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Decay of litter of salt marsh grasses occurs in three phases. First there is an early phase lasting less than a month, with fast rates of weight loss, during which 5 to 40% of the litter is lost, probably by leaching of soluble compounds. A second slower phase lasts up to a year. In this second phase, microbial degradation of organic matter and subsequent leaching of hydrolyzed substances remove an additional 40 to 70% of the original material. A third phase may last an additional year; in this phase decay is very slow because only relatively refractory materials remain. By this third stage as little as 10% of the original material may remain. Differences in the chemical makeup of litter are the major factors affecting the amount of decay during the leaching and decomposer phases. Such chemical differences may be due to differences in the chemistry of the plant species producing the litter or in nutrient supply. Spartina patens (Ait.) Muhl., for example, produces litter that decays more slowly than that of S. alterniflora Loisel. Increases in internal nitrogen content of litter increase loss of weight during the leaching and decomposer phases, while the external supply of nitrogen increases decay rates only during the decomposer phase. Temperature increases decay rates to some extent during the decomposer phase. The feeding activity of large detritus-feeding invertebrates produces a small but significant increase in decay rate during the decomposer phase. Decay rate in litterbags mimics decay of litter in the field, and makes possible estimates of litter turnover. The turnover of litter of S. alterniflora was 1.1-1.4 · yr-1. Litter of S. patens turns over more slowly, 2.1 · yr-1. Nutrient enrichment accelerates turnover of litter up to 24% compared to control litter. Since eutrophication of salt marshes both enriches litter and changes species of plants, it has broad consequences for ecological processes dependent on decomposition of organic matter. © 1985.

Objective: To investigate whether the breast lesion excision system (BLES) could render formal surgery unnecessary in patients with small indeterminate breast lesions.Methods: Following review board ethical permission and the consent of each patient, we aimed to perform a complete excision biopsy, with a margin, of small indeterminate breast lesions that measure less than 1 cm. 76 patients with small BIRADS type 3 breast lesions underwent a BLES biopsy. Mean radiological lesion size was 7.1 mm (range 2-10 mm).Results: 61 lesions had a final benign diagnosis, 6 of which underwent subsequent surgery although only 1 showing residual lesion. 15 lesions were malignant but with residual tumour at re-excision present in only 5 cases.Conclusion: The BLES biopsy is an efficacious technique at excising small indeterminate breast lesions with a complete margin without the need for follow-up diagnostic surgery in the majority. [ABSTRACT FROM AUTHOR]

The magnetic resonance imaging (MRI) appearances of recurrent prostate cancer following radical prostatectomy have been documented in the radiology literature; however little has been written on the range of normal post-operative appearances. Common routes of surgical access for radical prostatectomy include retropubic and transperineal, although newer minimally invasive methods are gaining increasing acceptance. Specifically the range of appearances of the anastomotic site, the prostatic bed, the position of the bladder base, periurethral tissue, levator sling, rectum and residual seminal vesicles (if present) are demonstrated. A non-enhancing low signal nodule is frequently seen at the vesicourethral anastomosis or within the seminal vesicle remnant and usually represents fibrosis. Appearances following different surgical accesses do not differ tremendously, although the retropubic fat pad is reduced or absent following a retropubic approach. Anterior rectal-wall scarring may be present following a transperineal approach. Other post-surgical findings that may mimic disease include a lymphocoele and injected bladder-neck bulking agent. Many patients referred for MRI following radical prostatectomy will have a pathological study showing disease recurrence, although in non-pathological studies the radiological features can differ significantly. It is important for the radiologist to be aware of the spectrum of normal post-surgical appearances so not to confuse these with locally recurrent disease. [ABSTRACT FROM AUTHOR]

To compare the diagnostic accuracy of MnDPDP MR imaging and diffusion-weighted imaging (DWI), alone and in combination, for detecting colorectal liver metastases in patients with suspected metastatic disease. Thirty-three consecutive patients with suspected colorectal liver metastases underwent MR imaging. Three image sets (MnDPDP, DWI and combined MnDPDP and DWI) were reviewed independently by two observers. Lesions were scored on a five-point scale for malignancy and the areas (Az) under the receiver operating characteristic curves were calculated for each observer and image set. The sensitivity and specificity for lesion detection were calculated for each image set and compared. There were 83 metastases, 49 cysts and 1 haemangioma. Using the combined set resulted in the highest diagnostic accuracy for both observers (Az=0.94 and 0.96), with improved averaged sensitivity of lesion detection compared with the DWI set (p=0.01), and a trend towards improved sensitivity compared with the MnDPDP set (p=0.06). There was no difference in the averaged specificity using any of the three image sets (p>0.5). Combination of MnDPDP MR imaging and DWI resulted in the highest diagnostic accuracy and can increase sensitivity without loss in specificity. [ABSTRACT FROM AUTHOR]

