A new method of meshing in discontinuous deformation analysis (DDA)

Includes bibliography.Discontinuous Deformation Analysis (DDA) is a discrete element method developed by Shi [1988] specifically for modelling blocky rock masses. The DDA method is based on the assumption that deformation and failure of such rock masses is primarily due to differential movements of rock blocks, rather than strain and fracture of intact rock material. Strains and stresses are assumed to be constant over the area of each rock block. Contact between blocks is modelled using penalty functions, with Coulomb's friction law controlling sliding along block boundaries. Tests show that while DDA is not well suited to dynamic simulations where the velocities of blocks become large, it can model rock masses to a reasonable degree of accuracy in static analyses. There are various analysis control parameters which have a marked effect on the solution, however, and the user should take care in choosing suitable values for these parameters. A method is proposed here, in which certain blocks can be sub-divided into Finite Element meshes in order to obtain a more accurate description of their deformation. The method takes advantage of the fact that both DDA and the Finite Element Method (FEM) use the principle of stationary potential energy to obtain the solution equations for block equilibrium. Both DDA blocks and FEM elements can therefore initially be treated as DDA blocks, using the standard DDA formulation, and then the solution equations for the FEM elements are converted into Finite Element format by a simple transformation procedure before solution. First and second order DDA blocks are considered in this report, along with their equivalents in FEM, the C0-linear and C0-quadratic triangular elements. The C0-linear elements are found to be too stiff in modelling bending deformation, due to the assumption of constant strain throughout the element. The C0-quadratic elements are able to accurately model bending, however. It is shown through tests that the performance of these FEM elements, formulated within the DDA method, is identical to that obtained using the corresponding elements in conventional Finite Element programs. The sub-meshing method therefore allows mixed-formulation analyses, with DDA blocks and FEM meshes interacting within a single system, while remaining efficient, and reasonably simple to incorporate into existing DDA program codes. It would also be possible to model material non-linearity and fracture using this method

A Toolkit for Integrating Menstrual Hygiene Management (MHM) Into Humanitarian Response: The Full Guide

The menstrual hygiene management (MHM) in Emergencies project is a collaboration between the International Rescue Committee and Columbia University's Mailman School of Public Health, and is supported by Research for Health in Humanitarian Crises (R2HC). The aim of this project is to improve the guidance available to humanitarian responders who need to incorporate MHM into their programming during emergencies. Formative assessments were conducted in two humanitarian response settings (Myanmar and Lebanon) at the onset of the project in addition to interviews with global humanitarian experts, a major meeting of specialists across sectors and agencies, and a desk review. The toolkit was then piloted in an on-going emergency context (refugee camps in Tanzania) where it was evaluated and further improved upon.The toolkit looks at MHM from a multi-sectoral perspective and aims to give practical, streamlined guidance to humanitarian workers. The toolkit is co-published by 27 leading organizations that work in the humanitarian sphere.

Physician-prescribed Asthma Treatment Regimen does not differ Between Smoking and Non-smoking Patients With Asthma in Seoul and Gyunggi province of Korea

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. ACKNOWLEDGMENTS The authors thank Lauren Weisenfluh and Melissa Stauffer, PhD, in collaboration with SCRIBCO, for medical writing assistance. Funding for this research was provided by Merck & Co., Inc. The authors also wish to thank Eric Maiese and Sharlette Everett for their contributions to the design and implementation of the study and the analytic plan. The authors would also like to thank the study investigators who contributed to patient enrollment and data collection: Drs. Young Il Hwang (Hallym University Sacred Heart Hospital), Young Min Ye (Ajou University Medical Center), Joo Hee Kim (Ajou University Medical Center), Heung Woo Park (Seoul National University Hospital), Tae Wan Kim (Seoul National University Hospital), Jae Jeong Shim (Korea University Guro Hospital), Gyu Young Hur (Korea University Guro Hospital), Soo Taek Uh (SoonChunHyang University Hospital), Sang Ha Kim (Wonju Christian Hospital), Myoung Kyu Lee (Wonju Christian Hospital), Soo Keol Lee (Dong-A Medical Center), Jin Hong Chung (Yeungnam University Medical Center), Kyu Jin Kim (Yeungnam University Medical Center), Young Koo Jee (Dankook University Hospital), Kyung Mook Kim (Dankook University Hospital), Young Il Koh (Chonnam National University Hospital), Cheol Woo Kim (Inha university Hospital), You Sook Cho (Seoul Asan Medical Center), Tae Bum Kim (Seoul Asan Medical Center), Jae Myung Lee (Myeong Internal Medicine), Young Mok Lee (Good Friends Internal Medicine), Bong Chun Lee (Namsan Hospital), So Yoen Park (A&A Clinic).Peer reviewedPublisher PD

