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Chloramphenicol (Systemic | Memorial Sloan Kettering Cancer Center
This information from Lexicomp® explains what you need to know about this medication, including what it’s used for, how to take it, its side effects, and when to call your healthcare provider.
Chloramphenicol (Systemic
Adult Medication
This information from Lexicomp ®explains what you need to know about this medication, including what it’s used for, how to take it, its side effects, and when to call your healthcare provider.
Brand Names: Canada
Chloromycetin Succinate
Warning
Very bad and sometimes deadly blood problems have happened with this drug. This may cause more chance of getting an infection, bleeding problems, or slow healing. Aplastic anemia that happened with this drug has led to a certain kind of cancer (leukemia). Blood problems have happened after both short-term use and long-term use. Have your blood work checked while taking this drug. Talk with your doctor.
What is this drug used for?
It is used to treat bacterial infections.
What do I need to tell my doctor BEFORE I take this drug?
If you have an allergy to chloramphenicol or any other part of this drug.
If you are allergic to this drug; any part of this drug; or any other drugs, foods, or substances. Tell your doctor about the allergy and what signs you had.
If you have any of these health problems: Bone marrow disease or low blood cell counts.
If you are taking any drugs that can raise the chance of blood problems. There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
This is not a list of all drugs or health problems that interact with this drug.
Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
Do not use longer than you have been told. A second infection may happen.
Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this drug while you are pregnant.
Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
Infants:
Very bad and sometimes deadly reactions have happened in premature and newborn babies. This has happened in a baby born to a mother who got this drug during labor. It has also happened in a 3-month old. Most of the time, this drug was used within the first 48 hours of life. Signs first show up after 3 to 4 days of getting this drug. Call your child’s doctor right away if your child has swelling of the stomach with or without throwing up, blue or gray skin color, or trouble breathing.
What are some side effects that I need to call my doctor about right away?
WARNING/CAUTION:Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
Signs of bleeding like throwing up or coughing up blood; vomit that looks like coffee grounds; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a cause or that get bigger; or bleeding you cannot stop.
Very bad dizziness or passing out.
Feeling very tired or weak.
Feeling confused.
Mood changes.
Change in eyesight.
A burning, numbness, or tingling feeling that is not normal.
Diarrhea is common with antibiotics. Rarely, a severe form called C diff–associated diarrhea (CDAD) may happen. Sometimes, this has led to a deadly bowel problem. CDAD may happen during or a few months after taking antibiotics. Call your doctor right away if you have stomach pain, cramps, or very loose, watery, or bloody stools. Check with your doctor before treating diarrhea.
What are some other side effects of this drug?
All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
Headache.
These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
You may report side effects to the FDA at 1-800-332-1088. You may also report side effects athttps://www.fda.gov/medwatch.
How is this drug best taken?
Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
It is given into a vein for a period of time.
What do I do if I miss a dose?
Call your doctor to find out what to do.
How do I store and/or throw out this drug?
If you need to store this drug at home, talk with your doctor, nurse, or pharmacist about how to store it.
General drug facts
If your symptoms or health problems do not get better or if they become worse, call your doctor.
Do not share your drugs with others and do not take anyone else’s drugs.
Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Consumer Information Use and Disclaimer
This generalized information is a limited summary of diagnosis, treatment, and/or medication information. It is not meant to be comprehensive and should be used as a tool to help the user understand and/or assess potential diagnostic and treatment options. It does NOT include all information about conditions, treatments, medications, side effects, or risks that may apply to a specific patient. It is not intended to be medical advice or a substitute for the medical advice, diagnosis, or treatment of a health care provider based on the health care provider’s examination and assessment of a patient’s specific and unique circumstances. Patients must speak with a health care provider for complete information about their health, medical questions, and treatment options, including any risks or benefits regarding use of medications. This information does not endorse any treatments or medications as safe, effective, or approved for treating a specific patient. UpToDate, Inc. and its affiliates disclaim any warranty or liability relating to this information or the use thereof. The use of this information is governed by the Terms of Use, available athttps://www.wolterskluwer.com/en/know/clinical-effectiveness-terms.
Monday, December 12, 2022
If you have any questions, contact a member of your care team directly. If you're a patient at MSK and you need to reach a provider after
5 p.m.
, during the weekend, or on a holiday, call
212-639-2000
.
If you have any questions, contact a member of your care team directly. If you're a patient at MSK and you need to reach a provider after
5 p.m.
, during the weekend, or on a holiday, call
212-639-2000
.
| https://www.mskcc.org/cancer-care/patient-education/medications/chloramphenicol-systemic |
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| https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20180117T225357/anc/eng/sasm1/sci_anc_sasm115_010_014.drf |
GM-CSF With Post-Transplant Cyclophosphamide - Full Text View - ClinicalTrials.gov
GM-CSF With Post-Transplant Cyclophosphamide
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT04237623 Recruitment Status :
Recruiting First Posted : January 23, 2020 Last Update Posted : October 20, 2022 See Contacts and Locations
Sponsor:
Northside Hospital, Inc.
Information provided by (Responsible Party):
Northside Hospital, Inc.
Study Details
Study Description
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:
Given the increased number of HLA-mismatched haploidentical transplantation with post-transplant cyclophosphamide performed each year and the high risk of infectious complications associated with this type of transplant, the investigators suggest that GM-CSF administration post-infusion of T-replete haploidentical stem cells and post-transplant cyclophosphamide can yield similar count recovery rates to G-CSF with a potential of lowering risk of infectious complications.
Condition or disease Intervention/treatment Phase Transplant-Related Hematologic Malignancy Drug: Sargramostim Other: Control Arm Phase 2
Study Design
Layout table for study information Study Type : Interventional
(Clinical Trial) Estimated Enrollment : 38 participants Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Supportive Care Official Title: Phase II Trial Evaluating the Efficacy and Safety of Sargramostim Post-Infusion of T-Replete HLA Mismatched Peripheral Blood Haploidentical Hematopoietic Stem Cells and With Post Transplant Cyclophosphamide Actual Study Start Date : May 18, 2020 Estimated Primary Completion Date : May 18, 2024 Estimated Study Completion Date : May 18, 2025
Resource links provided by the National Library of Medicine
Drug Information available for: Cyclophosphamide Sargramostim
U.S. FDA Resources
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Arm Intervention/treatment Experimental: GM-CSF post-transplant Sargramostim (GM-CSF) will start on Day +5 and continue until ANC >1000 x3 days or >1500 x1 day. GM-CSF will be administered not less than 24 hours after the last dose of cyclophosphamide and will be given at a dose of 250mcg/m2/day as an infusion over 2 hours. Drug: Sargramostim 250mcg/m2/day IV starting Day +5 Other Name: GM-CSF Other: Control Arm Standard G-CSF given to those who decline to receive GM-CSF Other Name: G-CSF
Outcome Measures
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Primary Outcome Measures
:
The number of patients who achieved neutrophil engraftment at 20 days after the initiation of treatment. [ Time Frame: 3 months after initial treatment ]
The aim of the study is to establish equivalent effectiveness of Sargramostim to a matched control cohort of G-CSF treated patients in time to achieve neutrophil (ANC >500 x3 days) post infusion of HLA-mismatched peripheral blood haploidentical stem cells with post-transplant cyclophosphamide. Patients will be followed for 3 months following the initiation of treatment to see engraftment numbers at 20 days after initial treatment.
Secondary Outcome Measures
:
How many patients are still alive measured by overall survival at 12 months following the initiation of treatment. [ Time Frame: 12 months following initiation of treatment ]
To estimate overall survival
How many patients have not relapsed measured by relapse rates at 12 months following the initiation of treatment. [ Time Frame: 12 months following initiation of treatment ]
To estimate relapse rates
How many patients develop graft-versus-host-disease (GVHD) measured by the incidence of GVHD at 12 months following initiation of treatment [ Time Frame: 12 months following initiation of treatment ]
To estimate incidence of GVHD
How many patients have not relapsed measured by progression-free survival at 12 months following the initiation of treatment [ Time Frame: 12 months following initiation of treatment ]
To estimate non-relapse mortality
How many patients died due to infections measured by the incidence and type of infections at 12 months following initiation of treatment [ Time Frame: 12 months following initiation of treatment ]
To estimate infection-related mortality
How many patients died due to a treatment-related adverse events grade 2 or greater as assessed by CTCAE v.4.0 [ Time Frame: 12 months following initiation of treatment ]
To estimate event-free survival
Number of patients to achieve full donor chimerisms at Days 30, 50, 100, and 6 months post-transplant as measured by donor chimerism data [ Time Frame: 12 months following initiation of treatment ]
To estimate graft failure
Number of patients that acquired an infection in the first 100-days post-transplant as measured by the incidence of infections [ Time Frame: 12 months following initiation of treatment ]
To estimate the rate of infections
Number of patients achieving platelet engraftment as measured by platelets reaching 20,000 without transfusion for 7 days [ Time Frame: 12 months following initiation of treatment ]
To assess time to platelet engraftment
Eligibility Criteria
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 18 Years to 78 Years (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Availability of 5/10 to 8/10 matched related donor
KPS >/= 70%
CML, AML, MDS, ALL, CLL, HD, NHL, MPS/CMML, MM, any other hematologic condition deemed an eligible indication for allogeneic transplant by the treating center
Exclusion Criteria:
Poor cardiac, pulmonary, liver, and renal function
HIV-positive
Patients who have a debilitating medical or psychiatric illness that would preclude them from giving informed consent
History of severe or serious allergic reaction to human GM-CSF or yeast-derived products
Contacts and Locations
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04237623
Contacts
Layout table for location contacts Contact: Stacey Brown, BA 404-780-7965 stacey.brown@northside.com
Locations
Layout table for location information United States, Georgia Northside Hospital Recruiting Atlanta, Georgia, United States, 30342 Contact: Stacey Brown, BA 404-780-7965 stacey.brown@northside.com Contact: Caitlin Guzowski, MBA, MHA 404-851-8523 caitlin.guzowski@northside.com Sub-Investigator: H. Kent Holland, MD Sub-Investigator: Asad Bashey, MD Sub-Investigator: Lawrence E Morris, MD Sub-Investigator: Scott Solomon, MD Principal Investigator: Melhem Solh, MD
Sponsors and Collaborators
Northside Hospital, Inc.
Investigators
Layout table for investigator information Principal Investigator: Melhem Solh, MD Northside Hospital
Layout table for additonal information Responsible Party: Northside Hospital, Inc. ClinicalTrials.gov Identifier: NCT04237623 History of Changes Other Study ID Numbers: NSH 1246 First Posted: January 23, 2020 Key Record Dates Last Update Posted: October 20, 2022 Last Verified: October 2022 Individual Participant Data (IPD) Sharing Statement: Plan to Share IPD: No
Layout table for additional information Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No
U.S. National Library of Medicine
U.S. Department of Health and Human Services
| https://clinicaltrials.gov/ct2/show/study/NCT04237623 |
Vascular endothelial growth factor-D: Signaling mechanisms, biology, and clinical relevance | Request PDF
Request PDF | Vascular endothelial growth factor-D: Signaling mechanisms, biology, and clinical relevance | Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that promotes growth of blood vessels (angiogenesis) and lymphatic... | Find, read and cite all the research you need on ResearchGate
July 2012 Growth factors (Chur, Switzerland)
30(5):283-96
DOI: 10.3109/08977194.2012.704917
Source PubMed
Authors:
Marc G Achen
Marc G Achen
This person is not on ResearchGate, or hasn't claimed this research yet.
Steven A Stacker
Peter MacCallum Cancer Centre
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Citations (34)
References (156)
Abstract
Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that promotes growth of blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis), and can induce remodeling of large lymphatics. VEGF-D enhances solid tumor growth and metastatic spread in animal models of cancer, and in some human cancers VEGF-D correlates with metastatic spread, poor patient outcome, and, potentially, with resistance to anti-angiogenic drugs. Hence, VEGF-D signaling is a potential target for novel anti-cancer therapeutics designed to enhance anti-angiogenic approaches and to restrict metastasis. In the cardiovascular system, delivery of VEGF-D in animal models enhanced angiogenesis and tissue perfusion, findings which have led to a range of clinical trials testing this protein for therapeutic angiogenesis in cardiovascular diseases. Despite these experimental and clinical developments, our knowledge of the signaling mechanisms driven by VEGF-D is still evolving-here we explore the biology of VEGF-D, its signaling mechanisms, and the clinical relevance of this growth factor.
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Citations (34) References (156)
... VEGF-C and VEGF-D are secreted protein growth factors that induce proliferation and sprouting of endothelial cells lining blood vessels and lymphatic vessels, and promote angiogenesis and lymphangiogenesis in developing tissues and pathologies such as cancer (1)(2)(3)(4). They induce metastasis in animal models of cancer, exhibit expression patterns in a range of human cancers that correlate with parameters of tumor development, and are considered potential targets for therapeutics designed to restrict tumor growth and spread (5)(6)(7)(8) (9)
(10)(11)(12)(13)(14)(15)(16)(17). VEGF-C and VEGF-D may also play roles in suppressing the immune response to cancer. ...
... For example, tumor-derived VEGF-C and associated lymph node lymphangiogenesis suppressed anti-tumor immunity in a murine melanoma model; this type of immunomodulatory effect, involving an immunosuppressive function of lymphatic endothelial cells (LECs), may be relevant for design of future immunotherapeutic strategies for cancer (18,19). In other disease settings, VEGF-C and VEGF-D are being explored in approaches to drive therapeutic angiogenesis and/or lymphangiogenesis for cardiovascular medicine and lymphedema (9,
20,21). ...
... There is considerable interest in therapeutically targeting VEGF-C and/or VEGF-D in the clinic to block their action and thereby restrict angiogenesis, lymphagiogenesis or vascular leakage in cancer, macular degeneration and other conditions (9,
(50)(51)(52)(53). The VEGF-D mAb 286 characterised here, which blocks the binding and cross-linking of VEGFR-2 and VEGFR-3 by VEGF-D as well as the proliferation and migration of LECs induced by VEGF-D, could facilitate development of therapeutic monoclonal antibodies that block the action of VEGF-D, or of bispecific antibodies that target both VEGF-D and VEGF-C. ...
Differential receptor binding and regulatory mechanisms for the lymphangiogenic growth factors VEGF-C and VEGF-D Article Full-text available
Nov 2016
Natalia Davydova Nicole Cayley Harris Sally Roufail Marc G Achen
VEGF-C(2) and VEGF-D are secreted glycoproteins that induce angiogenesis and lymphangiogenesis in cancer, thereby promoting tumor growth and spread. They exhibit structural homology and activate VEGFR-2 and VEGFR-3, receptors on endothelial cells that signal for growth of blood vessels and lymphatics. VEGF-C and VEGF-D were thought to exhibit similar bioactivities, yet recent studies indicated distinct signalling mechanisms, e.g. tumor-derived VEGF-C promoted expression of the prostaglandin biosynthetic enzyme COX-2 in lymphatics, a response thought to facilitate metastasis via the lymphatic vasculature, whereas VEGF-D did not. Here we explore the basis of the distinct bioactivities of VEGF-D using a neutralizing antibody, peptide-mapping and mutagenesis to demonstrate that the N-terminal α-helix of mature VEGF-D (F93 to R108) is critical for binding VEGFR-2 and VEGFR-3. Importantly, the N-terminal part of this α-helix, from F93 to T98, is required for binding VEGFR-3, but not VEGFR-2. Surprisingly, the corresponding part of the α-helix in mature VEGF-C did not influence binding to either VEGFR-2 or VEGFR-3, indicating distinct determinants of receptor binding by these growth factors. A variant of mature VEGF-D harbouring a mutation in the N-terminal α-helix, D103A, exhibited enhanced potency for activating VEGFR-3, was able to promote increased COX-2 mRNA levels in lymphatic endothelial cells and had enhanced capacity to induce lymphatic sprouting in vivo. This mutant may be useful for developing protein-based therapeutics to drive lymphangiogenesis in clinical settings such as lymphedema. Our studies shed light on the VEGF-D structure/function relationship and provide a basis for understanding functional differences compared to VEGF-C.
View Show abstract
... One of the most studied molecular systems in the regulation of tumor lymphangiogenesis is based on the interaction between vascular endothelial growth factor D (VEGF-D) and the corresponding VEGF receptor 3 (VEGFR-3), commonly expressed on the surface of lymphatic endothelial cells (10, 11)
. VEGF-D is a member of the VEGF family, which also includes VEGF-A, VEGF-B, VEGF-C, and placental growth factor (PlGF), and it is an important key regulator of both physiological and pathological angiogenesis and lymphangiogenesis (11). ...
... One of the most studied molecular systems in the regulation of tumor lymphangiogenesis is based on the interaction between vascular endothelial growth factor D (VEGF-D) and the corresponding VEGF receptor 3 (VEGFR-3), commonly expressed on the surface of lymphatic endothelial cells (10,11). VEGF-D is a member of the VEGF family, which also includes VEGF-A, VEGF-B, VEGF-C, and placental growth factor (PlGF), and it is an important key regulator of both physiological and pathological angiogenesis and lymphangiogenesis
(11)
. VEGF-D promotes lymphatic metastasis by inducing tumor-associated lymphangiogenesis in a mouse tumor model (12), and its over expression was associated with lymphatic tumor spread and poor patient prognosis in several human cancers (13)(14)(15)(16). ...
VEGF-D Serum Level as a Potential Predictor of Lymph Node Metastasis and Prognosis in Vulvar Squamous Cell Carcinoma Patients Article Full-text available
Apr 2022
Antonella Ravaggi Angela Gambino
Federico Ferrari Franco Edoardo Odicino
Background
Radical surgical resection of the primary tumor with mono/bilateral inguinofemoral lymph node dissection is the standard treatment for invasive vulvar squamous cell carcinoma (VSCC) and is frequently related to severe morbidity. Tailoring surgical treatment is of paramount importance, and a comprehensive preoperative evaluation is mandatory. Vascular endothelial growth factor D (VEGF-D) is considered a regulator of lymphangiogenesis involved in tumor spread via lymphatic vessels. The aim of this study was to evaluate the potential of VEGF-D in the prediction of inguinofemoral lymph node metastasis.