Background: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]., Patients and Methods: c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961)., Results: Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance., Conclusions: c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Invasive lobular breast carcinomas (ILC) account for approximately 15% of breast cancer diagnoses. They can be difficult to diagnose both clinically and radiologically, due to their infiltrative growth pattern. The pattern of metastasis of ILC is unusual, with spread to the serosal surfaces (pleura and peritoneum), retroperitoneum and gastrointestinal (GI)/genitourinary (GU) tracts and a higher rate of leptomeningeal spread than IDC. Routine staging and response assessment with computed tomography (CT) can be undertaken quickly and measurements can be reproduced easily, but this is challenging with metastatic ILC as bone-only/bone-predominant patterns are frequently seen and assessment of the disease status is limited in these scenarios. Functional imaging such as whole-body MRI (WBMRI) allows the assessment of bone and soft tissue disease by providing functional information related to differences in cellular density between malignant and benign tissues. A number of recent studies have shown that WBMRI can detect additional sites of disease in metastatic breast cancer (MBC), resulting in a change in systemic anti-cancer therapy. Although WBMRI and fluorodeoxyglucose-positron-emission tomography-computed tomography (FDG-PET/CT) have a comparable performance in the assessment of MBC, WBMRI can be particularly valuable as a proportion of ILC are non-FDG-avid, resulting in the underestimation of the disease extent. In this review, we explore the added value of WBMRI in the evaluation of metastatic ILC and compare it with other imaging modalities such as CT and FDG-PET/CT. We also discuss the spectrum of WBMRI findings of the different metastatic sites of ILC with CT and FDG-PET/CT correlation. KEY POINTS: • ILC has an unusual pattern of spread compared to IDC, with metastases to the peritoneum, retroperitoneum and GI and GU tracts, but the bones and liver are the commonest sites. • WBMRI allows functional assessment of metastatic disease, particularly in bone-only and bone-predominant metastatic cancers such as ILC where evaluation with CT can be challenging and limited. • WBMRI can detect more sites of disease compared with CT, can reveal disease progression earlier and provides the opportunity to change ineffective systemic treatment sooner., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Behavioral health (BH) problems are common in the military and can adversely affect force readiness. Research suggests that primary care-behavioral health (PCBH) integration can improve BH outcomes by making high-quality BH care available in more accessible settings. However, sustaining high-quality implementation of PCBH is challenging. The authors conducted a process evaluation of the PCBH program in the military health system to understand why the program is working as it is and provide recommendations for quality improvement. They conducted semistructured interviews, rigorously coded the qualitative data to identify causal links, and created and validated causal loop diagrams that provide a visualization of how the system is working. Findings fall into four key areas: staffing and capabilities, valued tasks, program stewardship, and fostering program awareness and support. Overall, the authors found that the PCBH program is highly valued by primary care staff. However, the PCBH care model is inconsistently adhered to, owing to a combination of staff preferences, local pressures, and lack of knowledge of PCBH staff roles. Recommendations are offered to improve program implementation., (Copyright © 2022 RAND Corporation.)

