrument operation modes: flow injection analysis with IM-MS (FIA/IM-MS), LC/MS, and LC/IM-MS. Metabolomics analyses of human plasma and HaCaT cells were used to compare the above three operation modes. LC/MS provides linearity in response, data processing automation, improved limits of detection, and ease of use. Advantages of LC/IM-MS and FIA/IM-MS include the ability to develop mobility-mass trend lines for structurally similar biomolecules, increased peak capacity, reduction of chemical/matrix noise, improvement in signal-to-noise, and separations of isobar/isomer compounds that are not resolved by LC. We further tested the feasibility of incorporating IM-MS into conventional LC/MS metabolomics workflows. In general, the addition of ion mobility dimension has increased the separation of compounds in complex biological matrixes and has the potential to largely improve the throughput of metabolomics analysis.

Background: Social anxiety disorder is one of the most persistent and common anxiety disorders. Individually delivered psychological therapies are the most effective treatment options for adults with social anxiety disorder, but they are associated with high intervention costs. Therefore, the objective of this study was to assess the relative cost effectiveness of a variety of psychological and pharmacological interventions for adults with social anxiety disorder., Methods: A decision-analytic model was constructed to compare costs and quality adjusted life years (QALYs) of 28 interventions for social anxiety disorder from the perspective of the British National Health Service and personal social services. Efficacy data were derived from a systematic review and network meta-analysis. Other model input parameters were based on published literature and national sources, supplemented by expert opinion., Results: Individual cognitive therapy was the most cost-effective intervention for adults with social anxiety disorder, followed by generic individual cognitive behavioural therapy (CBT), phenelzine and book-based self-help without support. Other drugs, group-based psychological interventions and other individually delivered psychological interventions were less cost-effective. Results were influenced by limited evidence suggesting superiority of psychological interventions over drugs in retaining long-term effects. The analysis did not take into account side effects of drugs., Conclusion: Various forms of individually delivered CBT appear to be the most cost-effective options for the treatment of adults with social anxiety disorder. Consideration of side effects of drugs would only strengthen this conclusion, as it would improve even further the cost effectiveness of individually delivered CBT relative to phenelzine, which was the next most cost-effective option, due to the serious side effects associated with phenelzine. Further research needs to determine more accurately the long-term comparative benefits and harms of psychological and pharmacological interventions for social anxiety disorder and establish their relative cost effectiveness with greater certainty.

Background: Social anxiety disorder-a chronic and naturally unremitting disease that causes substantial impairment-can be treated with pharmacological, psychological, and self-help interventions. We aimed to compare these interventions and to identify which are most effective for the acute treatment of social anxiety disorder in adults., Methods: We did a systematic review and network meta-analysis of interventions for adults with social anxiety disorder, identified from published and unpublished sources between 1988 and Sept 13, 2013. We analysed interventions by class and individually. Outcomes were validated measures of social anxiety, reported as standardised mean differences (SMDs) compared with a waitlist reference. This study is registered with PROSPERO, number CRD42012003146., Findings: We included 101 trials (13 164 participants) of 41 interventions or control conditions (17 classes) in the analyses. Classes of pharmacological interventions that had greater effects on outcomes compared with waitlist were monoamine oxidase inhibitors (SMD -1·01, 95% credible interval [CrI] -1·56 to -0·45), benzodiazepines (-0·96, -1·56 to -0·36), selective serotonin-reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs; -0·91, -1·23 to -0·60), and anticonvulsants (-0·81, -1·36 to -0·28). Compared with waitlist, efficacious classes of psychological interventions were individual cognitive-behavioural therapy (CBT; SMD -1·19, 95% CrI -1·56 to -0·81), group CBT (-0·92, -1·33 to -0·51), exposure and social skills (-0·86, -1·42 to -0·29), self-help with support (-0·86, -1·36 to -0·36), self-help without support (-0·75, -1·25 to -0·26), and psychodynamic psychotherapy (-0·62, -0·93 to -0·31). Individual CBT compared with psychological placebo (SMD -0·56, 95% CrI -1·00 to -0·11), and SSRIs and SNRIs compared with pill placebo (-0·44, -0·67 to -0·22) were the only classes of interventions that had greater effects on outcomes than appropriate placebo. Individual CBT also had a greater effect than psychodynamic psychotherapy (SMD -0·56, 95% CrI -1·03 to -0·11) and interpersonal psychotherapy, mindfulness, and supportive therapy (-0·82, -1·41 to -0·24)., Interpretation: Individual CBT (which other studies have shown to have a lower risk of side-effects than pharmacotherapy) is associated with large effect sizes. Thus, it should be regarded as the best intervention for the initial treatment of social anxiety disorder. For individuals who decline psychological intervention, SSRIs show the most consistent evidence of benefit., Funding: National Institute for Health and Care Excellence., (Copyright © 2014 Mayo-Wilson et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Sepsis results in a profound state of immunosuppression, which is temporally associated with impaired leukocyte function. The mechanism of leukocyte reprogramming in sepsis is incompletely understood. In this study, we explored mechanisms contributing to dysregulated inflammatory cytokine expression by pulmonary macrophages during experimental sepsis. Pulmonary macrophages (PM) recovered from the lungs of mice undergoing cecal ligation and puncture (CLP) display transiently reduced expression of some, but not all innate genes in response to LPS. Impaired expression of TNF-alpha and iNOS was associated with reduced acetylation and methylation of specific histones (AcH4 and H3K4me3) and reduced binding of RNA polymerase II to the promoters of these genes. Transient impairment in LPS-induced cytokine responses in septic PM temporally correlated with induction of IRAK-M mRNA and protein, which occurred in a MyD88-dependent fashion. PM isolated from IRAK-M(-/-) mice were largely refractory to CLP-induced impairment in cytokine expression, chromatin remodeling, recruitment of RNA polymerase II, and induction of histone deacetylase-2 observed during sepsis. Our findings indicate that systemic sepsis induces epigenetic silencing of cytokine gene expression in lung macrophages, and IRAK-M appears to be a critical mediator of this response.