Methods
We analyzed the preoperative levels of serum VEGF-D (sVEGF-D) from two independent cohorts of patients with VSCC by enzyme-linked immunosorbent assay and its protein expression on tumor tissue by immunohistochemistry. Logistic regression was performed to identify the independent risk factors for lymph node metastasis, and Cox proportional hazard model was used for survival analysis.
Results
High levels of sVEGF-D, but not tissue VEGF-D, significantly correlated with positive groin nodes and a more advanced International Federation of Gynecologists and Obstetricians (FIGO) stage. In multivariable analysis, a high sVEGF-D level was an independent predictor of lymph node metastasis and worse prognosis. A prediction model based on sVEGF-D, tumor grade assessed on biopsy, tumor diameter, and lymph node clinical evaluation was able to predict lymph node metastasis, reaching C-index values of 0.79 and 0.73 in the training and validation cohorts, respectively.
Conclusions
The preoperative sVEGF-D level might be a reliable biomarker for the prediction of lymph node metastasis and prognosis in patients with VSCC, supporting better clinical/surgical decision. Multicenter prospective studies are required to confirm our findings.
View Show abstract
... More importantly, we observed dramatically higher numbers of LYVE-1 + immune cells infiltrates in the MS brain vasculature compared to normal brain vasculature. Previous reports have shown CD11b + myeloid cells express LYVE-1 and Prox-1 only when attached to the tumor vasculature but not unattached, indicating that vascular-immune interactions might play a prominent role in the expression of these proteins in the immune cells [72][73] [74]
. This might result in more complex interactions between infiltrating immune cells and MS neurovasculature in lymphoid TLO formation in MS. ...
... Of all the proteins under study, VEGF-D showed significant induction in MS and MS animal models (except PLP-EAE serum) and in neurovascular inflammatory conditions in vitro. It was well known that VEGF-D is one of the most potent lymphangiogenic factors
[74]
. Based on the result VEGF-D is the only growth factor that is altered in all these conditions, we expect a much complex role of VEGF-D in MS pathophysiology. ...
Chaitanya J Neuroinflam 2013 with supple fig 5
Data Full-text available
Jul 2015
Ganta V Chaitanya Seiichi Omura
Fumitaka Sato Jonathan Alexander
View
... VEGF-C stimulates receptor dimerization, leading to the formation of VEGFR-2/VEGFR-3 heterodimers and VEGFR-3/VEGFR-3 homodimers, which are implicated in angiogenesis and lymphangiogenesis, respectively [12]. Moreover, VEGF-D activates both receptors, VEGFR-2 and VEGFR-3, and drives angiogenesis and lymphangiogenesis [13]
. In animal models of cancer, expression of VEGF-C and VEGF-D consistently promotes growth of blood vessels and lymphatics in and around tumors, thus facilitating tumor growth and enhancing lymph node and distant organ metastasis. ...
... The analysis of both ligands in tumor tissue is complicated by the fact that these are proteolytically processed proteins. VEGF-C and VEGF-D are produced as prepropeptides and are further processed to a biologically fully active form that effectively binds to VEGFR-2 and −3 [12, 13]
. These biomolecules can therefore be detected in various forms and subunit compositions with different functions, which should be taken into account in future investigations [35]. ...
The relevance of cell type- and tumor zone-specific VEGFR-2 activation in locally advanced colon cancer Article Full-text available
May 2015 J EXP CLIN CANC RES
Caren Jayasinghe Nektaria Simiantonaki Sylvia Habedank Charles James Kirkpatrick
For the successful therapeutic use of inhibitors of the vascular endothelial growth factor receptor (VEGFR) pathway detailed knowledge of the mechanisms leading to tumor progression is indispensable. The main goal of this study was to determine the relevance of the VEGFR-2 activating pathway for colon carcinoma (CC) metastasis. The initial event is ligand-induced receptor activation through tyrosine autophosphorylation.
VEGFR-2, its ligands VEGF-C and VEGF-D and the phosphorylated (activated) receptor forms pVEGFR-2(Tyr1175) and pVEGFR-2(Tyr1214) were investigated immunohistochemically in different tumor compartments (intratumoral (zone 1) - invasive front (zone 2) - extratumoral soft tissue (zone 3)) and various cell types (tumor cells, inflammatory cells, macro- and microvasculature) in 84 non-metastatic, lymphogenous-metastatic and haematogenous-metastatic CC.
VEGF-D produced by tumor cells has an autocrine affinity for its receptor VEGFR-2. In tumor budding regions VEGF-D-induced receptor activation by autophosphorylation at Tyr1214 seems to be a possible initial event of the VEGFR-2-mediated signaling pathway, but without effect on metastatic behaviour. In inflammatory cells of almost all CC VEGFR-2 phosphorylation at Tyr 1175 and Tyr 1214 was detectable without accompanying receptor expression, suggesting receptor activation without cell surface expression. Peritumoral inflammatory cells also expressed paracrine acting VEGF-C. The autocrine VEGF-D/VEGFR-2 signaling axis and receptor autophosphorylation at Tyr1214 appear to be main events for capillaries in all three tumor zones and for small vessels in zone 1 and 2. Independent of the metastatic status a large number of cases with capillary immunopositivity in the angiogenically active invasive front was documented, especially for VEGF-D, VEGFR-2 and pVEGFR-2(Tyr1214). VEGFR-2 positive extratumoral capillaries were significantly more common in distant metastatic CC. In all tumor compartments the investigated biomolecules were also detected in different frequencies in the macrovasculature, which is responsible for sufficient tumor vascularization. In addition, vascular paracrine-acting VEGF-C production was widely detected, but without zone and vessel-type dependence.
The VEGFR-2 activating pathway is closely involved in tumor cell-associated, vessel-mediated and immuno-inflammatory processes in colon carcinoma and appears to contribute to tumor survival and growth as well as maintenance of the infiltrative phenotype rather than to promote metastasis.
View Show abstract
... More importantly, we observed dramatically higher numbers of LYVE-1 + immune cells infiltrates in the MS brain vasculature compared to normal brain vasculature. Previous reports have shown CD11b + myeloid cells express LYVE-1 and Prox-1 only when attached to the tumor vasculature but not unattached, indicating that vascular-immune interactions might play a prominent role in the expression of these proteins in the immune cells [72][73] [74]
. This might result in more complex interactions between infiltrating immune cells and MS neurovasculature in lymphoid TLO formation in MS. ...
... Of all the proteins under study, VEGF-D showed significant induction in MS and MS animal models (except PLP-EAE serum) and in neurovascular inflammatory conditions in vitro. It was well known that VEGF-D is one of the most potent lymphangiogenic factors
[74]
. Based on the result VEGF-D is the only growth factor that is altered in all these conditions, we expect a much complex role of VEGF-D in MS pathophysiology. ...
Chaitanya J Neuroinflammation 2013
Data Full-text available
May 2015
Ganta V Chaitanya Seiichi Omura
Fumitaka Sato Jonathan Alexander
View
... The other ligand for VEGFR3 is VEGFD (FIGF -HUGO Gene Nomenclature Committee; Mouse Genome Informatics). A mouse knockout of Vegfd has confirmed that it is not essential for mammalian lymphatic vessel development (Baldwin et al., 2005); however, Vegfd can rescue the lymphatic hypoplasia in Vegfc −/− mice (Haiko et al., 2008) and is able to induce both lymphangiogenesis and angiogenesis in a variety of assays
(Achen and Stacker, 2012)
. ...
... In mammals, it has been shown that VEGFD is closely related in structure to VEGFC (Leppanen et al., 2011) and, like VEGFC, can activate both VEGFR3/FLT4 and VEGFR2, thereby promoting both angiogenesis and lymphangiogenesis
(Achen and Stacker, 2012)
. Unlike VEGFC, VEGFD does not appear to be essential for mammalian lymphatic vessel development (Baldwin et al., 2005), but it has been shown in Xenopus embryos to subtly modify lymphangioblast migration (Ny et al., 2008). ...
Vegfd can compensate for loss of Vegfc in zebrafish facial lymphatic sprouting
Article Full-text available
Jun 2014
Jonathan W. Astin Michael J L Haggerty
Kazuhide Shaun Okuda Philip Crosier
Lymphangiogenesis is a dynamic process that involves the sprouting of lymphatic endothelial cells (LECs) from veins to form lymphatic vessels. Vegfr3 signalling, through its ligand Vegfc and the extracellular protein Ccbe1, is essential for the sprouting of LECs to form the trunk lymphatic network. In this study we determined whether Vegfr3, Vegfc and Ccbe1 are also required for development of the facial and intestinal lymphatic networks in the zebrafish embryo. Whereas Vegfr3 and Ccbe1 are required for the development of all lymphatic vessels, Vegfc is dispensable for facial lymphatic sprouting but not for the complete development of the facial lymphatic network. We show that zebrafish vegfd is expressed in the head, genetically interacts with ccbe1 and can rescue the lymphatic defects observed following the loss of vegfc. Finally, whereas knockdown of vegfd has no phenotype, double knockdown of both vegfc and vegfd is required to prevent facial lymphatic sprouting, suggesting that Vegfc is not essential for all lymphatic sprouting and that Vegfd can compensate for loss of Vegfc during lymphatic development in the zebrafish head.
View Show abstract
... More importantly , we observed dramatically higher numbers of LYVE-1 + immune cells infiltrates in the MS brain vasculature compared to normal brain vasculature. Previous reports have shown CD11b + myeloid cells express LYVE-1 and Prox-1 only when attached to the tumor vasculature but not unattached, indicating that vascular-immune interactions might play a prominent role in the expression of these proteins in the immune cells7273 74
. This might result in more complex interactions between infiltrating immune cells and MS neurovasculature in lymphoid TLO formation in MS. ...
... Of all the proteins under study, VEGF-D showed significant induction in MS and MS animal models (except PLP-EAE serum) and in neurovascular inflammatory conditions in vitro. It was well known that VEGF-D is one of the most potent lymphangiogenic fac- tors
[74]
. Based on the result VEGF-D is the only growth factor that is altered in all these conditions, we expect a much complex role of VEGF-D in MS pathophysiology. ...
Inflammation induces neuro-lymphatic protein expression in multiple sclerosis brain neurovasculature Article Full-text available
Oct 2013 J NEUROINFLAMM
Ganta V Chaitanya Seiichi Omura
Fumitaka Sato Jonathan Alexander
Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation. Podoplanin+ (lymphatic marker) T helper17 (Th17) cells and B cell aggregates have been implicated in the formation of tertiary lymphoid organs (TLOs) in MS and experimental autoimmune encephalitis (EAE). Since podoplanin expressed by Th17 cells in MS brains is also expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature.
We assessed the protein levels of lymphatic vessel endothelial hyaluronan receptor and podoplanin, which are specific to the lymphatic system and prospero-homeobox protein-1, angiopoietin-2, vascular endothelial growth factor-D, vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons. Levels of these proteins were measured in postmortem brains and sera from MS patients, in the myelin proteolipid protein (PLP)-induced EAE and Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mouse models and in cell culture models of inflamed neurovasculature.Results and conclusions: Intense staining for LYVE-1 was found in neurons of a subset of MS patients using immunohistochemical approaches. The lymphatic protein, podoplanin, was highly expressed in perivascular inflammatory lesions indicating signaling cross-talks between inflamed brain vasculature and lymphatic proteins in MS. The profiles of these proteins in MS patient sera discriminated between relapsing remitting MS from secondary progressive MS and normal patients. The in vivo findings were confirmed in the in vitro cell culture models of neuroinflammation.
View Show abstract
... VEGF-C and VEGF-D, members of the VEGF family, have been demonstrated to stimulate the proliferation of lymphatic endothelial cells, and to promote lymphatic invasion and lymph node metastasis through VEGFR-3 signaling, which is critical for the growth of lymphatic vessels (44, 45)
. These findings provided theoretical evidence for the role of VEGF-C and VEGF-D in promoting cancer metastasis (46). ...
CCL25 promotes the migration and invasion of non‑small cell lung cancer cells by regulating VEGF and MMPs in a CCR9‑dependent manner Article Full-text available
Apr 2020
Yuxu Niu Dongfang Tang Liwen Fan Hui Lin
The CC chemokine receptor 9 (CCR9) and its natural secreted ligand CC motif chemokine ligand 25 (CCL25) have been implicated in cancer metastasis. However, their metastatic potential in non-small cell lung cancer (NSCLC) remains unclear. In the present study, immunohistochemistry was used to detect the expression and localization of CCR9, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-1 and MMP-7 in lung cancer tissue and adjacent normal tissue. The association between the expression of CCR9 and clinical variables was also examined. Reverse transcription-quantitative PCR and western blotting were conducted to detect the expression of VEGF-C, VEGF-D, MMP-1 and MMP-7 in lung cancer cell lines (A549 and SK-MES-1). Migration and invasion assays were conducted to examine cell migration and invasion. Survival and mutation analysis were conducted using published datasets. The expressions of CCR9, VEGF, MMP-1 and MMP-7 were upregulated in cancer tissue, compared with adjacent normal tissue (all P<0.05). Patients with lower expression of CCR9 or CCL25 had better overall survival (OS) compared with those with higher CCR9 or CCL25 expression (P<0.05 and P=0.05, respectively). Furthermore, the expressions of VEGF-C, VEGF-D, MMP-1 and MMP-7 were higher in the CCL25-treated cell lines (all P<0.05), but MMP-7 protein expression was not affected by CCL25 treatment in SK-MES-1 cells (P>0.05). Following treatment with CCL25, lung cancer cells demonstrated higher migratory and invasive potential, which could be blocked by the CCR9 antibody (P<0.05). Survival analysis demonstrated that low expression levels of both CCR9 and CCL25 mRNA indicated favorable OS in patients with NSCLC. Altogether, these results suggested that CCL25 enhanced the phenotype associated with migration and invasion in NSCLC by regulating the expression of VEGF-C, VEGF-D, MMP-1 and MMP-7.
View Show abstract
... VEGF-D is known to be a potent mediator involved in lymph and regular angiogenesis, endothelial proliferation as well as vascular and cardiac remodelling, through VEGFR-3 and/or VEGFR-2 binding [24,25]. It is expressed by a variety of tissues, most abundantly in heart, lungs and skeletal muscles
[26]
. VEGFR-3 is expressed in endothelial cells and crucial for primary vascular network maturation and early cardiovascular system development [27]. ...
Elevated plasma tyrosine kinases VEGF-D and HER4 in heart failure patients decrease after heart transplantation in association with improved haemodynamics Article Full-text available
Jan 2020
Salaheldin Ahmed Abdulla Ahmed
Joanna Säleby Göran Rådegran
Receptor tyrosine kinases (RTKs) are implicated in cardiovascular growth and remodelling. We aimed to identify the plasma levels of RTKs and related proteins and their association with haemodynamic alterations in heart failure (HF) and related pulmonary hypertension (PH) following heart transplantation (HT). Using proximity extension assay, 28 RTKs and related proteins were analysed in plasma from 20 healthy controls and 26 HF patients before and 1-year after HT. In end-stage HF, out of 28 RTKs, plasma vascular endothelial growth factor-D (VEGF-D) and human epidermal growth factor-4 (HER4) were elevated compared to controls (p < 0.001), but decreased (p < 0.0001) and normalised after HT. Following HT, plasma changes (Δ) of VEGF-D correlated with Δmean pulmonary artery pressure (rs = 0.65, p = 0.00049), Δpulmonary artery wedge pressure (rs = 0.72, p < 0.0001), Δpulmonary arterial compliance (PAC) (rs = − 0.52, p = 0.0083) and Δpulmonary vascular resistance (PVR) (rs = 0.58, p = 0.0032). ΔHER4 correlated with Δmean right atrial pressure (rs = 0.51, p = 0.012), ΔNT-proBNP (rs = 0.48, p = 0.016) and Δcardiac index (rs = − 0.56, p = 0.0044). In HF patients following HT, normalisation of VEGF-D reflected reversal of passive pulmonary congestion and restored PAC and PVR; whereas the normalisation of HER4 reflected decreased volume overload and improved cardiac function. The precise function of these proteins, their potential clinical use and pathophysiological relation in HF and related PH remain to be elucidated.
View Show abstract
... COX-2, which is closely related to inflammation, plays a significant role in the production of VEGF and ultimately injures the neurons in the retina [25][26][27]. VEGF is the principal mediator involved in retinal angiogenesis under physiological concentrations [28, 29]
, which leads to vascular degeneration when overexpressed [30]. Takahashi et al. [31] and Sin et al. [32] demonstrated the efficacy of COX inhibition in reducing the production of VEGF and neovascularization. ...
Extract of the Blood Circulation-Promoting Recipe-84 Can Protect Rat Retinas by Inhibiting the β-Catenin Signaling Pathway Article Full-text available
Sep 2018 INT J MOL SCI
Qiu-Fang Qin Min Liu Gui-Hua Tian Yu-Sang Li
Extract of the Blood Circulation-Promoting Recipe (EBR-84) from the Chinese Herbal medicine “Blood Circulation Promoting Recipe” could retard retinopathy development. This study investigated whether EBR-84 protects retinas by inhibiting the β-catenin pathway using a rat model of retinopathy and a retinal ganglion cell 5 (RGC-5) cell death model. RGC death was induced by either N-methyl-d-aspartic acid (NMDA) or TWS119 (an activator of the β-catenin pathway). After the corresponding treatment with EBR-84, RGC death and the protein expression levels of β-catenin, cyclooxygenase-2 (COX-2), and vascular endothelial growth factor (VEGF) in rat retinas were examined. β-Catenin accumulated in the retinal ganglion cell layer (GCL) of NMDA-treated rats. EBR-84 (3.9, 7.8, and 15.6 g/kg) significantly attenuated the NMDA-induced RGC loss accompanying the reduction of β-catenin expression. Moreover, the expression levels of COX-2 and VEGF were decreased by EBR-84 in a dose-dependent manner. For the TWS119-treated rats, EBR-84 also ameliorated RGC loss and lowered the expression levels of β-catenin, COX-2, and VEGF. In vitro, EBR-84 increased the viability of NMDA-treated RGC-5 while decreased β-catenin expression. In conclusion, EBR-84 retarded ratretinopathy, and the β-catenin signaling pathway played an important role during this protective process.