Standard oral rapamycin (that is, Rapamune) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mammalian target of rapamycin (mTOR) inhibitor has a narrow therapeutic window and numerous side effects and provides inadequate protection to transplanted cells and tissues. Furthermore, the hydrophobicity of rapamycin limits its use in parenteral formulations. Here, we demonstrate that subcutaneous delivery via poly(ethylene glycol)-b-poly(propylene sulfide) polymersome nanocarriers significantly alters rapamycin's cellular biodistribution to repurpose its mechanism of action for tolerance, instead of immunosuppression, and minimize side effects. While oral rapamycin inhibits T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes modulate antigen presenting cells in lieu of T cells, significantly improving maintenance of normoglycemia in a clinically relevant, major histocompatibility complex-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug by controlling cellular biodistribution., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Upon exposure to blood, a corona of proteins adsorbs to nanocarrier surfaces to confer a biological identity that interfaces with the immune system. While the nanocarrier surface chemistry has long been the focus of protein corona formation, the influence of nanostructure has remained unclear despite established influences on biodistribution, clearance, and inflammation. Here, combinations of nanocarrier morphology and surface chemistry are engineered to i) achieve compositionally distinct protein coatings in human blood and ii) control protein-mediated interactions with the immune system. A library of nine PEGylated nanocarriers differing in their combination of morphology (spheres, vesicles, and cylinders) and surface chemistry (methoxy, hydroxyl, and phosphate) are synthesized to represent properties of therapeutic and biomimetic delivery vehicles. Analysis by quantitative label-free proteomic techniques reveal that specific surface chemistry and morphology combinations adsorb unique protein signatures from human blood, resulting in differential complement activation and elicitation of distinct proinflammatory cytokine responses. Furthermore, nanocarrier morphology is shown to primarily influence uptake and clearance by human monocytes, macrophages, and dendritic cells. This comprehensive analysis provides mechanistic insights into rational design choices that impact the immunological identity of nanocarriers in human blood, which can be leveraged to engineer drug delivery vehicles for precision medicine and immunotherapy., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Checkpoint blocking antibodies that interfere in the PD-1/PD-L1 axis provide effective cancer immunotherapy for tumors that are immune inflamed or induced to become "hot". It has also been demonstrated that a small molecule inhibitor of the signaling hub kinase GSK3 can interfere in the PD-1/PD-L1 axis in T-cells by suppressing PD-1 expression. This provides an alternative approach to intervening in the PD-1/PD-L1 axis to provide cancer immunotherapy. In this communication, we demonstrate the remote loading of GSK3 inhibitor AZD1080 into the porous interior of mesoporous silica nanoparticles coated with a lipid bilayer (a.k.a. silicasomes). In a MC38 colon cancer model, intravenous injection (IV) of silicasome-encapsulated AZD1080 significantly improved biodistribution and drug delivery to the tumor site. The improved drug delivery was accompanied by cytotoxic MC38 tumor cell killing by perforin-releasing CD8 + T-cells, exhibiting reduced PD-1 expression. IV injection of encapsulated AZD1080 also resulted in significant tumor shrinkage in other syngeneic mouse tumor models, including another colorectal tumor (CT26), as well as pancreas (KPC) and lung (LLC) cancer models. Not only was the therapeutic efficacy of encapsulated AZD1080 similar or better than anti-PD-1 antibody, but the treatment was devoid of treatment toxicity. These results provide proof-of-principal demonstration of the feasibility of using encapsulated delivery of a GSK3 inhibitor to provide cancer immunotherapy, with the possibility to be used as a monotherapy or in combination with chemotherapy or other immunomodulatory agents., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The targeting of natural tolerogenic liver sinusoidal endothelial cells (LSEC) by nanoparticles (NPs), decorated with a stabilin receptor ligand, is capable of generating regulatory T-cells (Tregs), which can suppress antigen-specific immune responses, including to ovalbumin (OVA), a possible food allergen. In this regard, we have previously demonstrated that OVA-encapsulating poly(lactic- co -glycolic acid) (PLGA) nanoparticles eliminate allergic airway inflammation in OVA-sensitized mice, prophylactically and therapeutically. A competing approach is a nanocarrier platform that incorporates pharmaceutical agents interfering in mTOR (rapamycin) or NF-κB (curcumin) pathways, with the ability to induce a tolerogenic state in nontargeted antigen-presenting cells system-wide. First, we compared OVA-encapsulating, LSEC-targeting tolerogenic nanoparticles (TNPs) with nontargeted NPs incorporating curcumin and rapamycin (Rapa) in a murine eosinophilic airway inflammation model, which is Treg-sensitive. This demonstrated roughly similar tolerogenic effects on allergic airway inflammation by stabilin-targeting NP OVA versus nontargeted NPs delivering OVA plus Rapa. Reduction in eosinophilic inflammation and TH2-mediated immune responses in the lung was accompanied by increased Foxp3 + Treg recruitment and TGF-β production in both platforms. As OVA incorporates IgE-binding as well as non-IgE-binding epitopes, the next experiment explored the possibility of obtaining immune tolerance by non-anaphylactic T-cell epitopes. This was accomplished by incorporating OVA 323-339 and OVA 257-264 epitopes in liver-targeting NPs to assess the prophylactic and therapeutic impact on allergic inflammation in transgenic OT-II mice. Importantly, we demonstrated that the major histocompatibility complex (MHC)-II binding (former) but not the MHC-I binding (latter) epitope interfered in allergic airway inflammation, improving TNP OVA efficacy. The epitope-specific effect was transduced by TGF-β-producing Tregs. In the final phase of experimentation, we used an OVA-induced anaphylaxis model to demonstrate that targeted delivery of OVA and its MHC-II epitope could significantly suppress the anaphylaxis symptom score, mast cell release, and the late-phase inflammatory response. In summary, these results demonstrate comparable efficacy of LSEC-targeting versus pharmaceutical PLGA nanoparticles, as well as the ability of T-cell epitopes to achieve response outcomes similar to those of the intact allergens.