Innovative strategies for providing menstruation-supportive water, sanitation and hygiene (WASH) facilities: learning from refugee camps in Cox’s bazar, Bangladesh

Background There is growing attention to addressing the menstrual hygiene management (MHM) needs of the over 21 million displaced adolescent girls and women globally. Current approaches to MHM-related humanitarian programming often prioritize the provision of menstrual materials and information. However, a critical component of an MHM response includes the construction and maintenance of water, sanitation and hygiene (WASH) facilities, including more female-friendly toilets. This enables spaces for menstruating girls and women to change, dispose, wash and dry menstrual materials; all of which are integral tasks required for MHM. A global assessment identified a number of innovations focused on designing and implementing menstruation-supportive WASH facilities in the Rohingya refugee camps located in Cox’s Bazar (CXB), Bangladesh. These pilot efforts strove to include the use of more participatory methodologies in the process of developing the new MHM-supportive WASH approaches. This study aimed to capture new approaches and practical insights on innovating menstrual disposal, waste management and laundering in emergency contexts through the conduct of a qualitative assessment in CXB. Methods The qualitative assessment was conducted in the Rohingya refugee camps in CXB in September of 2019 to capture new approaches and practical insights on innovating for menstrual disposal, waste management and laundering. This included Key Informant Interviews with 19 humanitarian response staff from the WASH and Protection sectors of a range of non-governmental organizations and UN agencies; Focus Group Discussions with 47 Rohingya adolescent girls and women; and direct observations of 8 WASH facilities (toilets, bathing, and laundering spaces). Results Key findings included: one, the identification of new female-driven consultation methods aimed at improving female beneficiary involvement and buy-in during the design and construction phases; two, the design of new multi-purpose WASH facilities to increase female beneficiary usage; three, new menstrual waste disposal innovations being piloted in communal and institutional settings, with female users indicating at least initial acceptability; and four, novel strategies for engaging male beneficiaries in the design of female WASH facilities, including promoting dialogue to generate buy-in regarding the importance of these facilities and debate about their placement. Conclusions Although the identified innovative participatory methodologies and design approaches are promising, the long term viability of the facilities, including plans to expand them, may be dependent on the continued engagement of girls and women, and the availability of resources

What is the scope for addressing menstrual hygiene management in complex humanitarian emergencies? A global review.

Global attention on improving the integration of menstrual hygiene management (MHM) into humanitarian response is growing. However, there continues to be a lack of consensus on how best to approach MHM inclusion within response activities. This global review assessed the landscape of MHM practice, policy, and research within the field of humanitarian response. This included an analysis of the limited existing documentation and research on MHM in emergencies and global key informant interviews (n=29) conducted with humanitarian actors from relevant sectors (water, sanitation, and hygiene; women's protection; child protection; health; education; non-food items; camp management). The findings indicate that despite a growing dialogue around MHM in emergencies, there remains a lack of clarity on the key components for a complete MHM response, the responsible sectoral actors to implement MHM activities, and the most effective interventions to adapt in emergency contexts, and insufficient guidance on monitoring and evaluation. There is a critical need for improved technical guidance and documentation on how to integrate MHM into existing programming and monitoring systems and to ensure adequate coordination and communication about MHM across relevant sectors. There is also a need for improved evidence on effective MHM approaches, the development of MHM-specific indicators, improved consultation with girls and women in crisis-afflicted areas, and the documentation of practical learning. It is only through improving the resources available and enhancing this evidence base that MHM can be perceived as an integral and routine component of any humanitarian response

Understanding the menstrual hygiene management challenges facing displaced girls and women: findings from qualitative assessments in Myanmar and Lebanon.