View Show abstract
... In experimental settings, VEGF-D promoted angiogenesis and lymphangiogenesis within and at the periphery of solid tumors, as well as enhancing solid tumor growth and metastatic spread to lymph nodes and distant organs, in a range of mouse cancer models including transgenic, gene ablation and xenograft models [1,32,[67][68][69][70] [71]
. In addition to promoting the growth of small lymphatics adjacent to primary tumors, thus facilitating entry of tumor cells into the lymphatic vasculature, VEGF-D also promoted metastasis via dilation of collecting lymphatic vessels, which likely facilitates transport of tumor cells through the lymphatic vasculature [29]. ...
Emerging roles for VEGF-D in human disease
Article Full-text available
Jan 2018
Steven A Stacker Marc G Achen
Blood vessels and lymphatic vessels are located in many tissues and organs throughout the body, and play important roles in a wide variety of prevalent diseases in humans. Vascular endothelial growth factor-D (VEGF-D) is a secreted protein that can promote the remodeling of blood vessels and lymphatics in development and disease. Recent fundamental and translational studies have provided insight into the molecular mechanisms by which VEGF-D exerts its effects in human disease. Hence this protein is now of interest as a therapeutic and/or diagnostic target, or as a potential therapeutic agent, in a diversity of indications in cardiovascular medicine, cancer and the devastating pulmonary condition lymphangioleiomyomatosis. This has led to clinical trial programs to assess the effect of targeting VEGF-D signaling pathways, or delivering VEGF-D, in angina, cancer and ocular indications. This review summarizes our understanding of VEGF-D signaling in human disease, which is largely based on animal disease models and clinicopathological studies, and provides information about the outcomes of recent clinical trials testing agonists or antagonists of VEGF-D signaling.
View Show abstract
... Here, LYVE-1 is suggested to be involved in lymph angiogenesis [17]. VEGF-D is also one of the most potent lymphangiogenic factors [18]
and plays an important role in neuronal synaptic activity, dendritic length, and dendrite arborization [19]. We observed the alteration of VEGF-D expression levels in EAE/MS settings [16]. ...
Influx and Efflux of Immune Cells in the Central Nervous System
Article Full-text available
Jan 2017
M. Fujita Ikuo Tsunoda Seiichi Omura
Fumitaka Sato
View
... VEGF-D is an angiogenic and lymphangiogenic protein [7][8][9][10] that promotes cancer metastasis in animal models [9, [11]
[12][13] and can be expressed in human tumours [14][15][16]. Human VEGF-D activates the endothelial cell surface receptors VEGFR-2 and VEGFR-3 [8]; mouse Vegf-d activates Vegfr-3 but is a poor ligand for Vegfr-2 [17]. ...
VEGF-D promotes pulmonary oedema in hyperoxic acute lung injury
Article Full-text available
Feb 2016 J PATHOL
Teruhiko Sato Sophie Paquet-Fifield
Nicole Cayley Harris Marc G Achen
Leakage of fluid from blood vessels, leading to oedema, is a key feature of many diseases including hyperoxic acute lung injury (HALI) which can occur when patients are ventilated with high concentrations of oxygen (hyperoxia). The molecular mechanisms driving vascular leak and oedema in HALI are poorly understood. VEGF-D is a protein that promotes blood vessel leak and oedema when overexpressed in tissues, but the role of endogenous VEGF-D in pathological oedema was unknown. To address these issues, we exposed Vegfd-deficient mice to hyperoxia. The resulting pulmonary oedema in Vegfd-deficient mice was substantially reduced compared to wild-type as was the protein content of bronchoalveolar lavage fluid, consistent with reduced vascular leak. VEGF-D and its receptor VEGFR-3 were more highly expressed in lungs of hyperoxic, versus normoxic, wild-type mice indicating that components of the VEGF-D signalling pathway are up-regulated in hyperoxia. Importantly, VEGF-D and its receptors were co-localised on blood vessels in clinical samples of human lungs exposed to hyperoxia, hence VEGF-D may act directly on blood vessels to promote fluid leak. Our studies show that VEGF-D promotes oedema in response to hyperoxia in mice and support the hypothesis that VEGF-D signalling promotes vascular leak in human HALI.
View Show abstract
... One important inflammation-induced vascular effect mediated only by IL-1β is the up-regulation of the two major angioand lymphangiogenic mediators, VEGF-C and -D, following NF-κB activation (Ristimaki et al., 1998;Watari et al., 2008). Both events have consistently been implicated in inflammation-induced angiogenesis and lymphangiogenesis (Huggenberger et al., 2011;
Achen and Stacker, 2012;
Kim et al., 2012a). These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http:// www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,c Alexander et al., 2013a,b,c). ...
Interleukin-1 beta Reduces Tonic Contraction of Mesenteric Lymphatic Muscle Cells: Involvement of Cyclooxygenase-2 / Prostaglandin E2 Article Full-text available
May 2015 BRIT J PHARMACOL
Mahmoud Al-Kofahi Felix Becker
Felicity N Gavins Jonathan Alexander
The lymphatic system maintains tissue hemostasis by unidirectional lymph flow which is sustained by tonic and phasic contractions within subunits, 'lymphangions'. We show that the inflammatory cytokine IL-1ß decreases tonic contraction of rat mesenteric lymphatic muscle cells (RMLMC).
We measured IL-1β in colon conditioned media (CM) from acute (AC-CM, dextran sodium sulfate) and chronic (CC-CM, T-cell transfer) colitis induced mice and respective controls (Con-AC/CC-CM). We examined tonic contractility of RMLMC in response to CM, cytokines [h-IL-1β/h-TNF-α (5, 10, 20 ng/ml)], +/- COX inhibitors [TFAP (10(-5) M), diclofenac (0.2x10(-5) M)], prostanoids [PGE2 (10(-5) M)], IL-1-receptor antagonist [Anakinra (5 μg/ml)] or a selective EP4 receptor antagonist [GW627368X (10(-6) M and 10(-7) M)].
Tonic contractility of RMLMC was reduced by AC- and CC-CM compared with Con-AC/CC-CM. IL-1β and TNF-α was not found in Con-AC/CC-CM, but detected in AC- and CC-CM. h-IL-1β dose dependently decreased RMLMC contractility, whereas h-TNF-α showed no effect. Addition of Anakinra blocked h-IL-1β-induced RMLMC relaxation. AC-CM + Anakinra stimulated RMLMC showed restored contractility compared with AC-CM. IL-1β increased COX-2 protein levels and PGE2 production in RMLMC while PGE2 was able to produce relaxation effects similar to h-IL-1β. Conversely, COX-2 and EP4 receptor inhibition reversed the IL-1β relaxation effect.
Our results indicate IL-1β-induced decrease in RMLMC tonic contraction is COX-2 dependent, and mediated by PGE2 . We show a causal relationship between IL-1β and tonic lymphatic contractility in experimental colitis since this cascade is critical for the relaxation effects caused by AC-CM, while pharmacologicaly IL-1β blockade restored tonic contraction.
This article is protected by copyright. All rights reserved.
View Show abstract
... Vegfd, also called c-Fos induced growth factor, usually binds to VEGFR3 or VEGFR2 to regulate lymphangiogenesis and/or angiogenesis. 23
In zebrafish, vegfd is expressed in tail bud and its overexpression can trigger aberrant sprouting of intersegmental arteries , 24 but its role in hematopoiesis has not yet been reported. ...
Ncor2 is required for hematopoietic stem cell emergence by inhibiting Fos signaling in zebrafish Article Full-text available
Jul 2014
Yonglong Wei Dongyuan Ma Ya Gao
Feng Liu
Key Points
Ncor2 is essential for HSC emergence in zebrafish. Ncor2 inhibits Fos-Vegfd signaling through recruitment of histone deacetylase 3 (Hdac3).
View Show abstract
... VEGF-C and VEGF-D have an important role in regulation of angiogenesis and lymphangiogenesis [72,[76][77][78][79][80][81] [82]
by promoting mitogenesis, migration, and survival of the ECs [49,70,83,84]. Initially, premature forms of VEGF-C and [70,81,85]. ...
Roles of Vascular Endothelial Growth Factor in Amyotrophic Lateral Sclerosis
Article Full-text available
Apr 2014 BMRI
Ana Catarina Pronto-Laborinho
Susana Pinto Mamede de carvalho
Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder, involving progressive degeneration of motor neurons in spinal cord, brainstem, and motor cortex. Riluzole is the only drug approved in ALS but it only confers a modest improvement in survival. In spite of a high number of clinical trials no other drug has proved effectiveness. Recent studies support that vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, also plays a key role in the nervous system, including neurogenesis, neuronal survival, neuronal migration, and axon guidance. VEGF has been used in exploratory clinical studies with promising results in ALS and other neurological disorders. Although VEGF is a very promising compound, translating the basic science breakthroughs into clinical practice is the major challenge ahead. VEGF-B, presenting a single safety profile, protects motor neurons from degeneration in ALS animal models and, therefore, it will be particularly interesting to test its effects in ALS patients. In the present paper the authors make a brief description of the molecular properties of VEGF and its receptors and review its different features and therapeutic potential in the nervous system/neurodegenerative disease, particularly in ALS.
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... Conversely, VEGF-D can be downregulated by interleukin (IL)-1β (19), transforming growth factor (TGF)-α, betacellulin, heregulin-β1 (20), Wnt signaling and mobilization of β-catenin from cell membrane (21). Abnormal regulation of VEGF-D has been documented in several human diseases such as lymphangioleiomyomatosis (LAM) (22) and malignancy (reviewed in [23, 24]
). ...
Transforming Growth Factor-β1 Downregulates Vascular Endothelial Growth Factor-D Expression in Human Lung Fibroblasts via JNK Signaling Pathway. Article Full-text available
Feb 2014 MOL MED
Ye Cui Juan C. Osorio Cristobal Risquez Souheil El-Chemaly
Vascular endothelial growth factor (VEGF)-D, a member of the VEGF family, induces both angiogenesis and lymphangiogenesis by activating VEGF receptor-2 (VEGFR-2) and VEGFR-3 on the surface of endothelial cells. Transforming growth factor (TGF)-β1 has been shown to stimulate VEGF-A expression in human lung fibroblast via the Smad3 signaling pathway and to induce VEGF-C in human proximal tubular epithelial cells. However, the effects of TGF-β1 on VEGF-D regulation are unknown. To investigate the regulation of VEGF-D, human lung fibroblasts were studied under pro-fibrotic conditions in vitro and in idiopathic pulmonary fibrosis (IPF) lung tissue. We demonstrate that TGF-β1 downregulates VEGF-D expression in a dose- and time-dependent manner in human lung fibroblasts. This TGF-β1 effect can be abolished by inhibitors of TGF-β type I receptor kinase and JNK, but not by Smad3 knockdown. In addition, VEGF-D knockdown in human lung fibroblasts induces G1/S transition and promotes cell proliferation. Importantly, VEGF-D protein expression is decreased in lung homogenates from IPF patients compared to control lung. In IPF lung sections, fibroblastic foci show very weak VEGF-D immunoreactivity, whereas VEGF-D is abundantly expressed within alveolar interstitial cells in control lung. Taken together, our data identify a novel mechanism for downstream signal transduction induced by TGF-β1 in lung fibroblasts through which they may mediate tissue remodeling in IPF.
View Show abstract
... We include two major VEGF isoforms (VEGF 120 /VEGF 121 and VEGF 164 /VEGF 165 ); however, other isoforms such as VEGF 188 /VEGF 189 (52) and VEGF xxxb (53,54) also influence angiogenesis and may impact anti-VEGF therapies. Recent studies also show that other VEGF ligands and receptors contribute to angiogenesis
(55)
(56)(57), and the model can be expanded in the future to include these molecular species. Additionally, although platelets contain large amounts of VEGF and contribute to angiogenesis (58), we have not included them in the model as the rate and conditions under which they secrete or unload VEGF are unknown. ...
Compartment Model Predicts VEGF Secretion and Investigates the Effects of VEGF Trap in Tumor-Bearing Mice Article Full-text available
Jul 2013
Stacey D Finley Manjima Dhar
Aleksander S Popel
Angiogenesis, the formation of new blood vessels from existing vasculature, is important in tumor growth and metastasis. A key regulator of angiogenesis is vascular endothelial growth factor (VEGF), which has been targeted in numerous anti-angiogenic therapies aimed at inhibiting tumor angiogenesis. Systems biology approaches, including computational modeling, are useful for understanding this complex biological process and can aid in the development of novel and effective therapeutics that target the VEGF family of proteins and receptors. We have developed a computational model of VEGF transport and kinetics in the tumor-bearing mouse, which includes three compartments: normal tissue, blood, and tumor. The model simulates human tumor xenografts and includes human (VEGF121 and VEGF165) and mouse (VEGF120 and VEGF164) isoforms. The model incorporates molecular interactions between these VEGF isoforms and receptors (VEGFR1 and VEGFR2), as well as co-receptors (NRP1 and NRP2). We also include important soluble factors: soluble VEGFR1 (sFlt-1) and α-2-macroglobulin. The model accounts for transport via macromolecular transendothelial permeability, lymphatic flow, and plasma clearance. We have fit the model to available in vivo experimental data on the plasma concentration of free VEGF Trap and VEGF Trap bound to mouse and human VEGF in order to estimate the rates at which parenchymal cells (myocytes and tumor cells) and endothelial cells secrete VEGF. Interestingly, the predicted tumor VEGF secretion rates are significantly lower (0.007 – 0.023 molecules/cell/s, depending on the tumor microenvironment) than most reported in vitro measurements (0.03 – 2.65 molecules/cell/s). The optimized model is used to investigate the interstitial and plasma VEGF concentrations and the effect of the VEGF-neutralizing agent, VEGF Trap (aflibercept). This work complements experimental studies performed in mice and provides a framework with which to examine the effects of anti-VEGF agent
View Show abstract
... The discovery of lymphangiogenic growth factors such as VEGF-C [9] and VEGF-D [10, 11]
, and of lymphatic markers such as LYVE-1 [12] and podoplanin [13], has accelerated the study of tumor lymphangiogenesis, and the role of lymphatic vessels in cancer [14][15][16][17][18][19]. Approaches driving expression of these growth factors in mouse tumor models have demonstrated their potency at promoting both tumor angiogenesis and lymphagiogenesis, and lymph node and distant organ metastasis [14,18,[20][21][22]. ...
Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis Article Full-text available
Apr 2013 CLIN EXP METASTAS
Masataka Matsumoto Sally Roufail Rachael Inder Steven A Stacker
Metastasis to regional lymph nodes is an important and early event in many tumors. Vascular endothelial growth factor-C (VEGF-C), VEGF-D and their receptor VEGFR-3, play a role in tumor spread via the lymphatics, although the timing of their involvement is not understood. In contrast, VEGFR-2, activated by VEGF-A, VEGF-C and VEGF-D, is a mediator of angiogenesis and drives primary tumor growth. We demonstrate the critical role for VEGFR-3, but not VEGFR-2, in the early events of metastasis. In a tumor model exhibiting both VEGF-D-dependent angiogenesis and lymphangiogenesis, an antibody to VEGFR-2 (DC101) was capable of inhibiting angiogenesis (79 % reduction in PECAM + blood vessels) and growth (93 % reduction in tumor volume). However, unlike an anti-VEGFR-3 Mab (mF4-31C1), DC101 was not capable of eliminating either tumor lymphangiogenesis or lymphogenous metastasis (60 % reduction of lymph node metastasis by DC101 vs 95 % by mF4-31C1). Early excision of the primary tumors demonstrated that VEGF-D-mediated tumor spread precedes angiogenesis-induced growth. Small but highly metastatic primary human breast cancers had significantly higher lymphatic vessel density (23.1 vessels/mm(2)) than size-matched (11.7) or larger non-metastatic tumors (12.4) thus supporting the importance of lymphatic vessels, as opposed to angiogenesis-mediated primary tumor growth, for nodal metastasis. These results suggest that lymphangiogenesis via VEGF-D is more critical than angiogenesis for nodal metastasis.
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... Hence, the question arose as to why SK tumors were able to recruit neolymphatics more readily than BW tumors. The implication was that there may be differences in the character, type or density of the pre-existing lymphatics near the primary tumors, or in the ability of these vessels to respond to VEGF-D (for review see [45]
). To investigate the lymphatic vessel subtypes in the normal flank, we differentiated between LYVE-1 ? ...
Tumor location and nature of lymphatic vessels are key determinants of cancer metastasis Article Full-text available
Nov 2012 CLIN EXP METASTAS
Rachael Inder Ramin Shayan Tara Karnezis Steven A Stacker
Tumor metastasis to lymph nodes is a key indicator of patient survival, and is enhanced by the neo-lymphatics induced by tumor-secreted VEGF-C or VEGF-D, acting via VEGFR-3 signalling. These targets constitute important avenues for anti-metastatic treatment. Despite this new understanding, clinical observations linking metastasis with tumor depth or location suggest that lymphangiogenic growth factors are not the sole determinants of metastasis. Here we explored the influence of tumor proximity to lymphatics capable of responding to growth factors on nodal metastasis in a murine VEGF-D over-expression tumor model. We found that primary tumor location profoundly influenced VEGF-D-mediated lymph node metastasis: 89 % of tumors associated with the flank skin metastasised, in contrast with only 19 % of tumors located more deeply on the body wall (p < 0.01). Lymphatics in metastatic tumors arose from small lymphatics, and displayed distinct molecular and morphological profiles compared with those found in normal lymphatics. Smaller lymphatic subtypes were more abundant in skin (2.5-fold, p < 0.01) than in body wall, providing a richer source of lymphatics for VEGF-D(+) skin tumors, a phenomenon also confirmed in human samples. This study shows that the proximity of a VEGF-D(+) primary tumor to small lymphatics is an important determinant of metastasis. These observations may explain why tumor location relative to the lymphatic network is prognostically important for some human cancers.