Micro- and nano-plastics have widely been recognized as major global environmental problem due to its widespread use and inadequate waste management. The emergence of these plastic pollutants in agroecosystem is a legitimate ecotoxicological concerns for food web exchanges. In agriculture, micro/nano plastics are originated from a variety of different agricultural management practices, such as the use of compost, sewage sludge and mulching. A range of soil properties and plant traits are affected by their presence. With the increase of plastic debris, these pollutant materials have now begun to demonstrate serious implications for key soil ecosystem functions, such as soil microbial activity and nutrient cycling. Nitrogen (N) cycle is key predictor of ecological stability and management in terrestrial ecosystem. In this review, we evaluate ecological risks associated with micro-nano plastic for soil-plant system. We also discuss the consequence of plastic pollutants, either positive or negative, on soil microbial activities. In addition, we systematically summarize both direct and hypothesized implications for N cycling in agroecosystem. We conclude that soil N transformation had showed varied effects resulting from different types and sizes of plastic polymers present in soil. While mixed effects of microplastic pollution on plant growth and yield have been observed, biodegradable plastics have appeared to pose greater risk for plant growth compared to chemical plastic polymers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Bicontinuous nanospheres (BCNs) are underutilized self-assembled nanostructures capable of simultaneous delivery of both hydrophilic and hydrophobic payloads. Here, we demonstrate that BCNs assembled from poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS), an oxidation-sensitive copolymer, are stably retained within cell lysosomes following endocytosis, resisting degradation and payload release for days until externally triggered. The oxygen scavenging properties and enhanced stability of the bicontinuous PEG-b-PPS nanoarchitecture significantly protected cells from typically cytotoxic application of pro-apoptotic photo-oxidizer pheophorbide A and chemotherapeutic camptothecin. The photo-oxidation triggered transition from a bicontinuous to micellar morphology overcame this stability, allowing on-demand cytosolic delivery of camptothecin for enhanced control over off-on cytotoxicity. These results indicate that inducible transitions in the nanostructure morphology can influence intracellular stability and toxicity of self-assembled nanotherapeutics.

The principle cause of cardiovascular disease (CVD) is atherosclerosis, a chronic inflammatory condition characterized by immunologically complex fatty lesions within the intima of arterial vessel walls. Dendritic cells (DCs) are key regulators of atherosclerotic inflammation, with mature DCs generating pro-inflammatory signals within vascular lesions and tolerogenic DCs eliciting atheroprotective cytokine profiles and regulatory T cell (Treg) activation. Here, we engineered the surface chemistry and morphology of synthetic nanocarriers composed of poly(ethylene glycol)-b-poly(propylene sulfide) copolymers to selectively target and modulate DCs by transporting the anti-inflammatory agent 1, 25-Dihydroxyvitamin D3 (aVD) and ApoB-100 derived antigenic peptide P210. Polymersomes decorated with an optimized surface display and density for a lipid construct of the P-D2 peptide, which binds CD11c on the DC surface, significantly enhanced the cytosolic delivery and resulting immunomodulatory capacity of aVD in vitro . Intravenous administration of the optimized polymersomes achieved selective targeting of DCs in atheroma and spleen compared to all other cell populations, including both immune and CD45 - cells, and locally increased the presence of tolerogenic DCs and cytokines. aVD-loaded polymersomes significantly inhibited atherosclerotic lesion development in high fat diet-fed ApoE -/- mice following 8 weeks of administration. Incorporation of the P210 peptide generated the largest reductions in vascular lesion area (~33%, p<0.001 ), macrophage content (~55%, p<0.001 ), and vascular stiffness (4.8-fold). These results correlated with an ~6.5-fold increase in levels of Foxp3 + regulatory T cells within atherosclerotic lesions. Our results validate the key role of DC immunomodulation during aVD-dependent inhibition of atherosclerosis and demonstrate the therapeutic enhancement and dosage lowering capability of cell-targeted nanotherapy in the treatment of CVD.

B-cell lymphoma cells depend upon cholesterol to maintain pro-proliferation and pro-survival signaling via the B-cell receptor. Targeted cholesterol depletion of lymphoma cells is an attractive therapeutic strategy. We report here high-density lipoprotein mimicking magnetic nanostructures (HDL-MNSs) that can bind to the high-affinity HDL receptor, scavenger receptor type B1 (SR-B1), and interfere with cholesterol flux mechanisms in SR-B1 receptor positive lymphoma cells, causing cellular cholesterol depletion. In addition, the MNS core can be utilized for its ability to generate heat under an external radio frequency field. The thermal activation of MNS can lead to both innate and adaptive antitumor immune responses by inducing the expression of heat shock proteins that lead to activation of antigen presenting cells and finally lymphocyte trafficking. In the present study, we demonstrate SR-B1 receptor mediated binding and cellular uptake of HDL-MNS and prevention of phagolysosome formation by transmission electron microscopy, fluorescence microscopy, and ICP-MS analysis. The combinational therapeutics of cholesterol depletion and thermal activation significantly improves therapeutic efficacy in SR-B1 expressing lymphoma cells. HDL-MNS reduces the T 2 relaxation time under magnetic resonance imaging (MRI) more effectively compared with a commercially available contrast agent, and the specificity of HDL-MNS toward the SR-B1 receptor leads to differential contrast between SR-B1 positive and negative cells suggesting its utility in diagnostic imaging. Overall, we have demonstrated that HDL-MNSs have cell specific targeting efficiency, can modulate cholesterol efflux, can induce thermal activation mediated antitumor immune response, and possess high contrast under MRI, making it a promising theranostic platform in lymphoma.