BACKGROUND: There is a significant gap in empirical evidence on the menstrual hygiene management (MHM) challenges faced by adolescent girls and women in emergency contexts, and on appropriate humanitarian response approaches to meet their needs in diverse emergency contexts. To begin filling the gap in the evidence, we conducted a study in two diverse contexts (Myanmar and Lebanon), exploring the MHM barriers facing girls and women, and the various relevant sectoral responses being conducted (e.g. water, sanitation and hygiene (WASH), Protection, Health, Education and Camp Management). METHODS: Two qualitative assessments were conducted: one in camps for internally displaced populations in Myanmar, and one with refugees living in informal settlements and host communities in Lebanon. Key informant interviews were conducted with emergency response staff in both sites, and focus group discussion and participatory mapping activities conducted with adolescent girls and women. RESULTS: Key findings included that there was insufficient access to safe and private facilities for MHM coupled with displacement induced shifts in menstrual practices by girls and women. Among staff, there was a narrow interpretation of what an MHM response includes, with a focus on supplies; significant interest in understanding what an improved MHM response would include and acknowledgement of limited existing MHM guidance across various sectors; and insufficient consultation with beneficiaries, related to discomfort asking about menstruation, and limited coordination between sectors. CONCLUSIONS: There is a significant need for improved guidance across all relevant sectors for improving MHM response in emergency context, along with increased evidence on effective approaches for integrating MHM into existing responses

Tumour-retained activated CCR7⁺ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to an activation programme enriched in regulatory molecule expression, including PD-L1. However, the spatio-temporal dynamics of CCR7+ DCs in anti-tumour immune responses remain unclear. Here, we use photoconvertible mice to precisely track DC migration. We report that CCR7+ DCs are the dominant DC population that migrate to the dLN, but a subset remains tumour-resident despite CCR7 expression. These tumour-retained CCR7+ DCs are phenotypically and transcriptionally distinct from their dLN counterparts and heterogeneous. Moreover, they progressively downregulate the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour-residing CCR7+ DCs co-localise with PD-1+CD8+ T cells in human and murine solid tumours, and following anti-PD-L1 treatment, upregulate stimulatory molecules including OX40L, thereby augmenting anti-tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in CCR7+ DCs that may underpin a variable capacity to support intratumoural cytotoxic T cells.</p

Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson's disease.

The innate immune system is implicated in Parkinson's disease (PD), but peripheral in-vivo clinical evidence of the components and driving mechanisms involved and their relationship with clinical heterogeneity and progression to dementia remain poorly explored. We examined changes in peripheral innate immune-related markers in PD cases (n = 41) stratified according to risk of developing early dementia. 'Higher Risk'(HR) (n = 23) and 'Lower Risk' (LR) (n = 18) groups were defined according to neuropsychological predictors and MAPT H1/H2 genotype, and compared to age, gender and genotype-matched controls. Monocyte subsets and expression of key surface markers were measured using flow cytometry. Serum markers including alpha-synuclein, inflammasome-related caspase-1 and bacterial translocation-related endotoxin were measured using quantitative immuno-based assays. Specific markers were further investigated using monocyte assays and validated in plasma samples from a larger incident PD cohort (n = 95). We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the HR group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were also increased. Monocyte Human Leukocyte Antigen (HLA)-DR expression correlated with clinical variables, with lower levels associated with worse cognitive/motor performance. Notably, monocyte changes were accompanied by elevated serum bacterial endotoxin, again predominantly in the HR group. Serum alpha-synuclein and inflammasome-related caspase-1 were decreased in PD cases compared to controls regardless of group, with decreased monocyte alpha-synuclein secretion in HR cases. Further, alpha-synuclein and caspase-1 correlated positively in serum and monocyte lysates, and in plasma from the larger cohort, though no associations were seen with baseline or 36-month longitudinal clinical data. Principal Components Analysis of all monocyte and significant serum markers indicated 3 major components. Component 1 (alpha-synuclein, caspase-1, TLR2+ monocytes) differentiated PD cases and controls in both groups, while Component 2 (endotoxin, monocyte TREM2, alpha-synuclein) did so predominantly in the HR group. Component 3 (classical monocytes, alpha-synuclein) also differentiated cases and controls overall in both groups. These findings demonstrate that systemic innate immune changes are present in PD and are greatest in those at higher risk of rapid progression to dementia. Markers associated with PD per-se (alpha-synuclein, caspase-1), differ from those related to cognitive progression and clinical heterogeneity (endotoxin, TREM2, TLR4, classical monocytes, HLA-DR), with mechanistic and therapeutic implications. Alpha-synuclein and caspase-1 are associated, suggesting inflammasome involvement common to all PD, while bacterial translocation associated changes may contribute towards progression to Parkinson's dementia. Additionally, HLA-DR-associated variations in antigen presentation/clearance may modulate existing clinical disease