View Show abstract
... In pre-clinical animal models, VEGF-C and VEGF-D increase tumor-associated lymphangiogenesis and lymph node and distant organ metastasis[48][49][50], and there is a strong correlation between VEGF-C and/or VEGF-D expression and metastatic spread and poor patient outcome in a variety of human cancers[49][50][51][52]. VEGF-C and VEGF-D are secreted homodimeric glycoproteins with a central VEGF homology domain (VHD) containing receptor binding sites for VEGFR-2 and VEGFR-3. The VHD is flanked by N-and C-terminal propeptides which can be proteolytically processed to produce mature forms, consisting of the VHD, with high affinity for VEGFR-2 and VEGFR-3[16,[53][54][55][56][57][58][59] [60]
[61]. The capacity of VEGF-C and VEGF-D to promote tumor angiogenesis and lymphangiogenesis, as well as tumor growth and/or spread, was blocked when the proteolytic cleavage sites were abolished by mutation, demonstrating that processing of these proteins is important for their biological effects in cancer[62][63,64]. ...
The connection between lymphangiogenic signalling and prostaglandin biology: A missing link in the metastatic pathway Article Full-text available
Aug 2012
Tara Karnezis Ramin Shayan
Stephen Fox Steven A Stacker
Substantial evidence supports important independent roles for lymphangiogenic growth factor signaling and prostaglandins in the metastatic spread of cancer. The significance of the lymphangiogenic growth factors, vascular endothelial growth factor (VEGF)-C and VEGF-D, is well established in animal models of metastasis, and a strong correlation exits between an increase in expression of VEGF-C and VEGF-D, and metastatic spread in various solid human cancers. Similarly, key enzymes that control the production of prostaglandins, cyclooxygenases (COX-1 and COX-2, prototypic targets of Non-steroidal anti-inflammatory drugs (NSAIDs)), are frequently over-expressed or de-regulated in the progression of cancer. Recent data have suggested an intersection of lymphangiogenic growth factor signaling and the prostaglandin pathways in the control of metastatic spread via the lymphatic vasculature. Furthermore, this correlates with current clinical data showing that some NSAIDs enhance the survival of cancer patients through reducing metastasis. Here, we discuss the potential biochemical and cellular basis for such anti-cancer effects of NSAIDs through the prostaglandin and VEGF signaling pathways.
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Significance and Molecular Regulation of Lymphangiogenesis in Cancer
Chapter
Oct 2019
Mihaela Skobe Bronislaw Pytowski
Lymphatic dissemination of tumor cells involves invasion into tumor-associated lymphatic vessels, seeding of metastases in the lymph nodes, and, ultimately, delivery into the blood circulation and to distant organs. Tumor lymphangiogenesis is induced by factors released by tumor or stromal cells, such as macrophages, and facilitates metastasis by providing pathways for cancer cell spread. Vascular Endothelial Growth FactorsVEGF-C and VEGF-D are the most specific lymphangiogenic factors that mediate signals for lymphatic endothelial cell growth and migration by binding to and activating VEGFR-3 receptors. Extensive preclinical data in mouse tumor models with specific inhibitors of lymphangiogenic signaling pathways provided the impetus for clinical trials of such agents in patients. In clinical practice, the presence of tumor cells in sentinel lymph nodes is an adverse prognostic factor for patients with solid tumors and constitutes a major consideration in tumor staging. Lymphovascular invasion, lymphatic vessel densities, and the expression of lymphangiogenic factors are also strongly correlated with poor prognosis. Although lymphatic and blood vascular endothelium share many molecular features, they are structurally and functionally distinct and play very different roles in tumors. Here, we discuss the distinct functions and significance of the lymphatic vascular system in cancer.
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Significance and Molecular Regulation of Lymphangiogenesis in Cancer
Chapter
Jan 2019
Mihaela Skobe Bronislaw Pytowski
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Application of Microscale Culture Technologies for Studying Lymphatic Vessel Biology Article
Apr 2019
Chia-Wen Chang Alex J. Seibel Jonathan W. Song
Immense progress in microscale engineering technologies have significantly expanded the capabilities of in vitro cell culture systems for reconstituting physiological microenvironments that are mediated by biomolecular gradients, fluid transport, and mechanical forces. Here, we examine the innovative approaches based on microfabricated vessels for studying lymphatic biology. To help understand the necessary design requirements for microfluidic models, we first summarize lymphatic vessel structure and function. Next, we provide an overview of the molecular and biomechanical mediators of lymphatic vessel function. Then we discuss the past achievements and new opportunities for microfluidic culture models to a broad range of applications pertaining to lymphatic vessel physiology. We emphasize the unique attributes of microfluidic systems that enable the recapitulation of multiple physicochemical cues in vitro for studying lymphatic pathophysiology. Current challenges and future outlooks of microscale technology for studying lymphatics are also discussed. Collectively, we make the assertion that further progress in the development of microscale models will continue to enrich our mechanistic understanding of lymphatic biology and physiology to help realize the promise of the lymphatic vasculature as a therapeutic target for a broad spectrum of diseases.
This article is protected by copyright. All rights reserved.
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The fibrinolysis inhibitor α 2 -antiplasmin restricts lymphatic remodelling and metastasis in a mouse model of cancer Article Full-text available
Jul 2017
You-Fang Zhang Sophie Paquet-Fifield
Sally Roufail Marc G Achen
Remodelling of lymphatic vessels in tumours facilitates metastasis to lymph nodes. The growth factors VEGF-C and VEGF-D are well known inducers of lymphatic remodelling and metastasis in cancer. They are initially produced as full-length proteins requiring proteolytic processing in order to bind VEGF receptors with high affinity and thereby promote lymphatic remodelling. The fibrinolytic protease plasmin promotes processing of VEGF-C and VEGF-D in vitro, but its role in processing them in cancer was unknown. Here we explore plasmin’s role in proteolytically activating VEGF-D in vivo, and promoting lymphatic remodelling and metastasis in cancer, by co-expressing the plasmin inhibitor α2-antiplasmin with VEGF-D in a mouse tumour model. We show that α2-antiplasmin restricts activation of VEGF-D, enlargement of intra-tumoural lymphatics and occurrence of lymph node metastasis. Our findings indicate that the fibrinolytic system influences lymphatic remodelling in tumours which is consistent with previous clinicopathological observations correlating fibrinolytic components with cancer metastasis.
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A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Article
Mar 2016 JoVE
Steven A. Stacker Michael M. Halford Sally Roufail Marc G Achen
The analysis of receptor tyrosine kinases and their interacting ligands involved in vascular biology is often challenging due to the constitutive expression of families of related receptors, a broad range of related ligands and the difficulty of dealing with primary cultures of specialized endothelial cells. Here we describe a bioassay for the detection of ligands to the vascular endothelial growth factor receptor-2 (VEGFR-2), a key transducer of signals that promote angiogenesis and lymphangiogenesis. A cDNA encoding a fusion of the extracellular (ligand-binding) region of VEGFR-2 with the transmembrane and cytoplasmic regions of the erythropoietin receptor (EpoR) is expressed in the factor-dependent cell line Ba/F3. This cell line grows in the presence of interleukin-3 (IL-3) and withdrawal of this factor results in death of the cells within 24 hr. Expression of the VEGFR-2/EpoR receptor fusion provides an alternative mechanism to promote survival and potentially proliferation of stably transfected Ba/F3 cells in the presence of a ligand capable of binding and cross-linking the extracellular portion of the fusion protein (i.e., one that can cross-link the VEGFR-2 extracellular region). The assay can be performed in two ways: a semi-quantitative approach in which small volumes of ligand and cells permit a rapid result in 24 hr, and a quantitative approach involving surrogate markers of a viable cell number. The assay is relatively easy to perform, is highly responsive to known VEGFR-2 ligands and can accommodate extracellular inhibitors of VEGFR-2 signaling such as monoclonal antibodies to the receptor or ligands, and soluble ligand traps.
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Effect of the adenovirus expressing the short interfering RNA targeting VEGFR-3 on inhibiting the proliferation and migration in colorectal cancer cell Article
Mar 2015
Z.-C. Lü Z.-L. Su X. Zhang L. Dong
OBJECTIVE: To investigate the effect of the adenovirus expressing the short interfering RNA targeting vascular endothelial growth factor receptor-3(VEGFR-3) on inhibiting the proliferation and migration in colorectal cancer cell lines LoVo cells. METHODS: The adenovirus expressing the small interfering RNA targeting VEGFR-3 was synthesized and transfected into the LoVo cells. The expressions of VEGFR-3 were measure by qRT-PCR and Western blotting. The proliferation and migration were detected respectively by MTT and Transwell method. RESULTS: The expressions of VEGFR-3 mRNA(0.13±0.19) and protein(0.12±0.14) were significantly decreased by the recombinant adenovirus (F=65.389, P<;0.001; F=68.050, P<;0.001), compared with the naked control group (0.94±0.12; 0.94±0.15) and negative control group(0.97±0.14; 0.97±0.16). The proliferation was significantly decreased by the recombinant adenovires(0.52±0.06) (F=80.135, P<;0.001), compared with the naked control group(0.89±0.03) and negative control group(0.87±0.05).The migration was significantly decreased by the recombinant adenovirus(25.26±1.52)% (F=63.809, P<;0.001), compared with the naked control group(68.24±1.51)% and negative control group(65.18±1.73)%. CONCLUSION: The adenovirus expressing the short interfering RNA targeting VEGFR-3 could inhibit the proliferation and migration in colorectal cancer cells. ©, 2015, The Editorial Board of Chinese Journal of Cancer Prevention and Treatment. All right reserved.
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An Overview of VEGF-Mediated Signal Transduction
Article Full-text available
Aug 2015
Ian M Evans
Vascular endothelial growth factor (VEGF) plays a fundamental role in angiogenesis and endothelial cell biology, and has been the subject of intense study as a result. VEGF acts via a diverse and complex range of signaling pathways, with new targets constantly being discovered. This review attempts to summarize the current state of knowledge regarding VEGF cell signaling in endothelial and cardiovascular biology, with a particular emphasis on its role in angiogenesis.
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SiRNA-mediated silencing of VEGFR-3 reduces proliferation, adhesion and migration of colorectal cancer cells Article
Jan 2014
Zhi-Lan Su
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Vascular Endothelial Growth Factor C Disrupts the Endothelial Lymphatic Barrier to Promote Colorectal Cancer Invasion Article
Mar 2015
Carlotta Tacconi Carmen Correale
Alessandro Gandelli Silvio Danese
Background & aims:
Colorectal cancer (CRC) is highly metastatic. Metastases spread directly into local tissue or invade distant organs via blood and lymphatic vessels, but the role of lymphangiogenesis in CRC progression has not been determined. Lymphangiogenesis is induced via vascular endothelial growth factor C (VEGFC) activation of its receptor, VEGFR3; high levels of VEGFC have been measured in colorectal tumors undergoing lymphangiogenesis and correlated with metastasis. We investigated VEGFC signaling and lymphatic barriers in human tumor tissues and mice with orthotopic colorectal tumors.
Methods:
We performed immunohistochemical, immunoblot, and real-time polymerase chain reaction analyses of colorectal tumor specimens collected from patients; healthy intestinal tissues collected during operations of patients without CRC were used as controls. CT26 CRC cells were injected into the distal posterior rectum of BALB/c-nude mice. Mice were given injections of an antibody against VEGFR3 or an adenovirus encoding human VEGFC before orthotopic tumors and metastases formed. Lymph node, lung, and liver tissues were collected and evaluated by flow cytometry. We measured expression of vascular endothelial cadherin (CDH5) on lymphatic vessels in mice and in human intestinal lymphatic endothelial cells.
Results:
Levels of podoplanin (a marker of lymphatic vessels), VEGFC, and VEGFR3 were increased in colorectal tumor tissues, compared with controls. Mice that expressed VEGFC from the adenoviral vector had increased lymphatic vessel density and more metastases in lymph nodes, lungs, and livers, compared with control mice. Anti-VEGFR3 antibody reduced numbers of lymphatic vessels in colons and prevented metastasis. Expression of VEGFC compromised the lymphatic endothelial barrier in mice and endothelial cells, reducing expression of CDH5, increasing permeability, and increasing trans-endothelial migration by CRC cells. Opposite effects were observed in mice and cells when VEGFR3 was blocked.
Conclusions:
VEGFC signaling via VEGFR3 promotes lymphangiogenesis and metastasis by orthotopic colorectal tumors in mice and reduces lymphatic endothelial barrier integrity. Levels of VEGFC and markers of lymphatic vessels are increased in CRC tissues from patients, compared with healthy intestine. Strategies to block VEGFR3 might be developed to prevent CRC metastasis in patients.
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The Proteolytic Activation of Angiogenic and Lymphangiogenic Growth Factors in Cancer - Its Potential Relevance for Therapeutics and Diagnostics Article
Dec 2013
Nicole Cayley Harris Marc G Achen
The growth of blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) in and around solid tumors is central to the growth and metastatic spread of cancer. The therapeutic targeting of angiogenesis has become an established modality of cancer treatment, however, more comprehensive targeting of angiogenic signaling pathways may be required to enhance the clinical benefits of this approach. Angiogenesis and lymphangiogenesis are driven, or modulated, by a range of secreted glycoproteins including vascular endothelial growth factors, platelet-derived growth factors, and transforming growth factor-β. These key regulatory growth factors are subject to proteolytic activation, involving highly specific cleavage events, which can occur at the cell surface or in the extracellular milieu. These cleavage events are catalysed by a variety of enzymes including proprotein convertases. This proteolysis can regulate the activity of these growth factors by enhancing binding affinities for cell surface receptors and co-receptors, or by altering their interactions with heparan sulfate proteoglycans, thereby modulating bioavailability. The proteolytic processing of these growth factors complicates strategies for targeting them for diagnostic and/or therapeutic purposes in cancer, as processing can generate various forms with distinct biological properties. Hence it has been important to determine which forms are biologically active for promoting angiogenesis and lymphangiogenesis in cancer, so as to indicate clinical relevance. Here we review the regulation of tumor angiogenesis and lymphangiogenesis by proteolytic activation of growth factors, and the potential therapeutic and diagnostic strategies arising from our understanding of this process.
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Vascular remodeling in cancer
Article
Aug 2013
Rae Farnsworth Martin Lackmann Marc G Achen Steven A Stacker
The growth and dissemination of tumors rely on an altered vascular network, which supports their survival and expansion and provides accessibility to the vasculature and a route of transport for metastasizing tumor cells. The remodeling of vascular structures through generation of new vessels (for example, via tumor angiogenesis) is a well studied, even if still quite poorly understood, process in human cancer. Antiangiogenic therapies have provided insight into the contribution of angiogenesis to the biology of human tumors, yet have also revealed the ease with which resistance to antiangiogenic drugs can develop, presumably involving alterations to vascular signaling mechanisms. Furthermore, cellular and/or molecular changes to pre-existing vessels could represent subtle pre-metastatic alterations to the vasculature, which are important for cancer progression. These changes, and associated molecular markers, may forecast the behavior of individual tumors and contribute to the early detection, diagnosis and prognosis of cancer. This review, which primarily focuses on the blood vasculature, explores current knowledge of how tumor vessels can be remodeled, and the cellular and molecular events responsible for this process.Oncogene advance online publication, 5 August 2013; doi:10.1038/onc.2013.304.
View Show abstract
VEGF-C and VEGF-D blockade inhibits inflammatory skin carcinogenesis
Article
May 2013 CANCER RES
Annamari Alitalo Steven Proulx
Sinem Karaman Michael Detmar
Vascular endothelial growth factor-C (VEGF-C) and VEGF-D were identified as lymphangiogenic growth factors and later shown to promote tumor metastasis, but their effects on carcinogenesis are poorly known. We have here studied the effects of VEGF-C and VEGF-D on tumor development in the murine multi-step chemical carcinogenesis model of squamous cell carcinoma (SCC) by using a soluble VEGF-C/D inhibitor. After topical treatment with a tumor initiator and repeated tumor promoter applications, transgenic mice expressing a soluble VEGF-C/D receptor (sVEGFR-3) in the skin developed significantly fewer squamous cell tumors with a delayed onset when compared to wild-type mice or mice expressing sVEGFR-3 lacking the ligand-binding site. Epidermal proliferation was reduced in the carcinogen treated transgenic skin, whereas epidermal keratinocyte proliferation in vitro was not affected by VEGF-C or VEGF-D, indicating indirect effects of sVEGFR-3 expression. Importantly, transgenic mouse skin was less sensitive to tumor promoter induced inflammation, with reduced angiogenesis and blood vessel leakage. Cutaneous leukocytes, especially macrophages, were reduced in transgenic skin without major changes in macrophage polarization or blood monocyte numbers. Several macrophage-associated cytokines were also reduced in transgenic papillomas, although the dermal macrophages themselves did not express VEGFR-3. These findings indicate that VEGF-C/D are involved in shaping the inflammatory tumor microenvironment that regulates early tumor progression. Our results support the use of VEGF-C/D blocking agents not only to inhibit metastatic progression, but also during the early stages of tumor growth.