Self-assembled soft nanocarriers that are capable of simultaneous encapsulation of both lipophilic and water soluble payloads have significantly enhanced controlled delivery applications in biomedicine. These nanoarchitectures, such as liposomes, polymersomes and cubosomes, are primarily composed of either amphiphilic polymers or lipids, with the polymeric variants generally possessing greater stability and control over biodistribution and bioresponsive release. Polymersomes have long demonstrated such advantages over their lipid analogs, liposomes, but only recently have bicontinuous nanospheres emerged as a polymeric cubic phase alternative to lipid cubosomes. In this review, we summarize the current state of the field for bicontinuous nanosphere formulation and characterization and suggest future directions for this nascent delivery platform as it is adopted for biomedical applications.

In this work, the hydrophobic small molecule NF-κB inhibitor celastrol was loaded into poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) micelles. PEG-b-PPS micelles demonstrated high loading efficiency, low polydispersity, and no morphological changes upon loading with celastrol. Encapsulation of celastrol within these nanocarriers significantly reduced cytotoxicity compared to free celastrol, while simultaneously expanding the lower concentration range for effective inhibition of NF-κB signaling by nearly 50 000-fold. Furthermore, celastrol-loaded micelles successfully reduced TNF-α secretion after LPS stimulation of RAW 264.7 cells and reduced the number of neutrophils and inflammatory monocytes within atherosclerotic plaques of ldlr-/- mice. This reduction in inflammatory cells was matched by a reduction in plaque area, suggesting that celastrol-loaded nanocarriers may serve as an anti-inflammatory treatment for atherosclerosis.

Bicontinuous nanospheres (BCNs) are polymeric analogs to lipid cubosomes, possessing cubic liquid crystalline phases with high internal surface area, aqueous channels for loading hydrophilic molecules, and high hydrophobic volume for lipophilic payloads. Primarily due to difficulties in scalable and consistent fabrication, neither controlled delivery of payloads via BCNs nor their organ or cellular biodistributions following in vivo administration have been demonstrated or characterized. We have recently validated flash nanoprecipitation as a rapid method of assembling uniform monodisperse 200-300 nm diameter BCNs from poly(ethylene glycol) -b-poly(propylene sulfide) (PEG -b-PPS) co-polymers. Here, we compare these BCNs both in vitro and in vivo to 100 nm PEG -b-PPS polymersomes (PSs), which have been well characterized as nanocarriers for controlled delivery applications. Using a small molecule fluorophore and a fluorescently tagged protein as respective lipophilic and water-soluble model cargos, we demonstrate that BCNs can achieve significantly higher encapsulation efficiencies for both payloads on a per unit mass basis. At time points of 4 and 24 h after intravenous administration to mice, we found significant differences in organ-level uptake between BCNs and PSs, with BCNs showing reduced accumulation in the liver and increased uptake in the spleen. Despite these organ-level differences, BCNs and PSs displayed strikingly similar uptake profiles by immune cell populations in vitro and in the liver, spleen, and blood, as assayed by flow cytometry. In conclusion, we have found PEG -b-PPS BCNs to be well suited for dual loading and delivery of molecular payloads, with a favorable organ biodistribution and high cell uptake by therapeutically relevant immune cell populations.

Polymeric bicontinuous nanospheres (BCNs) that are analogous to lipid cubosomes possess high internal surface area and porosity that can accommodate the loading of a wide range of hydrophobic and hydrophilic molecules for diverse applications. Self-assembly of BCNs has been reported using complex amphiphilic polymeric structures, with co-solvent dispersion being the only documented method of formation. Here, we report a simple amphiphilic diblock copolymer, poly(ethylene glycol) 17 -block-poly(propylene sulfide) 75 (PEG 17 -bl-PPS 75 ), to form BCNs using the rapid and scalable technique of flash nanoprecipitation (FNP). Dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryoTEM) verified low polydispersity and the formation of bicontinuous structures with internal aqueous channels, respectively. Small-angle X-ray scattering (SAXS) confirmed a primitive cubic (Im3m) internal organization for BCNs assembled by FNP. Both hydrophobic and hydrophilic molecules were effectively loaded into BCNs via FNP, and encapsulated payloads were found to release in controlled manner in aqueous solutions. Due to the oxidation-sensitivity of PPS, biologically relevant concentrations of reactive oxygen species could trigger payload release on demand. BCNs were found to be non-toxic and endocytosed by phagocytic cells. Furthermore, an in vitro functional assay showed BCNs co-loaded with antigen ovalbumin and adjuvant monophosphoryl lipid A (MPL) to promote peptide/MHCI surface presentation by dendritic cells, a critical step for vaccine formulations during immunization. In conclusion, FNP supports the facile and scalable assembly and loading of PEG-bl-PPS BCNs, making them an attractive nanoscale delivery vehicle for both hydrophilic and hydrophobic molecules.