In many settings, public reporting of health care outcomes still reflects the "name-shame-blame" culture that has permeated large areas of the health care sector for decades. A new approach to public reporting in Queensland, based on statistical process control, emphasises the dynamic nature of performance against specified outcome measures by focusing on the actions that hospitals are taking if their indicators vary from the average. The aim is for public reporting to contribute to, rather than detract from, the creation of an internal culture that emphasises rigorous investigation and improvement rather than merely assigning blame for problems.

Experiments were performed to determine the contribution of TLR9 to the generation of protective immunity against the intracellular respiratory bacterial pathogen Legionella pneumophila. In initial studies, we found that the intratracheal (i.t.) administration of L. pneumophila to mice deficient in TLR9 (TLR9(-/-)) resulted in significantly increased mortality, which was associated with an approximately 10-fold increase in the number of lung CFU compared to that of wild-type BALB/c mice. Intrapulmonary bacterial challenge in TLR9(-/-) mice resulted in the reduced accumulation of myeloid dendritic cells (DC) and activated CD4(+) T cells. Lung macrophages isolated from Legionella-infected TLR9(-/-) mice displayed the impaired internalization of bacteria and evidence of alternative rather than classical activation, as manifested by the markedly reduced expression of nitric oxide and type 1 cytokines, whereas the expression of Fizz-1 and arginase-1 was enhanced. The adoptive transfer of bone marrow-derived DC from syngeneic wild-type, but not TLR9(-/-), mice administered i.t. reconstituted anti-legionella immunity and restored the macrophage phenotype in TLR9(-/-) mice. Finally, the i.t., but not intraperitoneal, administration of the TLR9 agonist molecule CpG oligodeoxynucleotide stimulated protective immunity in Legionella-infected mice. In total, our findings indicate that TLR9 is required for effective innate immune responses against the intracellular bacterial pathogen L. pneumophila, and approaches to maximize TLR9-mediated responses may serve as a means to augment antibacterial immunity in pneumonia.

Profound hypothermia is associated with high mortality and morbidity. Optimal outcomes have been reported with invasive extracorporeal warming techniques not readily available in most hospitals. Endovascular warming devices may provide a less invasive alternative. A 68-year-old woman developed profound hypothermia after environmental exposure. On arrival, she was comatose, severely bradycardic, without palpable pulses, and with a core body temperature of 23.0 degrees C (72 degrees F). Attempts to warm her with traditional methods during 2 hours were ineffective. An endovascular temperature control system was placed and effectively warmed the patient at about 3 degrees C (4.5 degrees F) per hour, with return of hemodynamic stability. When hypothermia is profound, surface warming works poorly and invasive strategies, including cardiopulmonary bypass, are recommended. Rapid warming from profound hypothermia can be accomplished with endovascular systems, and these may be an effective alternative to more invasive extracorporeal methods.

The often fatal sepsis syndrome is characterized by the systemic release of inflammatory mediators, which is regulated and counterbalanced by the coordinated expression of anti-inflammatory molecules. The magnitude of sepsis-induced tissue injury and subsequent risk of infectious complications is dictated by the balance between the expression of pro- and anti-inflammatory mediators. As our understanding of the pathophysiology of sepsis continues to evolve, we have gained a greater appreciation for the profound effects that sepsis and similar states of overwhelming stress have on host innate and adaptive immunity. Impaired leukocyte function in sepsis has important clinical consequences, as high mortality rates have been observed in patients who display evidence of sepsis-induced immune dysregulation. Functional defects in leukocytes isolated from patients with sepsis include diminished expression of important cell surface molecules, dysregulated cytokine production, alterations in antigen-presenting ability, and accelerated apoptosis. In this article, we review the current literature supporting the notion that dysregulation of host immunity occurs during sepsis syndrome, and describe novel therapeutic interventions directed at augmenting host immunity during sepsis.

Synopsis A new quaternary ammonium compound, hydrolysed ginseng-saponin quaternary (HGSQ), from Korean ginseng saponin and 2,3-epoxypropyltrimethyl ammonium chloride, has been developed as a conditioning agent for hair care products. This structure has a hydrophobic group from the aglycone of ginseng saponin which is biologically active and considered as the most important component of Korean ginseng. Its properties of surface tension, conductivity, critical micelle concentration (CMC), eye irritation, sorption onto hair, tensile strength for 20% extension and moisture retention effect were studied. Its cationic character allows the molecule to be more substantive than ginseng saponin. HGSQ had good physical properties and was safe enough as a cosmetic raw material. Also half-head tests of HGSQ-containing shampoo were carried out to evaluate the conditioning effects in shampoos. HGSQ showed good conditioning properties in a shampoo.