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The Propeptides of VEGF-D Determine Heparin Binding, Receptor Heterodimerization, and Effects on Tumor Biology Article Full-text available
Feb 2013 J BIOL CHEM
Nicole Cayley Harris Natalia Davydova Sally Roufail Marc G Achen
VEGF-D is an angiogenic and lymphangiogenic glycoprotein that can be proteolytically processed generating various forms differing in subunit composition due to the presence or absence of N- and C-terminal propeptides. These propeptides flank the central VEGF homology domain, that contains the binding sites for VEGF receptors (VEGFRs), but their biological functions were unclear. Characterization of propeptide function will be important to clarify which forms of VEGF-D are biologically active and therefore clinically relevant. Here we use VEGF-D mutants deficient in either propeptide, and in the capacity to process the remaining propeptide, to monitor the functions of these domains. We report for the first time that VEGF-D binds heparin, and that the C-terminal propeptide significantly enhances this interaction. Removal of this propeptide from full-length VEGF-D completely prevents heparin binding. We also show that removal of either the N- or C-terminal propeptide is required for VEGF-D to drive formation of VEGFR-2/VEGFR-3 heterodimers which have recently been shown to positively regulate angiogenic sprouting. The mature form of VEGF-D, lacking both propeptides, can also promote formation of these receptor heterodimers. In a mouse tumor model, removal of only the C-terminal propeptide from full-length VEGF-D was sufficient to enhance angiogenesis and tumor growth. In contrast, removal of both propeptides is required for high rates of lymph node metastasis. The findings reported here show that the propeptides profoundly influence molecular interactions of VEGF-D with VEGF receptors, co-receptors and heparin, and its effects on tumor biology.
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Effect of Daily Aspirin on Long-Term Risk of Death Due to Cancer: Analysis of Individual Patient Data From Randomized Trials Article Full-text available Apr 2011 OBSTET GYNECOL SURV Peter M Rothwell F Gerald R Fowkes Jill Belch T W Meade Treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof in man is lacking. We studied deaths due to cancer during and after randomised trials of daily aspirin versus control done originally for prevention of vascular events. Methods We used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries. Results In eight eligible trials (25 570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0.79, 95% CI 0.68-0.92, p=0.003). On analysis of individual patient data, which were available from seven trials (23 535 patients, 657 cancer deaths), benefit was apparent only after 5 years' follow-up (all cancers, hazard ratio [HR] 0.66, 0.50-0.87; gastrointestinal cancers, 0.46, 0.27-0.77; both p=0.003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0.80, 0.72-0.88, p<0.0001; gastrointestinal cancers, 0.65, 0.54-0.78, p= 7.5 years: all solid cancers, 0.69, 0.54-0.88, p=0.003; gastrointestinal cancers, 0.41, 0.26-0.66, p=0.0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0.66, 0.56-0.77, p<0.0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age the absolute reduction in 20-year risk of cancer death reaching 7.08% (2.42-11.74) at age 65 years and older. Interpretation Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention. View Show abstract Signal Transduction by Vascular Endothelial Growth Factor Receptors Article Full-text available Jul 2012 Sina Gerbach Lena Claesson-Welsh Vascular endothelial growth factors (VEGFs) are master regulators of vascular development and of blood and lymphatic vessel function during health and disease in the adult. It is therefore important to understand the mechanism of action of this family of five mammalian ligands, which act through three receptor tyrosine kinases (RTKs). In addition, coreceptors like neuropilins (NRPs) and integrins associate with the ligand/receptor signaling complex and modulate the output. Therapeutics to block several of the VEGF signaling components have been developed with the aim to halt blood vessel formation, angiogenesis, in diseases that involve tissue growth and inflammation, such as cancer. In this review, we outline the current information on VEGF signal transduction in relation to blood and lymphatic vessel biology. View Show abstract Supplemental Data Blocking Neuropilin-2 Function Inhibits Tumor Cell Metastasis Article Full-text available Nov 2007 CANCER CELL Maresa Caunt Wei-Ching Liang Ian Kasman Judy Mak View Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3 Article Full-text available Sep 2001 EMBO J Taija M|[auml]|kinen Satu Mustjoki Tanja Veikkola Kari Alitalo Vascular endothelial growth factor receptor-3 (VEGFR-3/Flt4) binds two known members of the VEGF ligand family, VEGF-C and VEGF-D, and has a critical function in the remodelling of the primary capillary vasculature of midgestation embryos. Later during development, VEGFR-3 regulates the growth and maintenance of the lymphatic vessels. In the present study, we have isolated and cultured stable lineages of blood vascular and lymphatic endothelial cells from human primary microvascular endothelium by using antibodies against the extracellular domain of VEGFR-3. We show that VEGFR-3 stimulation alone protects the lymphatic endothelial cells from serum deprivation-induced apoptosis and induces their growth and migration. At least some of these signals are transduced via a protein kinase C-dependent activation of the p42/p44 MAPK signalling cascade and via a wortmannin-sensitive induction of Akt phosphorylation. These results define the critical role of VEGF-C/VEGFR-3 signalling in the growth and survival of lymphatic endothelial cells. The culture of isolated lymphatic endothelial cells should now allow further studies of the molecular properties of these cells. View Show abstract Proteolytic processing regulates receptor specificity and activity of VEGF-C Article Full-text available Jul 1997 EMBO J Vladimir Joukov Tarja Sorsa Vijaya Kumar Kari Alitalo The recently identified vascular endothelial growth factor C (VEGF-C) belongs to the platelet-derived growth factor (PDGF)/VEGF family of growth factors and is a ligand for the endothelial-specific receptor tyrosine kinases VEGFR-3 and VEGFR-2. The VEGF homology domain spans only about one-third of the cysteine-rich VEGF-C precursor. Here we have analysed the role of post-translational processing in VEGF-C secretion and function, as well as the structure of the mature VEGF-C. The stepwise proteolytic processing of VEGF-C generated several VEGF-C forms with increased activity towards VEGFR-3, but only the fully processed VEGF-C could activate VEGFR-2. Recombinant 'mature' VEGF-C made in yeast bound VEGFR-3 (KD = 135 pM) and VEGFR-2 (KD = 410 pM) and activated these receptors. Like VEGF, mature VEGF-C increased vascular permeability, as well as the migration and proliferation of endothelial cells. Unlike other members of the PDGF/VEGF family, mature VEGF-C formed mostly non-covalent homodimers. These data implicate proteolytic processing as a regulator of VEGF-C activity, and reveal novel structure–function relationships in the PDGF/VEGF family. View Show abstract The Specificity of Receptor Binding by Vascular Endothelial Growth Factor-D Is Different in Mouse and Man Article Full-text available Jun 2001 Megan E Baldwin Bruno Catimel Edouard Nice Marc G Achen Human vascular endothelial growth factor-D (VEGF-D) binds and activates VEGFR-2 and VEGFR-3, receptors expressed on vascular
and lymphatic endothelial cells. As VEGFR-2 signals for angiogenesis and VEGFR-3 is thought to signal for lymphangiogenesis,
it was proposed that VEGF-D stimulates growth of blood vessels and lymphatic vessels into regions of embryos and tumors. Here
we report the unexpected finding that mouse VEGF-D fails to bind mouse VEGFR-2 but binds and cross-links VEGFR-3 as demonstrated
by biosensor analysis with immobilized receptor domains and bioassays of VEGFR-2 and VEGFR-3 cross-linking. Mutation of amino
acids in mouse VEGF-D to those in the human homologue indicated that residues important for the VEGFR-2 interaction are clustered
at, or are near, the predicted receptor-binding surface. Coordinated expression of VEGF-D and VEGFR-3 in mouse embryos was
detected in the developing skin where theVEGF-D gene was expressed in a layer of cells beneath the developing epidermis and VEGFR-3 was localized on a network of vessels
immediately beneath the VEGF-D-positive cells. This suggests that VEGF-D and VEGFR-3 may play a role in establishing vessels
of the skin by a paracrine mechanism. Our study of receptor specificity suggests that VEGF-D may have different biological
functions in mouse and man. View Show abstract Angiogenic Responses of Vascular Endothelial Growth Factors in Periadventitial Tissue Article Full-text available Oct 2003 Marcin Gruchala Shalini Bhardwaj Himadri Roy Seppo Ylä-Herttuala Recent discovery of new members of the vascular endothelial growth factor (VEGF) family has generated much interest as to which members may be best suited for therapeutic angiogenesis in various tissues. In this study we evaluated angiogenic responses of the different members of the VEGF family in vivo using adenoviral gene transfer. Adenoviruses (1 x 10(9) plaque-forming units [pfu]) encoding for VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-C(deltaNdeltaC) and VEGF-D(deltaNdeltaC) (deltaNdeltaC are proteolytically cleaved forms) were transferred locally to the periadventitial space of the rabbit carotid arteries using a collar technique that allows efficient local transfection of the periadventitial tissue. Expression of the transfected VEGFs was confirmed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Seven days after the gene transfer maximum neovessel formation was observed in VEGF-A-, VEGF-D-, and VEGF-D(deltaNdeltaC)-transfected arteries. VEGF-C(deltaNdeltaC) also showed angiogenic activity whereas VEGF-B was not effective in inducing angiogenesis. Pericytes were detected around the neovessels, which also frequently showed the presence of intraluminal erythrocytes. Infiltration of inflammatory cells in response to VEGF-D and VEGF-D(deltaNdeltaC) was less prominent than that caused by other VEGFs. In line with the absence of lymphatics in the normal carotid arteries no significant evidence of lymphatic vessel formation was seen in response to any of the studied VEGFs in the periadventitial space. The results help to define possibilities for local angiogenic therapy around blood vessels and support the concept that angiogenic effects may be tissue-specific and depend both on the growth factor ligands and the target tissues. It is concluded that VEGF-A, VEGF-D, and VEGF-D(deltaNdeltaC) are the best candidates for therapeutic angiogenesis when delivered around large arteries. View Show abstract Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling Article Full-text available Mar 2012 NATURE Rui Benedito Susana F Rocha Marina Woeste Ralf H Adams Developing tissues and growing tumours produce vascular endothelial growth factors (VEGFs), leading to the activation of the corresponding receptors in endothelial cells. The resultant angiogenic expansion of the local vasculature can promote physiological and pathological growth processes. Previous work has uncovered that the VEGF and Notch pathways are tightly linked. Signalling triggered by VEGF-A (also known as VEGF) has been shown to induce expression of the Notch ligand DLL4 in angiogenic vessels and, most prominently, in the tip of endothelial sprouts. DLL4 activates Notch in adjacent cells, which suppresses the expression of VEGF receptors and thereby restrains endothelial sprouting and proliferation. Here we show, by using inducible loss-of-function genetics in combination with inhibitors in vivo, that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 signalling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGF-A receptor and is considered to be indispensable for these processes. By contrast, VEGFR3, the main receptor for VEGF-C, was strongly modulated by Notch. VEGFR3 kinase-activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signalling activity. Our results establish that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. We propose that successful anti-angiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signalling. View Show abstract Proprotein Convertases in Health and Disease Article Full-text available Dec 2011 NEW ENGL J MED Andrew W Artenstein Steven M Opal View VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling Article Full-text available Sep 2011 NAT CELL BIOL Georgia Zarkada Harri Nurmi Tuomas Tammela Kari Alitalo Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and decreased the level of Notch signalling, indicating that VEGFR-3 possesses passive and active signalling modalities. Furthermore, macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points, and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. FoxC2 is a known regulator of Notch ligand and target gene expression, and Foxc2(+/-);Vegfr3(+/-) compound heterozygosity recapitulated homozygous loss of Vegfr3. These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts. View Show abstract A Role for Bone Morphogenetic Protein-4 in Lymph Node Vascular Remodeling and Primary Tumor Growth Article Full-text available Aug 2011 CANCER RES Rae Farnsworth Tara Karnezis Ramin Shayan Steven A Stacker Lymph node metastasis, an early and prognostically important event in the progression of many human cancers, is associated with expression of VEGF-D. Changes to lymph node vasculature that occur during malignant progression may create a metastatic niche capable of attracting and supporting tumor cells. In this study, we sought to characterize molecules expressed in lymph node endothelium that could represent therapeutic or prognostic targets. Differential mRNA expression profiling of endothelial cells from lymph nodes that drained metastatic or nonmetastatic primary tumors revealed genes associated with tumor progression, in particular bone morphogenetic protein-4 (BMP-4). Metastasis driven by VEGF-D was associated with reduced BMP-4 expression in high endothelial venules, where BMP-4 loss could remodel the typical high-walled phenotype to thin-walled vessels. VEGF-D expression was sufficient to suppress proliferation of the more typical BMP-4-expressing high endothelial venules in favor of remodeled vessels, and mechanistic studies indicated that VEGF receptor-2 contributed to high endothelial venule proliferation and remodeling. BMP-4 could regulate high endothelial venule phenotype and cellular function, thereby determining morphology and proliferation responses. Notably, therapeutic administration of BMP-4 suppressed primary tumor growth, acting both at the level of tumor cells and tumor stromal cells. Together, our results show that VEGF-D-driven metastasis induces vascular remodeling in lymph nodes. Furthermore, they implicate BMP-4 as a negative regulator of this process, suggesting its potential utility as a prognostic marker or antitumor agent. View Show abstract Signal transduction by vascular endothelial growth factor receptors Article Full-text available Jul 2011 BIOCHEM J Sina Gerbach Sonia Tugues Xiujuan Li Lena Claesson-Welsh VEGFs (vascular endothelial growth factors) control vascular development during embryogenesis and the function of blood vessels and lymphatic vessels in the adult. There are five related mammalian ligands, which act through three receptor tyrosine kinases. Signalling is modulated through neuropilins, which act as VEGF co-receptors. Heparan sulfate and integrins are also important modulators of VEGF signalling. Therapeutic agents that interfere with VEGF signalling have been developed with the aim of decreasing angiogenesis in diseases that involve tissue growth and inflammation, such as cancer. The present review will outline the current understanding and consequent biology of VEGF receptor signalling. View Show abstract Deletion of Vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos Article Full-text available Aug 2008 MOL CELL BIOL Paula Haiko Salla Keskitalo Taija Mäkinen Kari Alitalo Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and
are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3)
is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted
to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the
Vegfr3−/− embryos, the Vegfc−/−; Vegfd−/− embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3−/− embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly,
the Vegfr3neo hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression
of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc+/− mice in the K14-VEGF-D; Vegfc+/− compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis.
Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo. View Show abstract Proteolytic processing of vascular endothelial growth factor-D is essential for its capacity to promote the growth and spread of cancer Article Full-text available Apr 2011 FASEB J Nicole Cayley Harris Karri Paavonen Natalia Davydova Marc G Achen VEGF-D is a mitogen for endothelial cells that promotes tumor growth and metastatic spread in animal models, and expression of which correlates with lymph node metastasis in some human cancers. It is secreted from the cell as a full-length form with propeptides flanking a central region containing binding sites for VEGFR-2 and VEGFR-3, receptors that signal for angiogenesis and lymphangiogenesis. The propeptides can be cleaved from VEGF-D, enhancing affinity for VEGFR-2 and VEGFR-3 in vitro; however, the importance of this processing in cancer is unclear. To explore the necessity of processing for the effects of VEGF-D in cancer, we use a mutant full-length form that cannot be processed, and show that, in contrast to full-length VEGF-D that is processed, this mutant does not promote tumor growth and lymph node metastasis in a mouse tumor model. Processing of VEGF-D is required for tumor angiogenesis, lymphangiogenesis, and recruitment of tumor-associated macrophages. These observations may be explained by the requirement of processing for VEGF-D to bind neuropilin receptors and activate VEGFR-2. Our results indicate that proteolytic processing is necessary for VEGF-D to promote the growth and spread of cancer, and suggest that enzymes catalyzing this processing could be targets for antimetastatic therapeutics. View Show abstract Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis Article Full-text available Mar 2011 NEW ENGL J MED Yoshikazu Inoue Joel Moss Bruce C Trapnell Francis X Mccormack Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM.
We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)).
During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups.