Background: An increased risk of breast cancer following radiotherapy for Hodgkin lymphoma (HL) has now been robustly established. In order to estimate the dose-response relationship more accurately, and to aid clinical decision making, a retrospective estimation of the radiation dose delivered to the site of the subsequent breast cancer is required., Methods: For 174 Dutch and 170 UK female patients with breast cancer following HL treatment, the 3-dimensional position of the breast cancer in the affected breast was determined and transferred onto a CT-based anthropomorphic phantom. Using a radiotherapy treatment planning system the dose distribution on the CT-based phantom was calculated for the 46 different radiation treatment field set-ups used in the study population. The estimated dose at the centre of the breast cancer, and a margin to reflect dose uncertainty were determined on the basis of the location of the tumour and the isodose lines from the treatment planning. We assessed inter-observer variation and for 47 patients we compared the results with a previously applied dosimetry method., Results: The estimated median point dose at the centre of the breast cancer location was 29.75 Gy (IQR 5.8-37.2), or about 75% of the prescribed radiotherapy dose. The median dose uncertainty range was 5.97 Gy. We observed an excellent inter-observer variation (ICC 0.89 (95% CI: 0.74-0.95)). The absolute agreement intra-class correlation coefficient (ICC) for inter-method variation was 0.59 (95% CI: 0.37-0.75), indicating (nearly) good agreement. There were no systematic differences in the dose estimates between observers or methods., Conclusion: Estimates of the dose at the point of a subsequent breast cancer show good correlation between methods, but the retrospective nature of the estimates means that there is always some uncertainty to be accounted for.

Atherosclerosis, a leading cause of heart disease, results from chronic vascular inflammation that is driven by diverse immune cell populations. Nanomaterials may function as powerful platforms for diagnostic imaging and controlled delivery of therapeutics to inflammatory cells in atherosclerosis, but efficacy is limited by nonspecific uptake by cells of the mononuclear phagocytes system (MPS). MPS cells located in the liver, spleen, blood, lymph nodes, and kidney remove from circulation the vast majority of intravenously administered nanomaterials regardless of surface functionalization or conjugation of targeting ligands. Here, we report that nanostructure morphology alone can be engineered for selective uptake by dendritic cells (DCs), which are critical mediators of atherosclerotic inflammation. Employing near-infrared fluorescence imaging and flow cytometry as a multimodal approach, we compared organ and cellular level biodistributions of micelles, vesicles (i.e., polymersomes), and filomicelles, all assembled from poly(ethylene glycol)-bl-poly(propylene sulfide) (PEG-bl-PPS) block copolymers with identical surface chemistries. While micelles and filomicelles were respectively found to associate with liver macrophages and blood-resident phagocytes, polymersomes were exceptionally efficient at targeting splenic DCs (up to 85% of plasmacytoid DCs) and demonstrated significantly lower uptake by other cells of the MPS. In a mouse model of atherosclerosis, polymersomes demonstrated superior specificity for DCs (p < 0.005) in atherosclerotic lesions. Furthermore, significant differences in polymersome cellular biodistributions were observed in atherosclerotic compared to naïve mice, including impaired targeting of phagocytes in lymph nodes. These results present avenues for immunotherapies in cardiovascular disease and demonstrate that nanostructure morphology can be tailored to enhance targeting specificity.

We examined whether a maximum threshold of time spent in nonmaternal care exists, beyond which infants have an increased risk of forming a disorganized infant-mother attachment. The hours per week infants spent in nonmaternal care at 7-8 months were examined as a continuous measure and as a dichotomous threshold (over 40, 50 and 60 hr/week) to predict infant disorganization at 12-15 months. Two different samples (Austin and NICHD) were used to replicate findings and control for critical covariates: mothers' unresolved status and frightening behavior (assessed in the Austin sample, N = 125), quality of nonmaternal caregiving (assessed in the NICHD sample, N = 1,135), and family income and infant temperament (assessed in both samples). Only very extensive hours of nonmaternal care (over 60 hr/week) and mothers' frightening behavior independently predicted attachment disorganization. A polynomial logistic regression performed on the larger NICHD sample indicated that the risk of disorganized attachment exponentially increased after exceeding 60 hr/week. In addition, very extensive hours of nonmaternal care only predicted attachment disorganization after age 6 months (not prior). Findings suggest that during a sensitive period of attachment formation, infants who spend more than 60 hr/week in nonmaternal care may be at an increased risk of forming a disorganized attachment.