RAG1 Core and V(D)J Recombination Signal Sequences Were Derived from Transib Transposons

The V(D)J recombination reaction in jawed vertebrates is catalyzed by the RAG1 and RAG2 proteins, which are believed to have emerged approximately 500 million years ago from transposon-encoded proteins. Yet no transposase sequence similar to RAG1 or RAG2 has been found. Here we show that the approximately 600-amino acid “core” region of RAG1 required for its catalytic activity is significantly similar to the transposase encoded by DNA transposons that belong to the Transib superfamily. This superfamily was discovered recently based on computational analysis of the fruit fly and African malaria mosquito genomes. Transib transposons also are present in the genomes of sea urchin, yellow fever mosquito, silkworm, dog hookworm, hydra, and soybean rust. We demonstrate that recombination signal sequences (RSSs) were derived from terminal inverted repeats of an ancient Transib transposon. Furthermore, the critical DDE catalytic triad of RAG1 is shared with the Transib transposase as part of conserved motifs. We also studied several divergent proteins encoded by the sea urchin and lancelet genomes that are 25%−30% identical to the RAG1 N-terminal domain and the RAG1 core. Our results provide the first direct evidence linking RAG1 and RSSs to a specific superfamily of DNA transposons and indicate that the V(D)J machinery evolved from transposons. We propose that only the RAG1 core was derived from the Transib transposase, whereas the N-terminal domain was assembled from separate proteins of unknown function that may still be active in sea urchin, lancelet, hydra, and starlet sea anemone. We also suggest that the RAG2 protein was not encoded by ancient Transib transposons but emerged in jawed vertebrates as a counterpart of RAG1 necessary for the V(D)J recombination reaction

Understanding how the V(D)J recombinase catalyzes transesterification: distinctions between DNA cleavage and transposition

The Rag1 and Rag2 proteins initiate V(D)J recombination by introducing site-specific DNA double-strand breaks. Cleavage occurs by nicking one DNA strand, followed by a one-step transesterification reaction that forms a DNA hairpin structure. A similar reaction allows Rag transposition, in which the 3′-OH groups produced by Rag cleavage are joined to target DNA. The Rag1 active site DDE triad clearly plays a catalytic role in both cleavage and transposition, but no other residues in Rag1 responsible for transesterification have been identified. Furthermore, although Rag2 is essential for both cleavage and transposition, the nature of its involvement is unknown. Here, we identify basic amino acids in the catalytic core of Rag1 specifically important for transesterification. We also show that some Rag1 mutants with severe defects in hairpin formation nonetheless catalyze substantial levels of transposition. Lastly, we show that a catalytically defective Rag2 mutant is impaired in target capture and displays a novel form of coding flank sensitivity. These findings provide the first identification of components of Rag1 that are specifically required for transesterification and suggest an unexpected role for Rag2 in DNA cleavage and transposition