In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.). View Show abstract An important role of lymphatic vessel activation in limiting acute inflammation Article Full-text available Mar 2011 BLOOD Shoib Siddiqui Daniela Brander Reto Huggenberger Michael Detmar In contrast to the established role of blood vessel remodeling in inflammation, the biologic function of the lymphatic vasculature in acute inflammation has remained less explored. We studied 2 established models of acute cutaneous inflammation, namely, oxazolone-induced delayed-type hypersensitivity reactions and ultraviolet B irradiation, in keratin 14-vascular endothelial growth factor (VEGF)-C and keratin 14-VEGF-D transgenic mice. These mice have an expanded network of cutaneous lymphatic vessels. Transgenic delivery of the lymphangiogenic factors VEGF-C and the VEGFR-3 specific ligand mouse VEGF-D significantly limited acute skin inflammation in both experimental models, with a strong reduction of dermal edema. Expression of VEGFR-3 by lymphatic endothelium was strongly down-regulated at the mRNA and protein level in acutely inflamed skin, and no VEGFR-3 expression was detectable on inflamed blood vessels and dermal macrophages. There was no major change of the inflammatory cell infiltrate or the composition of the inflammatory cytokine milieu in the inflamed skin of VEGF-C or VEGF-D transgenic mice. However, the increased network of lymphatic vessels in these mice significantly enhanced lymphatic drainage from the ear skin. These results provide evidence that specific lymphatic vessel activation limits acute skin inflammation via promotion of lymph flow from the skin and reduction of edema formation. View Show abstract Structural determinants of vascular endothelial growth factor-D receptor binding and specificity Article Full-text available Feb 2011 BLOOD Andrey Anisimov Veli-Matti Leppánen Michael Jeltsch Kari Alitalo Vascular endothelial growth factors (VEGFs) and their tyrosine kinase receptors (VEGFR-1-3) are central mediators of angiogenesis and lymphangiogenesis. VEGFR-3 ligands VEGF-C and VEGF-D are produced as precursor proteins with long N- and C-terminal propeptides and show enhanced VEGFR-2 and VEGFR-3 binding on proteolytic removal of the propeptides. Two different proteolytic cleavage sites have been reported in the VEGF-D N-terminus. We report here the crystal structure of the human VEGF-D Cys117Ala mutant at 2.9 Å resolution. Comparison of the VEGF-D and VEGF-C structures shows similar extended N-terminal helices, conserved overall folds, and VEGFR-2 interacting residues. Consistent with this, the affinity and the thermodynamic parameters for VEGFR-2 binding are very similar. In comparison with VEGF-C structures, however, the VEGF-D N-terminal helix was extended by 2 more turns because of a better resolution. Both receptor binding and functional assays of N-terminally truncated VEGF-D polypeptides indicated that the residues between the reported proteolytic cleavage sites are important for VEGF-D binding and activation of VEGFR-3, but not of VEGFR-2. Thus, we define here a VEGFR-2-specific form of VEGF-D that is angiogenic but not lymphangiogenic. These results provide important new insights into VEGF-D structure and function. View Show abstract Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation Article Full-text available Sep 2010 J EXP MED Reto Huggenberger Stefan Ullmann Steven Proulx Michael Detmar The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin 14 (K14)-VEGF-A transgenic (Tg) mouse model of chronic cutaneous inflammation. Although treatment with an anti-VEGFR-2 antibody inhibited skin inflammation, epidermal hyperplasia, inflammatory infiltration, and angiogenesis, systemic inhibition of VEGFR-3, surprisingly, increased inflammatory edema formation and inflammatory cell accumulation despite inhibition of lymphangiogenesis. Importantly, chronic Tg delivery of the lymphangiogenic factor VEGF-C to the skin of K14-VEGF-A mice completely inhibited development of chronic skin inflammation, epidermal hyperplasia and abnormal differentiation, and accumulation of CD8 T cells. Similar results were found after Tg delivery of mouse VEGF-D that only activates VEGFR-3 but not VEGFR-2. Moreover, intracutaneous injection of recombinant VEGF-C156S, which only activates VEGFR-3, significantly reduced inflammation. Although lymphatic drainage was inhibited in chronic skin inflammation, it was enhanced by Tg VEGF-C delivery. Together, these results reveal an unanticipated active role of lymphatic vessels in controlling chronic inflammation. Stimulation of functional lymphangiogenesis via VEGFR-3, in addition to antiangiogenic therapy, might therefore serve as a novel strategy to treat chronic inflammatory disorders of the skin and possibly also other organs. View Show abstract Phage-Derived Fully Human Monoclonal Antibody Fragments to Human Vascular Endothelial Growth Factor-C Block Its Interaction with VEGF Receptor-2 and 3 Article Full-text available Aug 2010 PLOS ONE Matthias Rinderknecht Alessandra Villa Kurt Ballmer-Hofer Michael Detmar Vascular endothelial growth factor C (VEGF-C) is a key mediator of lymphangiogenesis, acting via its receptors VEGF-R2 and VEGF-R3. High expression of VEGF-C in tumors correlates with increased lymphatic vessel density, lymphatic vessel invasion, sentinel lymph node metastasis and poor prognosis. Recently, we found that in a chemically induced skin carcinoma model, increased VEGF-C drainage from the tumor enhanced lymphangiogenesis in the sentinel lymph node and facilitated metastatic spread of cancer cells via the lymphatics. Hence, interference with the VEGF-C/VEGF-R3 axis holds promise to block metastatic spread, as recently shown by use of a neutralizing anti-VEGF-R3 antibody and a soluble VEGF-R3 (VEGF-C/D trap). By antibody phage-display, we have developed a human monoclonal antibody fragment (single-chain Fragment variable, scFv) that binds with high specificity and affinity to the fully processed mature form of human VEGF-C. The scFv binds to an epitope on VEGF-C that is important for receptor binding, since binding of the scFv to VEGF-C dose-dependently inhibits the binding of VEGF-C to VEGF-R2 and VEGF-R3 as shown by BIAcore and ELISA analyses. Interestingly, the variable heavy domain (V(H)) of the anti-VEGF-C scFv, which contains a mutation typical for camelid heavy chain-only antibodies, is sufficient for binding VEGF-C. This reduced the size of the potentially VEGF-C-blocking antibody fragment to only 14.6 kDa. Anti-VEGF-C V(H)-based immunoproteins hold promise to block the lymphangiogenic activity of VEGF-C, which would present a significant advance in inhibiting lymphatic-based metastatic spread of certain cancer types. View Show abstract Vascular endothelial growth factor-D over-expressing tumor cells induce differential effects on uterine vasculature in a mouse model of endometrial cancer Article Full-text available Jul 2010 REPROD BIOL ENDOCRIN Jane E Girling Jacqueline F Donoghue Fiona L Lederman Peter Rogers It has been hypothesised that increased VEGF-D expression may be an independent prognostic factor for endometrial cancer progression and lymph node metastasis; however, the mechanism by which VEGF-D may promote disease progression in women with endometrial cancer has not been investigated. Our aim was to describe the distribution of lymphatic vessels in mouse uterus and to examine the effect of VEGF-D over-expression on these vessels in a model of endometrial cancer. We hypothesised that VEGF-D over-expression would stimulate growth of new lymphatic vessels into the endometrium, thereby contributing to cancer progression.
We initially described the distribution of lymphatic vessels (Lyve-1, podoplanin, VEGFR-3) and VEGF-D expression in the mouse uterus during the estrous cycle, early pregnancy and in response to estradiol-17beta and progesterone using immunohistochemistry. We also examined the effects of VEGF-D over-expression on uterine vasculature by inoculating uterine horns in NOD SCID mice with control or VEGF-D-expressing 293EBNA tumor cells.
Lymphatic vessels positive for the lymphatic endothelial cell markers Lyve-1, podoplanin and VEGFR-3 profiles were largely restricted to the connective tissue between the myometrial circular and longitudinal muscle layers; very few lymphatic vessel profiles were observed in the endometrium. VEGF-D immunostaining was present in all uterine compartments (epithelium, stroma, myometrium), although expression was generally low. VEGF-D immunoexpression was slightly but significantly higher in estrus relative to diestrus; and in estradiol-17beta treated mice relative to vehicle or progesterone treated mice. The presence of VEGF-D over-expressing tumor cells did not induce endometrial lymphangiogenesis, although changes were observed in existing vessel profiles. For myometrial lymphatic and endometrial blood vessels, the percentage of profiles containing proliferating endothelial cells, and the cross sectional area of vessel profiles were significantly increased in response to VEGF-D in comparison to control tumor cells. In contrast, no significant changes were noted in myometrial blood vessels. In addition, examples of invading cells or tumor emboli were observed in mice receiving VEGF-D expressing 293EBNA cells.
These results illustrate that VEGF-D over-expression has differential effects on the uterine vasculature. These effects may facilitate VEGF-D's ability to promote endometrial cancer metastasis and disease progression. View Show abstract Serum Vascular Endothelial Growth Factor-D Prospectively Distinguishes Lymphangioleiomyomatosis From Other Diseases Article Full-text available Apr 2010 CHEST Lisa R Young Rhonda Vandyke Peter M Gulleman Francis X Mccormack The majority of women with lymphangioleiomyomatosis (LAM) present with cystic lung disease, and most require lung biopsy for definitive diagnosis. The purpose of this study was to determine the prospective diagnostic usefulness of a serologic test for vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor.
We prospectively measured serum VEGF-D levels by enzyme-linked immunoassay in 48 women presenting with cystic lung disease. Diagnostic test performance was determined from a cohort of 195 women, with tuberous sclerosis complex (TSC), TSC-LAM, sporadic LAM (S-LAM), and other cystic lung diseases in the differential diagnosis, including biopsy-proven or genetically proven pulmonary Langerhans cell histiocytosis, emphysema, Sjögren syndrome, or Birt-Hogg-Dubé syndrome.
Serum VEGF-D levels were significantly greater in S-LAM (median 1,175 [interquartile range (IQR): 780-2,013] pg/mL; n = 56) than in other cystic lung diseases (median 281 [IQR 203-351] pg/mL; n = 44, P < .001). In the cohort evaluated prospectively, 12 of the 15 individuals ultimately diagnosed with LAM by biopsy had VEGF-D levels of > 800 pg/mL, whereas levels were < 600 pg/mL in all 18 subjects later diagnosed with other causes of cystic lung disease. Receiver operating characteristic curves demonstrated that VEGF-D effectively identified LAM, with an area under the curve of 0.961(95% CI, 0.923-0.992). A VEGF-D level of > 600 pg/mL was highly associated with a diagnosis of LAM (specificity 97.6%, likelihood ratio 35.2) and values > 800 pg/mL were diagnostically specific. Serum VEGF-D levels were significantly elevated in women with TSC-LAM (median 3,465 [IQR 1,970-7,195] pg/mL) compared with women with TSC only (median 370 [IQR 291-520] pg/mL), P < .001).
A serum VEGF-D level of > 800 pg/mL in a woman with typical cystic changes on high-resolution CT (HRCT) scan is diagnostically specific for S-LAM and identifies LAM in women with TSC. A negative VEGF-D result does not exclude the diagnosis of LAM. The usefulness of serum VEGF-D testing in men or in women who do not have cystic lung disease on HRCT scan is unknown. View Show abstract Aspirin Intake and Survival After Breast Cancer Article Full-text available Feb 2010 J CLIN ONCOL Michelle D Holmes Wendy Y Chen Lisa Li Susan E Hankinson Animal and in vitro studies suggest that aspirin may inhibit breast cancer metastasis. We studied whether aspirin use among women with breast cancer decreased their risk of death from breast cancer.
This was a prospective observational study based on responses from 4,164 female registered nurses in the Nurses' Health Study who were diagnosed with stages I, II, or III breast cancer between 1976 and 2002 and were observed until death or June 2006, whichever came first. The main outcome was breast cancer mortality risk according to number of days per week of aspirin use (0, 1, 2 to 5, or 6 to 7 days) first assessed at least 12 months after diagnosis and updated.
There were 341 breast cancer deaths. Aspirin use was associated with a decreased risk of breast cancer death. The adjusted relative risks (RRs) for 1, 2 to 5, and 6 to 7 days of aspirin use per week compared with no use were 1.07 (95% CI, 0.70 to 1.63), 0.29 (95% CI, 0.16 to 0.52), and 0.36 (95% CI, 0.24 to 0.54), respectively (test for linear trend, P < .001). This association did not differ appreciably by stage, menopausal status, body mass index, or estrogen receptor status. Results were similar for distant recurrence. The adjusted RRs were 0.91 (95% CI, 0.62 to 1.33), 0.40 (95% CI, 0.24 to 0.65), and 0.57 (95% CI, 0.39 to 0.82; test for trend, P = .03) for 1, 2 to 5, and 6 to 7 days of aspirin use, respectively.
Among women living at least 1 year after a breast cancer diagnosis, aspirin use was associated with a decreased risk of distant recurrence and breast cancer death. View Show abstract Structural determinants of growth factor binding and specificity by VEGF receptor 2 Article Full-text available Feb 2010 P NATL ACAD SCI USA Veli-Matti Leppánen Andrea E Prota Michael Jeltsch Kari Alitalo Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel formation through activation of three receptor tyrosine kinases, VEGFR-1, -2, and -3. The extracellular domain of VEGF receptors consists of seven immunoglobulin homology domains, which, upon ligand binding, promote receptor dimerization. Dimerization initiates transmembrane signaling, which activates the intracellular tyrosine kinase domain of the receptor. VEGF-C stimulates lymphangiogenesis and contributes to pathological angiogenesis via VEGFR-3. However, proteolytically processed VEGF-C also stimulates VEGFR-2, the predominant transducer of signals required for physiological and pathological angiogenesis. Here we present the crystal structure of VEGF-C bound to the VEGFR-2 high-affinity-binding site, which consists of immunoglobulin homology domains D2 and D3. This structure reveals a symmetrical 22 complex, in which left-handed twisted receptor domains wrap around the 2-fold axis of VEGF-C. In the VEGFs, receptor specificity is determined by an N-terminal alpha helix and three peptide loops. Our structure shows that two of these loops in VEGF-C bind to VEGFR-2 subdomains D2 and D3, while one interacts primarily with D3. Additionally, the N-terminal helix of VEGF-C interacts with D2, and the groove separating the two VEGF-C monomers binds to the D2/D3 linker. VEGF-C, unlike VEGF-A, does not bind VEGFR-1. We therefore created VEGFR-1/VEGFR-2 chimeric proteins to further study receptor specificity. This biochemical analysis, together with our structural data, defined VEGFR-2 residues critical for the binding of VEGF-A and VEGF-C. Our results provide significant insights into the structural features that determine the high affinity and specificity of VEGF/VEGFR interactions. View Show abstract Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3 Article Full-text available Jan 2010 J EXP MED Yunling Xu Li Yuan Judy Mak Anil Bagri Vascular sprouting is a key process-driving development of the vascular system. In this study, we show that neuropilin-2 (Nrp2), a transmembrane receptor for the lymphangiogenic vascular endothelial growth factor C (VEGF-C), plays an important role in lymphatic vessel sprouting. Blocking VEGF-C binding to Nrp2 using antibodies specifically inhibits sprouting of developing lymphatic endothelial tip cells in vivo. In vitro analyses show that Nrp2 modulates lymphatic endothelial tip cell extension and prevents tip cell stalling and retraction during vascular sprout formation. Genetic deletion of Nrp2 reproduces the sprouting defects seen after antibody treatment. To investigate whether this defect depends on Nrp2 interaction with VEGF receptor 2 (VEGFR2) and/or 3, we intercrossed heterozygous mice lacking one allele of these receptors. Double-heterozygous nrp2vegfr2 mice develop normally without detectable lymphatic sprouting defects. In contrast, double-heterozygote nrp2vegfr3 mice show a reduction of lymphatic vessel sprouting and decreased lymph vessel branching in adult organs. Thus, interaction between Nrp2 and VEGFR3 mediates proper lymphatic vessel sprouting in response to VEGF-C. View Show abstract Integrin-α9 Is Required for Fibronectin Matrix Assembly during Lymphatic Valve Morphogenesis Article Full-text available Sep 2009 Eleni Bazigou Sherry Xie Chun Chen Taija Mäkinen Dysfunction of lymphatic valves underlies human lymphedema, yet the process of valve morphogenesis is poorly understood. Here, we show that during embryogenesis, lymphatic valve leaflet formation is initiated by upregulation of integrin-alpha9 expression and deposition of its ligand fibronectin-EIIIA (FN-EIIIA) in the extracellular matrix. Endothelial cell-specific deletion of Itga9 (encoding integrin-alpha9) in mouse embryos results in the development of rudimentary valve leaflets characterized by disorganized FN matrix, short cusps, and retrograde lymphatic flow. Similar morphological and functional defects are observed in mice lacking the EIIIA domain of FN. Mechanistically, we demonstrate that in primary human lymphatic endothelial cells, the integrin-alpha9-EIIIA interaction directly regulates FN fibril assembly, which is essential for the formation of the extracellular matrix core of valve leaflets. Our findings reveal an important role for integrin-alpha9 signaling during lymphatic valve morphogenesis and implicate it as a candidate gene for primary lymphedema caused by valve defects. View Show abstract Vascular endothelial growth factor C induces angiogenesis in vivo Article Full-text available Dec 1998 Yihai Cao Philip Linden Jacob Farnebo Kari Alitalo Vascular endothelial growth factor C (VEGF-C) recently has been described to be a relatively specific growth factor for the lymphatic vascular system. Here we report that ectopic application of recombinant VEGF-C also has potent angiogenic effects in vivo. VEGF-C is sufficiently potent to stimulate neovascularization from limbal vessels in the mouse cornea. Similar to VEGF, the angiogenic response of corneas induced by VEGF-C is intensive, with a high density of new capillaries. However, the outgrowth of microvessels stimulated by VEGF-C was significantly longer than that induced by VEGF. In the developing embryo, VEGF-C was able to induce branch sprouts from the established blood vessels. VEGF-C also induced an elongated, spindle-like cell shape change and actin reorganization in both VEGF receptor (VEGFR)-2 and VEGFR-3-overexpressing endothelial cells, but not in VEGFR-1-expressing cells. Further, both VEGFR-2 and VEGFR-3 could mediate proliferative and chemotactic responses in endothelial cells on VEGF-C stimulation. Thus, VEGF-C may regulate physiological angiogenesis and participate in the development and progression of angiogenic diseases in addition to lymphangiogenesis. View Show abstract A novel vascular endothelial growth factor, VEGF‐C, is a ligand for the Flt4 (VEGFR‐3) and KDR (VEGFR‐2) receptor tyrosine kinases. Article Jan 1996 EMBO J Katri Pajusola Arja Kaipainen Vladimir Joukov Kari Alitalo Angiogenesis, the sprouting of new blood vessels from pre-existing ones, and the permeability of blood vessels are regulated by vascular endothelial growth factor (VEGF) via its two known receptors Flt1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2). The Flt4 receptor tyrosine kinase is related to the VEGF receptors, but does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. In this study, we have purified the Flt4 ligand, VEGF-C, and cloned its cDNA from human prostatic carcinoma cells. While VEGF-C is homologous to other members of the VEGF/platelet derived growth factor (PDGF) family, its C-terminal half contains extra cysteine-rich motifs characteristic of a protein component of silk produced by the larval salivary glands of the midge, Chironomus tentans. VEGF-C is proteolytically processed, binds Flt4, which we rename as VEGFR-3 and induces tyrosine autophosphorylation of VEGFR-3 and VEGFR-2. In addition, VEGF-C stimulated the migration of bovine capillary endothelial cells in collagen gel. VEGF-C is thus a novel regulator of endothelia, and its effects may extend beyond the lymphatic system, where Flt4 is expressed. View Show abstract Vascular endothelial growth factors (VEGF) and VEGF receptor expression as predictive biomarkers for benefit with bevacizumab in metastatic colorectal cancer (mCRC): Analysis of the phase III MAX study. Article May 2011 Andrew Weickhardt David Sebastian Williams C. Lee Niall Tebbutt View Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins Article Jan 2003 Marika J Karkkainen Kirsi Sainio Tatiana V Petrova Paula Haiko View Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials Article Jan 2012 M. Wilson J.F. Price Z. Mehta Peter M Rothwell Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control. Methods Our analysis included all five large randomised trials of daily aspirin (>= 75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics. Findings Of 17 285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6.5 years (SD 2.0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0.64, 95% CI 0.48-0.84, p=0.001; adenocarcinoma, HR 0.54, 95% CI 0.38-0.77, p=0.0007; other solid cancers, HR 0.82, 95% CI 0.53-1.28, p=0.39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0.52, 95% CI 0.35-0.75, p=0.0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0.69, 95% CI 0.50-0.95, p=0.02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0.45, 95% CI 0.28-0.72, p=0.0009), particularly in patients with colorectal cancer (HR 0.26, 95% CI 0.11-0.57, p=0.0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0.31, 95% CI 0.15-0.62, p=0.0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0.50, 95% CI 0.34-0.74, p=0.0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0.65, 95% CI 0.53-0.82, p=0.0002), but not the risk of other fatal cancers (HR 1.06, 95% CI 0.84-1.32, p=0.64; difference, p=0.003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses. Interpretation That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis. View Show abstract Towards the biomarker-guided rational use of antiangiogenic agents in the treatment of metastatic colorectal cancer Article Apr 2012 Michael M. Halford Niall Tebbutt Jayesh Desai Steven A Stacker View Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials Article Jan 2012 Year Bk Med J.T. Thigpen View Embryonic expression pattern of the murine figf gene, a growth factor belonging to platelet-derived growth factor/vascular endothelial growth factor family Article Jan 1998 MECH DEVELOP Donal Desmond Dario Compagnone Bill Lane Antonio Simeone View Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta ZEffect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomized trials. Lancet 379: 1591-1601 Article Mar 2012 LANCET Jacqueline F Price Ziyah Mehta P. Rothwell Michelle Wilson Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control.