Purpose: To evaluate the efficacy of a BLES procedure as a primary excisional biopsy rather than a surgical wide local excision for treatment of a high risk or a malignant lesion., Methods: 41 patients underwent a BLES procedure in order to attempt to remove a small breast lesion using a 15 mm or 20 mm wand from August 2007 to January 2009. The lesions were either proven on prior core biopsy to show high risk or malignant pathology or were considered to be indeterminate or suspicious on ultrasound or mammography. The pathology was reviewed to include the final status of lesion excision. If margin involvement was demonstrated then a formal surgical excision was subsequently recommended. Follow up mammography or ultrasound was performed annually in patients following the final pathological diagnosis., Results: 9 patients had a primary diagnosis of atypia (columnar cell change with atypia or atypical ductal hyperplasia (ADH)), 23 patients had ductal carcinoma in situ (DCIS) and 9 had an invasive carcinoma (IC) at the original BLES pathology. Clear BLES margins of >1 mm were obtained in 3/9 atypia lesions, 15/23 DCIS and 0/9 IC. 12/13 low grade DCIS were completely excised. Subsequent surgical margin excisions were undertaken in 20 patients. After at least 5 years of follow up (mean 66 months), 1 lesion had recurred on imaging., Conclusion: A BLES excision has potential as an alternative technique to traditional surgical wide local excision in the management of certain small breast lesions with high risk and low grade malignant potential., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To retrospectively review diagnostic mammography in women diagnosed with breast cancer who previously had mantle field radiation therapy for Hodgkin disease in England and Wales over a period of 30 years., Materials and Methods: From a national cohort study of 5002 women treated with supradiaphragmatic radiation therapy when they were younger than 36 years (mean, 22.1 years) during 1956-2003, 392 patients developed breast cancer. With ethics committee approval and informed consent, mammograms were obtained that showed 230 tumors in 222 (56.6%) patients from 95 hospitals, and the size and appearance of each carcinoma was recorded by two breast radiologists. Comparison was made with a historical report of more than 1000 general-population breast cancers by using Pearson χ(2) test., Results: Thirty-eight tumors were occult on mammograms. Mean tumor maximum diameter was 12.3 mm (n = 81) on oblique view. The quadrant distribution of the tumors was significantly different (P < .001) from the historic controls, and chest radiation therapy patients had a greater proportion of tumors in the upper outer (66.9% [107 of 160] vs 48.7% [385 of 784]) and, to a lesser extent, lower inner (10.6% [17 of 160] vs 7.8% [61 of 784]) quadrants. The dominant radiologic feature was of an irregular mass (56.8% [109 of 192]) followed by microcalcifications (25.0% [48 of 192])., Conclusion: This study suggests that in patients who previously underwent mantle radiation therapy for Hodgkin disease, breast cancers are more commonly seen within the upper outer quadrants than are cancers in the general population. Poorly defined masses were the most common appearance., (© RSNA, 2014.)

Purpose: To document the apparent diffusion coefficient (ADC) of fibroglandular breast tissue in women at high-risk of developing breast cancer and investigate the relationship between ADC and breast density., Materials and Methods: Local research ethics approval was obtained. A total of 33 high-risk women including 17 BRCA1/2 mutation carriers (mean age, 43 years) and 16 women postmantle irradiation (mean age 40 years) underwent diffusion-weighted MRI between days 6 and 16 of their menstrual cycle. ADC histograms from a region of interest in fibroglandular tissue and mammographic breast density measurements were obtained. Mean, percentile ADC values (10th, 25th, 50th, 75th, 90th) and skew were compared for the two groups; ADC and mammographic breast density were correlated., Results: Mean ADC values (×10(-6) mm(2) /s) were 2017 ± 197 in postmantle irradiated women and 1827 ± 289 in BRCA1/2 mutation carriers (P = 0.035) with significant differences at all percentiles (P < 0.0001) but not skew (P = 0.44). ADC values showed weak positive correlation with mammographic breast density in BRCA1/2 mutation carriers (r = 0.51, P = 0.043) but not in postmantle radiotherapy patients (r = 0.49, P = 0.13)., Conclusion: Higher ADC values seen in fibroglandular tissue postmantle irradiation compared with BRCA1/2 mutation carriers has potential to improve tumor detection in these patients. Lack of correlation between ADC and breast density postmantle irradiation may be a result of microstructural changes., (Copyright © 2013 Wiley Periodicals, Inc.)