Our analysis included all five large randomised trials of daily aspirin (≥75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics.
Of 17,285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6·5 years (SD 2·0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0·64, 95% CI 0·48-0·84, p=0·001; adenocarcinoma, HR 0·54, 95% CI 0·38-0·77, p=0·0007; other solid cancers, HR 0·82, 95% CI 0·53-1·28, p=0·39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0·52, 95% CI 0·35-0·75, p=0·0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0·69, 95% CI 0·50-0·95, p=0·02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0·45, 95% CI 0·28-0·72, p=0·0009), particularly in patients with colorectal cancer (HR 0·26, 95% CI 0·11-0·57, p=0·0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0·31, 95% CI 0·15-0·62, p=0·0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0·50, 95% CI 0·34-0·74, p=0·0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0·65, 95% CI 0·53-0·82, p=0·0002), but not the risk of other fatal cancers (HR 1·06, 95% CI 0·84-1·32, p=0·64; difference, p=0·003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses.
That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis.
None. View Show abstract Effects of regular aspirin on long-term cancer incidence and metastasis: A systematic comparison of evidence from observational studies versus randomised trials Article Mar 2012 Annemijn M Algra P. Rothwell Background:
Long-term follow-up of randomised trials of aspirin in prevention of vascular events showed that daily aspirin reduced the incidence of colorectal cancer and several other cancers and reduced metastasis. However, statistical power was inadequate to establish effects on less common cancers and on cancers in women. Observational studies could provide this information if results can be shown to be reliable. We therefore compared effects of aspirin on risk and outcome of cancer in observational studies versus randomised trials.
Methods:
For this systematic review, we searched for case-control and cohort studies published from 1950 to 2011 that reported associations between aspirin use and risk or outcome of cancer. Associations were pooled across studies by meta-analysis and stratified by duration, dose, and frequency of aspirin use and by stage of cancer. We compared associations from observational studies with the effect of aspirin on 20-year risk of cancer death and on metastasis in the recent reports of randomised trials.
Findings:
In case-control studies, regular use of aspirin was associated with reduced risk of colorectal cancer (pooled odds ratio [OR] 0·62, 95% CI 0·58-0·67, p(sig)<0·0001, 17 studies), with little heterogeneity (p(het)=0·13) in effect between studies, and good agreement with the effect of daily aspirin use on 20-year risk of death due to colorectal cancer from the randomised trials (OR 0·58, 95% CI 0·44-0·78, p(sig)=0·0002, p(het)=0·45). Similarly consistent reductions were seen in risks of oesophageal, gastric, biliary, and breast cancer. Overall, estimates of effect of aspirin on individual cancers in case-control studies were highly correlated with those in randomised trials (r(2)=0·71, p=0·0006), with largest effects on risk of gastrointestinal cancers (case-control studies, OR 0·62, 95% CI 0·55-0·70, p<0·0001, 41 studies; randomised trials, OR 0·54, 95% CI 0·42-0·70, p<0·0001). Estimates of effects in cohort studies were similar when analyses were stratified by frequency and duration of aspirin use, were based on updated assessments of use during follow-up, and were appropriately adjusted for baseline characteristics. Although fewer observational studies stratified analyses by the stage of cancer at diagnosis, regular use of aspirin was associated with a reduced proportion of cancers with distant metastasis (OR 0·69, 95% CI 0·57-0·83, p(sig)<0·0001, p(het)=0·89, five studies), but not with any reduction in regional spread (OR 0·98, 95% CI 0·88-1·09, p(sig)=0·71, p(het)=0·88, seven studies), consistent again with the findings in randomised trials.
Interpretation:
Observational studies show that regular use of aspirin reduces the long-term risk of several cancers and the risk of distant metastasis. Results of methodologically rigorous studies are consistent with those obtained from randomised controlled trials, but sensitivity is particularly dependent on appropriately detailed recording and analysis of aspirin use.
Funding:
None. View Show abstract Vascular Endothelial Growth Factor-C Promotes Alloimmunity by Amplifying Antigen-Presenting Cell Maturation and Lymphangiogenesis Article Jan 2012 Amir R. Hajrasouliha Toshinari Funaki Zahra Sadrai Reza Dana To investigate the role of anti-vascular endothelial growth factor (VEGF)-C therapy in corneal graft survival and concomitant suppression of hem- and lymph-angiogenesis.
Corneal suture model in BALB/c mice was placed and immunohistochemical staining was performed with CD31/PECAM-1 and LYVE-1 to quantify the level of blood and lymphatic vessels. Corneal transplants were done in BALB/c mice from C57BL/6 mice donors; grafts were subsequently scored for opacity. VEGF-C was blocked in the angiogenesis and transplant model using neutralizing monoclonal anti-VEGF-C (VGX-100) by intraperitoneal injection. To determine the function of VEGF-C in maturation of antigen-presenting cells (APCs), bone marrow-derived dendritic cells were generated and matured in the presence or absence of VEGF-C.
VEGF-C expression was demonstrated to be markedly upregulated in corneal graft rejection. VEGF-C blockade, through administration of a VEGF-C blocking monoclonal antibody, suppresses corneal angiogenic responses, inhibits trafficking and maturation of APCs, and significantly improves allotransplant survival.
These data suggest VEGF-C as a potentially important target in corneal transplant pharmacotherapy and immunobiology. View Show abstract Preparation of human vascular endothelial growth factor-D for structural and preclinical therapeutic studies Article Mar 2012 PROTEIN EXPRES PURIF Natalia Davydova Victor A Streltsov Sally Roufail Marc G Achen Vascular endothelial growth factor-D (VEGF-D), a secreted angiogenic and lymphangiogenic glycoprotein, enhances tumor growth and metastasis in animal models, and its expression correlates with metastasis and poor patient outcome in some cancers - it is therefore considered a target for novel anti-cancer therapeutics. The definition of the structure of the complex of VEGF-D bound to its receptors would be beneficial for design of inhibitors of VEGF-D signaling aimed at restricting the growth and spread of cancer. In addition, there is interest in using VEGF-D protein for therapeutic angiogenesis and lymphangiogenesis in the settings of cardiovascular diseases and lymphedema, respectively. However, VEGF-D has proven difficult to express and purify in a highly bioactive form due to a tendency to exist as monomers rather than bioactive dimers. Here we describe a protocol for expression and purification of mature human VEGF-D, and a mutant thereof with reduced glycosylation, potentially suitable for preclinical therapeutic and structural studies, respectively. The degree of glycosylation in mature VEGF-D was reduced by eliminating one of the two N-glycosylation sites, and expressing the protein in Lec3.2.8.1 cells which had reduced glycosylation capacity. Mature VEGF-D and the glycosylation mutant were each enriched for the biologically active dimeric form by optimizing the separation of dimer from monomer via gel filtration, followed by conversion of remaining monomers to dimers via treatment with cysteine. The glycosylation mutant of VEGF-D intended for structural studies preserved all the cysteine residues of mature VEGF-D, in contrast to previous structural studies, exhibited comparable receptor binding to mature VEGF-D and might facilitate structural studies of the VEGF-D/VEGFR-3 complex. View Show abstract VEGF-D Promotes Tumor Metastasis by Regulating Prostaglandins Produced by the Collecting Lymphatic Endothelium Article Feb 2012 Tara Karnezis Ramin Shayan Caesar Steven A Stacker Lymphatic metastasis is facilitated by lymphangiogenic growth factors VEGF-C and VEGF-D that are secreted by some primary tumors. We identified regulation of PGDH, the key enzyme in prostaglandin catabolism, in endothelial cells of collecting lymphatics, as a key molecular change during VEGF-D-driven tumor spread. The VEGF-D-dependent regulation of the prostaglandin pathway was supported by the finding that collecting lymphatic vessel dilation and subsequent metastasis were affected by nonsteroidal anti-inflammatory drugs (NSAIDs), known inhibitors of prostaglandin synthesis. Our data suggest a control point for cancer metastasis within the collecting lymphatic endothelium, which links VEGF-D/VEGFR-2/VEGFR-3 and the prostaglandin pathways. Collecting lymphatics therefore play an active and important role in metastasis and may provide a therapeutic target to restrict tumor spread. View Show abstract Molecular Control of Lymphatic Metastasis Article May 2008 Steven A Stacker Marc G Achen The metastatic spread of tumor cells is the most lethal aspect of cancer and often occurs via the lymphatic vasculature. Both experimental tumor models and human clinicopathologic data indicate that growth of lymphatic vessels (lymphangiogenesis) near solid tumors is often associated with lymph node metastasis. Changes in the adhesive properties of lymphatic endothelium near tumors may also facilitate metastatic spread via the lymphatics. Lymphangiogenic growth factors have been identified that promote formation of tumor lymphatics and metastatic spread of tumor cells to lymph nodes. These include the secreted glycoproteins vascular endothelial growth factor-C (VEGF-C) and VEGF-D, which act via their cognate receptor tyrosine kinase VEGF receptor-3 (VEGFR-3) located on lymphatic endothelial cells. Other signaling molecules that have been reported to promote lymphangiogenesis and/or lymphatic metastasis in cancer include VEGF-A, platelet-derived growth factor-BB, and hepatocyte growth factor. However, the quantitative contribution of these proteins to tumor lymphangiogenesis and lymphatic metastasis in different tumor types requires further investigation. In addition, chemokines are thought to play a role in attracting tumor cells and lymphatic vessels to each other. Moreover, it has recently been shown that lymphangiogenic growth factors secreted from a primary tumor can induce lymphangiogenesis in nearby lymph nodes, even before arrival of tumor cells, which may facilitate further metastasis. This article provides an overview of the molecular mechanisms that control lymphatic metastasis and discusses potential therapeutic approaches for inhibiting this process in human cancer. View Show abstract Distinct Roles of Vascular Endothelial Growth Factor-D in Lymphangiogenesis and Metastasis Article Apr 2007 Lucie Kopfstein Tanja Veikkola Valentin Djonov Gerhard Christofori In many human carcinomas, expression of the lymphangiogenic factor vascular endothelial growth factor-D (VEGF-D) correlates with up-regulated lymphangiogenesis and regional lymph node metastasis. Here, we have used the Rip1Tag2 transgenic mouse model of pancreatic beta-cell carcinogenesis to investigate the functional role of VEGF-D in the induction of lymphangiogenesis and tumor progression. Expression of VEGF-D in beta cells of single-transgenic Rip1VEGF-D mice resulted in the formation of peri-insular lymphatic lacunae, often containing leukocyte accumulations and blood hemorrhages. When these mice were crossed to Rip1Tag2 mice, VEGF-D-expressing tumors also exhibited peritumoral lymphangiogenesis with lymphocyte accumulations and hemorrhages, and they frequently developed lymph node and lung metastases. Notably, tumor outgrowth and blood microvessel density were significantly reduced in VEGF-D-expressing tumors. Our results demonstrate that VEGF-D induces lymphangiogenesis, promotes metastasis to lymph nodes and lungs, and yet represses hemangiogenesis and tumor outgrowth. Because a comparable transgenic expression of vascular endothelial growth factor-C (VEGF-C) in Rip1Tag2 has been shown previously to provoke lymphangiogenesis and lymph node metastasis in the absence of any distant metastasis, leukocyte infiltration, or angiogenesis-suppressing effects, these results reveal further functional differences between VEGF-D and VEGF-C. View Show abstract Neuropilin-1 Is Expressed by Endothelial and Tumor Cells as an Isoform-Specific Receptor for Vascular Endothelial Growth Factor Article Mar 1998 CELL Shay Soker Seiji Takashima Hua Quan Miao Michael Klagsbrun Vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, binds to two receptor tyrosine kinases, KDR/Flk-1 and Flt-1. We now describe the purification and the expression cloning from tumor cells of a third VEGF receptor, one that binds VEGF165 but not VEGF121. This isoform-specific VEGF receptor (VEGF165R) is identical to human neuropilin-1, a receptor for the collapsin/semaphorin family that mediates neuronal cell guidance. When coexpressed in cells with KDR, neuropilin-1 enhances the binding of VEGF165 to KDR and VEGF165-mediated chemotaxis. Conversely, inhibition of VEGF165 binding to neuropilin-1 inhibits its binding to KDR and its mitogenic activity for endothelial cells. We propose that neuropilin-1 is a novel VEGF receptor that modulates VEGF binding to KDR and subsequent bioactivity and therefore may regulate VEGF-induced angiogenesis. View Show abstract The VD1 Neutralizing Antibody to Vascular Endothelial Growth Factor-D: Binding Epitope and Relationship to Receptor Binding Article Feb 2011 J MOL BIOL Natalia Davydova Sally Roufail Victor A Streltsov Marc G Achen Vascular endothelial growth factor-D (VEGF-D) is a secreted protein that promotes tumor growth and metastatic spread in animal models of cancer. Expression of VEGF-D in prevalent human cancers was reported to correlate with lymph node metastasis and patient outcome-hence, this protein is a potential target for novel anticancer therapeutics designed to restrict tumor growth and spread. Here, we define the binding site in VEGF-D of a neutralizing antibody, designated VD1, which blocks the interaction of VEGF-D with its cell surface receptors vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 and is being used for the development of therapeutic antibodies. We show by peptide-based mapping and site-directed mutagenesis that the VD1 binding site includes the five residues (147)NEESL(151) and that immunization with a synthetic peptide containing this motif generates antibodies that neutralize VEGF-D. The tertiary structure of VEGF-D indicates that the (147)NEESL(151) epitope is located in the L2 loop of the growth factor, which is important for receptor binding. Mutation of any of these five residues influences receptor binding; for example, mutations to E148, which abolished binding to VD1, impaired the interaction with VEGFR-2 but enhanced binding to VEGFR-3. This structure/function study indicates that the VD1 binding epitope is part of the receptor binding site of VEGF-D, identifies a region of VEGF-D critical for binding of receptors and explains why VD1 does not bind other members of the VEGF family of growth factors. View Show abstract Growth Factor Therapy and Autologous Lymph Node Transfer in Lymphedema Article Feb 2011 CIRCULATION Markku Lähteenvuo Krista Honkonen Tomi Tervala Anne Saaristo Lymphedema after surgery, infection, or radiation therapy is a common and often incurable problem. Application of lymphangiogenic growth factors has been shown to induce lymphangiogenesis and to reduce tissue edema. The therapeutic effect of autologous lymph node transfer combined with adenoviral growth factor expression was evaluated in a newly established porcine model of limb lymphedema.
The lymphatic vasculature was destroyed within a 3-cm radius around an inguinal lymph node. Lymph node grafts and adenovirally (Ad) delivered vascular endothelial growth factor (VEGF)-C (n=5) or VEGF-D (n=9) were used to reconstruct the lymphatic network in the inguinal area; AdLacZ (β-galactosidase; n=5) served as a control. Both growth factors induced robust growth of new lymphatic vessels in the defect area, and postoperative lymphatic drainage was significantly improved in the VEGF-C/D-treated pigs compared with controls. The structure of the transferred lymph nodes was best preserved in the VEGF-C-treated pigs. Interestingly, VEGF-D transiently increased accumulation of seroma fluid in the operated inguinal region postoperatively, whereas VEGF-C did not have this side effect.
These results show that growth factor gene therapy coupled with lymph node transfer can be used to repair damaged lymphatic networks in a large animal model and provide a basis for future clinical trials of the treatment of lymphedema. View Show abstract Rothwell PM, Fowkes FGR, Belch JFF, Ogawa H, Warlow CP, Meade TWEffect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377: 31-41 Article Jan 2011 LANCET F Gerald R Fowkes Jill Belch P. Rothwell T W Meade Treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof in man is lacking. We studied deaths due to cancer during and after randomised trials of daily aspirin versus control done originally for prevention of vascular events.
We used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries.