Our measurements of micro-plasma following laser-induced optical breakdown of nitro compound explosive simulants, here 3-nitrobenzoic acid, show well-developed molecular spectra during the first several hundreds of nanoseconds. Analysis of recorded carbon spectra is accomplished using accurate line strengths for the diatomic molecular Swan system. Presence of hydrogen-beta allows us to infer electron density in the plasma evolution. Computational challenges include accounting for background variation and appropriate modeling of hydrogen embedded in molecular spectra. Recorded and computed spectra agree nicely for time delays on the order of 1.6 μs from optical breakdown when using a single temperature for local thermodynamic equilibrium plasma.

Initial presentation of invasive fungal infections such as histoplasmosis can include non-specific clinical manifestations, especially in immunocompromised patients. A high index of suspicion is required to identify atypical manifestations of these diseases, which carry a high risk of mortality, if the diagnosis is delayed or missed. We describe a case of a kidney transplant recipient with cutaneous lesions as initial manifestation of progressive disseminated histoplasmosis where a skin biopsy was crucial to an early diagnosis., (© 2013 John Wiley & Sons A/S.)

We aim to identify preoperative factors at diagnosis which could predict whether women undergoing wide local excision (WLE) would require further operations. 1593 screen-detected invasive and non-invasive breast cancers were reviewed. Age, presence of ductal carcinoma in situ (DCIS), invasive cancer size on mammography, mammographic sign, tumour type, grade and confidence of the radiologist in malignancy were compared. 83%(1315/1593) of women had a WLE. Of these, 70%(919/1315) had a single operation, and 30%(396/1315) multiple operations. These included repeat WLE to clear margins (60%(238/396)), mastectomy (34%(133/396)) and axillary dissection (6%(25/396)). The presence of mammographic microcalcification, lobular carcinoma and grade 2 malignancy on core biopsy were independent risk factors for multiple operations on multivariate analysis. Women with mammographic DCIS >30 mm were 3.4 times more likely to undergo repeat surgery than those with smaller foci. The multidisciplinary team should pay particular attention to these factors when planning surgery., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

It is well known that cross reactions with other fungal pathogens including Histoplasma capsulatum can occur with the use of the Platelia™ Aspergillus galactomannan assay. We report two patients with confirmed blastomycosis whose bronchoalveolar lavage (BAL) fluid tested positive for Aspergillus galactomannan despite no evidence of aspergillosis.

Positive and negative third-order optical nonlinearities have been investigated in single-stranded DNA wrapped semiconducting single-walled carbon nanotubes. It is found that the redox reactions of hydrogen peroxide can reverse the sign of the third-order nonlinearity. The observation proves that the lowest unoccupied molecular orbital has a lower density of electronic states than that of the highest occupied molecular orbital. A three-energy-level model is used to explain the effect of the redox reactions. Raman spectroscopy has also been used to investigate the interaction between single-walled carbon nanotubes and single-stranded DNA.

The rate of methicillin-resistant Staphylococcus aureus (MRSA) infection continues to rise in many health care settings. Rapid detection of MRSA colonization followed by appropriate isolation can reduce transmission and infection. We compared the performance of the new Roche LightCycler MRSA advanced test to that of the BD GeneOhm MRSA test and culture. Double-headed swabs were used to collect anterior nasal specimens from each subject. For both tests, DNA was extracted and real-time PCR was performed according to manufacturer's instructions. For culture, one swab of the pair was plated directly to CHROMagar MRSA. The swab paired with the BD GeneOhm MRSA test was also placed into an enrichment broth and then plated to CHROMagar MRSA. Colonies resembling staphylococci were confirmed as S. aureus by standard methods. Discrepant specimens had further testing with additional attempts to grow MRSA as well as sample amplicon sequencing. Agreement between results for the two swabs was 99.3% for those with valid results. A total of 1,402 specimens were tested using direct culture detection of MRSA as the gold standard; 187 were culture positive for MRSA. The LightCycler MRSA advanced test had relative sensitivity and specificity of 95.2% (95% confidence interval [CI]: 91.1% to 97.8%) and 96.4% (95% CI: 95.2% to 97.4%), respectively. The BD GeneOhm assay had relative sensitivity and specificity of 95.7% (95% CI: 91.7% to 98.1%) and 91.7% (95% CI: 90.0% to 93.2%), respectively. Following discrepancy analysis, the relative sensitivities of the LightCycler MRSA advanced test and the BD GeneOhm MRSA assay were 92.2 and 93.2%, respectively; relative specificities were 98.9 and 94.2%, respectively. Specificity was significantly better (P<0.001) with the LightCycler MRSA advanced test. The sensitivity of direct culture was 80.4%. The LightCycler MRSA advanced test is a useful tool for sensitive and rapid detection of MRSA nasal colonization.