In eight eligible trials (25 570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0·79, 95% CI 0·68-0·92, p=0·003). On analysis of individual patient data, which were available from seven trials (23 535 patients, 657 cancer deaths), benefit was apparent only after 5 years' follow-up (all cancers, hazard ratio [HR] 0·66, 0·50-0·87; gastrointestinal cancers, 0·46, 0·27-0·77; both p=0·003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0·80, 0·72-0·88, p<0·0001; gastrointestinal cancers, 0·65, 0·54-0·78, p<0·0001), and benefit increased (interaction p=0·01) with scheduled duration of trial treatment (≥7·5 years: all solid cancers, 0·69, 0·54-0·88, p=0·003; gastrointestinal cancers, 0·41, 0·26-0·66, p=0·0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0·66, 0·56-0·77, p<0·0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age-the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42-11·74) at age 65 years and older.
Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention.
None. View Show abstract Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials Article Oct 2010 LANCET P. Rothwell Michelle Wilson Carl-Eric Elwin T W Meade High-dose aspirin (≥500 mg daily) reduces long-term incidence of colorectal cancer, but adverse effects might limit its potential for long-term prevention. The long-term effectiveness of lower doses (75-300 mg daily) is unknown. We assessed the effects of aspirin on incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour.
We followed up four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) and established the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data.
In the four trials of aspirin versus control (mean duration of scheduled treatment 6·0 years), 391 (2·8%) of 14 033 patients had colorectal cancer during a median follow-up of 18·3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0·76, 0·60-0·96, p=0·02; mortality HR 0·65, 0·48-0·88, p=0·005), but not rectal cancer (0·90, 0·63-1·30, p=0·58; 0·80, 0·50-1·28, p=0·35). Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0·45, 0·28-0·74, p=0·001; 0·34, 0·18-0·66, p=0·001), but not the distal colon (1·10, 0·73-1·64, p=0·66; 1·21, 0·66-2·24, p=0·54; for incidence difference p=0·04, for mortality difference p=0·01). However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0·35, 0·20-0·63; 0·24, 0·11-0·52; both p<0·0001) and also reduced risk of rectal cancer (0·58, 0·36-0·92, p=0·02; 0·47, 0·26-0·87, p=0·01). There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1·76% (0·61-2·91; p=0·001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75-300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2·02, 0·70-6·05, p=0·15).
Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy.
None. View Show abstract VEGF-D △N△C mediated angiogenesis in skeletal muscles of diabetic WHHL rabbits Article May 2010 EUR J CLIN INVEST Himadri Roy Shalini Bhardwaj Mohan Babu Seppo Ylä-Herttuala Arterial occlusive disease is often associated with diabetes mellitus and hypercholesterolaemia which may reduce angiogenic potential of several growth factors. Accordingly, the usefulness of therapeutic angiogenesis in the presence of diabetes and hypercholesterolaemia has remained unclear. We evaluated angiogenic effects of the mature form of vascular endothelial growth factor-D (VEGF-D(deltaNdeltaC)) in skeletal muscles in the presence of severe diabetes and hypercholesterolaemia.
Intra muscular injections of adenoviruses encoding human VEGF-D(deltaNdeltaC) (AdVEGF-D(deltaNdeltaC)) were given in the hind limbs of a group of diabetic hypercholesterolaemic rabbits and adenoviruses encoding LacZ (AdLacZ) were used as a control. All animals were killed 6 days after the gene transfer.
Capillary count, capillary area, capillary permeability and perfusion were significantly higher in the AdVEGF-D(deltaNdeltaC) transduced muscles compared with the AdLacZ controls. Expressions of endothelial nitric oxide synthase (eNOS) and VEGF receptor(R)-2 were also significantly increased in the VEGF-D(deltaNdeltaC) transduced muscles, along with an increased expression of angiopoietins (Angs) and neuropilin-2 (NP-2). Furthermore, VEGF-D(deltaNdeltaC) gene transfer to the skeletal muscles increased localized recruitment of cells with endothelial progenitor-like characteristics.
VEGF-D(deltaNdeltaC) gene transfer can induce efficient angiogenesis in the presence of severe diabetes and hypercholesterolaemia by upregulating eNOS and VEGFR-2 expression. VEGF-D(deltaNdeltaC) appears to be a promising agent for inducing therapeutic angiogenesis even in cases with severe diabetes and hypercholesterolaemia. View Show abstract Lymphangioleiomyomatosis: A Disease Involving the Lymphatic System Article Mar 2010 Masatoshi Kurihara Teruhiko Sato Kuniaki Seyama Toshio Kumasaka Background:
Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease in which abnormal smooth muscle-like cells (LAM cells) proliferate in the lungs and along the axial lymphatic systems, including the lymph nodes and thoracic ducts. LAM cells are transformed due to loss-of-function type mutations of either the TSC1 or TSC2 tumor suppressor genes. The pathological features include the proliferation of benign-looking LAM cells and the existence of abundant lymphatic vessels that are associated with clinical conditions such as chyle leakage. LAM cells produce potent lymphangiogenic growth factors (VEGF-C and VEGF-D) and the lymphatic vessel density within LAM lesions correlates with the histologic severity of LAM. The serum VEGF-D level increases in LAM, especially in patients with lymphatic involvement. LAM cell clusters (LCCs), which are postulated pathologically to be generated by lymphangiogenesis-mediated fragmentation and subsequent shedding into the lymphatic circulation, are observed in both chylous effusion and LAM-associated lymphatics within LAM tissue specimens. The identification of LCCs in chylous effusion together with the characteristic clinical manifestations can therefore be an alternative for a lung biopsy if LAM patients are complicated with chylous effusion.
Conclusion:
LAM appears to be a disease involving a dysfunction of the lymphatic system and a fascinating model of tumor dissemination that is exclusively lymphangitic. LAM-associated lymphangiogenesis that mediates the shedding of LCCs seems to play a central role in the dissemination of LAM cells and progression in LAM and it may also be a potential therapeutic target as well as the dysregulated mTOR signaling pathway. View Show abstract Tammela T, Alitalo KLymphangiogenesis: Molecular mechanisms and future promise. Cell 140:460-476 Article Feb 2010 Tuomas Tammela Kari Alitalo The growth of lymphatic vessels (lymphangiogenesis) is actively involved in a number of pathological processes including tissue inflammation and tumor dissemination but is insufficient in patients suffering from lymphedema, a debilitating condition characterized by chronic tissue edema and impaired immunity. The recent explosion of knowledge on the molecular mechanisms governing lymphangiogenesis provides new possibilities to treat these diseases. View Show abstract VEGF-D deficiency in mice does not affect embryonic or postnatal lymphangiogenesis but reduces lymphatic metastasis Article Nov 2009 J PATHOL Marta Koch Daniela Dettori An Van Nuffelen Mieke Dewerchin Vascular endothelial growth factor-D (VEGF-D) is one of the two ligands of the VEGFR-3 receptor on lymphatic endothelial cells. Gene-silencing studies in mice and Xenopus tadpoles recently showed that the role of endogenous VEGF-D in lymphatic development is moderate. By contrast, exogenous VEGF-D is capable of stimulating lymphangiogenesis. Nonetheless, its endogenous role in pathological conditions remains largely unknown. Hence, we reassessed its role in disease, using Vegf-d(null) mice. Vegf-d(null) mice were generated that, under physiological conditions, displayed normal embryonic and postnatal lymphangiogenesis and lymphatic remodelling, efficient lymphatic functioning and normal health. Vegf-d(null) mice also reponded normally in models of skin wound healing and healing of infarcted myocardium, despite enhanced expression of VEGF-D in these models in wild-type mice. In contrast, Vegf-d(null) mice displayed reduced peritumoral lymphangiogenesis and lymph node metastasis in an orthotopic pancreatic tumour model. Together, our data indicate that endogenous VEGF-D in mice is dispensible for lymphangiogenesis during development, in postnatal and adult physiology and in several pathological conditions, but significantly contributes to lymphatic metastasis. View Show abstract Cytologic, Immunocytochemical and Ultrastructural Characterization of Lymphangioleiomyomatosis Cell Clusters in Chylous Effusions of Patients with Lymphangioleiomyomatosis Article Jul 2009 ACTA CYTOL Keiko Mitani Toshio Kumasaka Hiroyuki Takemura Kuniaki Seyama To establish the cytologic and immunocytochemical features of lymphangioleiomyomatosis (LAM) cell clusters (LCCs) and to clarify its diagnostic significance for LAM.
We evaluated 17 samples of LAM-associated chylous effisions from 13 patients with LAM. We performed Papanicolaou staining and immunocytochemistry for muscular antigens, melanoma-related antigens, female 'hormone receptors and markers for lymphatic endothelial cells (LECs).
The cytologic features of LCCs were a well-organized, globular cluster consisting of LAM cells enveloped by LECs. The LAM cells were observed to form a tightly cohesive core and had a moderate nuclear/cytoplasmic ratio. These are distinct characteristics from cancer cell clusters. Immunocytochemical examinations revealed the LAM cells to be positive for muscular antigens, melanoma-related antigens and progesterone receptor, but only 2 of 7 specimens were positive for estrogen receptor. The surface monolayer cells were confirmed to be immunopositive for various LEC markers. Ultrastructural study confirmed that LCCs were covered by LECs.
LCCs were detected in all LAM-associated chylous effusion samples. The cytologic and immunocytochemical examinations of chylous effusions are thus considered to have diagnostic significance for LAM that may therefore enable patients to avoid undergoing such invasive tests as lung biopsies. View Show abstract Show more
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VEGF Receptor Signaling in the Cardiac Lymphatics
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Antti I Nykänen
Since the discovery of angiogenic vascular endothelial growth factor (VEGF)-A in 1983 and lymphangiogenic VEGF-C in 1997, an increasing amount of knowledge has accumulated on the essential roles of VEGF ligands and receptors in physiological and pathological angiogenesis and lymphangiogenesis. We will review the properties of VEGF ligands and receptors concentrating on their lymphatic vessel ... [Show full abstract]
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Blood and lymphatic vessel formation is an indispensable factor for cancer progression and metastasis. Therefore, various strategies designed to block angiogenesis and lymphangiogenesis are being investigated in the hope to arrest and reverse tumor development. Monoclonal antibodies, owing to their unequalled diversity and specificity, might be applied to selectively inhibit the pathways that ... [Show full abstract]
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Expression of lymphatic markers and lymphatic growth factors in psoriasis before and after anti-TNF...
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Aikaterini-Evangelia Moustou Paraskevi Alexandrou Alexander J Stratigos [...]
Christina Antoniou
BACKGROUND
Angiogenesis is an early stage of psoriatic lesion development, but less is known
about lymphagiogenesis and its role in the development of psoriasis.
OBJECTIVE
To examine the expression of specific lymphatic markers and lymphatic growth
factors in untreated psoriatic skin, in the unaffected skin of patients and skin
of healthy volunteers, as well as their alteration after treatment ... [Show full abstract]
with an
anti-TNF agent.
METHODS
Immunohistochemistry for the lymphatic markers D2-40 and LYVE-1, in addition to
the VEGF-C and VEGF-D growth factors, was performed in the skin biopsies of
psoriatic lesions and adjacent non-psoriatic skin of 19 patients before and after
treatment with etanercept, as well as in the skin biopsies of 10 healthy
volunteers.
RESULTS
The expressions of D2-40, VEGF-C and VEGF-D on lymphatic vessels underwent
statistically significant increases in untreated psoriatic skin compared with
non-lesional skin, in contrast to LYVE-1, which did not involve significant
increase in expression in psoriatic skin. VEGF-C expression on lymphatic vessels
diminished after treatment with etanercept. Moreover VEGF-C and VEGF-D staining on
fibroblasts presented with higher expression in lesional skin than in non-lesional
adjacent skin.
CONCLUSION
Remodeling of lymphatic vessels possibly occurs during psoriatic lesion
development, parallel to blood vessel formation. The exact role of this alteration
is not yet clear and more studies are necessary to confirm these results.
View full-text
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The nuclear cycle of the myxomycete Echinostelium minutum: I. Cytophotometric analysis of the nuclear DNA content of the amoebal and plasmodial phases | Request PDF
Request PDF | The nuclear cycle of the myxomycete Echinostelium minutum: I. Cytophotometric analysis of the nuclear DNA content of the amoebal and plasmodial phases | The nuclear DNA content of amoebae and protoplasmodia of five sublines of Echinostelium minutum, isolate D-3, has been determined by... | Find, read and cite all the research you need on ResearchGate
The nuclear cycle of the myxomycete Echinostelium minutum: I. Cytophotometric analysis of the nuclear DNA content of the amoebal and plasmodial phases
March 1978
Experimental Mycology 2(1):32-40
DOI: 10.1016/S0147-5975(78)80039-5
Abstract
The nuclear DNA content of amoebae and protoplasmodia of five sublines of Echinostelium minutum, isolate D-3, has been determined by Feulgen-cytophotometry. Measurements of three of the sublines (D-3 1965, 1966, and 1967) gave a mean DNA value for the amoebal nuclear DNA of 0.57 and a mean DNA value for the protoplasmodial nuclear DNA of 0.58. In the two remaining sublines (D-3 1971 and 1976) the amoebae had a mean nuclear DNA value of 1.87, and the corresponding nuclear DNA value for the protoplasmodia was 1.88. These data suggest that the plasmodia of E. minutum D-3 develop apogamically, with no alternation of distinct haploid and diploid life cycle stages. Furthermore, these data indicate that E. minutum D-3 has undergone a ploidal increase, with the ploidal level of the 1971 and 1976 sublines being approximately three times greater than that of the 1965 subline.
... Within each morphospecies , there can be nonheterothallic and heterothallic isolates, with the heterothallic isolates being divided up into a number of geographically based sibling species that may have overlapping ranges (Betterley and Collins 1983, Clark and Stephenson 1990, Clark and Haskins 1998, Haskins et al 2000, ElHage et al 2000). Nonheterothallic isolates, on the other hand, can complete their life cycle from a single isolated myxameoba and are therefore homothallic (crossing without mating types, not documented in the slime molds), automictic [the products of meiosis I fuse to produce a diploid nucleus, Sherman and Mims (1985) ], or apomictic [no crossing or ploidy changes, Haskins and
Therrien (1978)]
. This variability in reproductive systems and its effect on how genes are transmitted raises questions concerning the relationships of these genetic groups to the often-cosmopolitan morphospecies of current usage. ...
Biosystematics of the Myxomycete Badhamia gracilis
Jan 2003
Jim Clark
Edward Haskins
Steve Stephenson
Sixty-four isolates that conformed to the general morphological description of Badhamia gracilis were isolated from several arid regions in the southwestern USA, northern Mexico, Puerto Rico, and the Canary Islands. These isolates were then subjected to a biosystematic study in which reproductive systems, culture characteristics, and morphology were examined. Five of the isolates were heterothallic and were divided into two separate biological species with multiple allelic mating systems: A1 consisting of three isolates (Arz 4, Arz 5, Arz 6) displaying four alleles, and A2 consisting of two isolates (NM 3, NM 4) also displaying four alleles. The remaining 59 isolates were nonheterothallic and presumably apomictic. All of the isolates had similar culture characteristics in that they had white (rarely with a yellowish tinge) plasmodia that sporulated at a relatively small size. While all of the isolates generally conformed to the standard species description, there were several variations from the norm that occurred at a high frequency. The sporotheca was often laterally flattened instead of globose or ovate, the spores generally averaged 10 μm instead of 14 μm in diam, and the capillitium often appeared physaroid instead of badhamoid. This study indicates that Badhamia gracilis is probably a widespread species complex consisting of a number of local sexual populations and numerous asexual clones that are adapted to arid conditions.
In the Pan 4 isolate of Didymium iridis, a heterothallic line was spontaneously derived from an apomictic one. Genetical and cytological evidence shows that in the heterothallic state amoebal clones are self-sterile and cross-fertile, whereas in the apomictic condition each clone produces plasmodia without benefit of crossing.
A new taxon of slime molds, Semimorula liquescens, is described. Light, TEM, and SEM studies were performed to assess the possible affinity of this taxon with the Myxomycetes and protostelids.
Synaptonemal Complexes in an Apomictic Line of Stemonitis Flavogenita (Myxomycetes, Stemonitales)
Thomas W. Gaither
The Occurrence of Synaptonemal Complexes in the Slime Mold Semimorula Liquescens
Heterothallic mating systems in the Echinostelium minutum complex
Jim Clark
Six cultures of an Echinostelium sp. slime mold were isolated from cholla cactus detritus collected in Death Valley National Park, California. All six isolates are heterothallic and belong to a single, multiple-allelic mating series with four known mating types. Although the spores, stalks and columella of these isolates resembled a reduced E. minutum, the nearly complete absence of a capillitium prevents a definitive identification. A seventh isolate from cholla collected near Tucson, Arizona and identified as a small desert form of E. minutum, also is heterothallic, but does not cross with the first mating series. This is the first detailed description of a heterothallic mating system in the Echinosteliales.
Biosystematics of the myxomycete Badhamia gracilis
Jim Clark
Sixty-four isolates that conformed to the general morphological description of Badhamia gracilis were isolated from several arid regions in the southwestern USA, northern Mexico, Puerto Rico, and the Canary Islands. These isolates were then subjected to a biosystematic study in which reproductive systems, culture characteristics, and morphology were examined. Five of the isolates were heterothallic and were divided into two separate biological species with multiple allelic mating systems: A1 consisting of three isolates (Arz 4, Arz 5, Arz 6) displaying four alleles, and A2 consisting of two isolates (NM 3, NM 4) also displaying four alleles. The remaining 59 isolates were nonheterothallic and presumably apomictic. All of the isolates had similar culture characteristics in that they had white (rarely with a yellowish tinge) plasmodia that sporulated at a relatively small size. While all of the isolates generally conformed to the standard species description, there were several variations from the norm that occurred at a high frequency. The sporotheca was often laterally flattened instead of globose or ovate, the spores generally averaged 10 μm instead of 14 μm in diam, and the capillitium often appeared physaroid instead of badhamoid. This study indicates that Badhamia gracilis is probably a widespread species complex consisting of a number of local sexual populations and numerous asexual clones that are adapted to arid conditions.
Mycosphere Essays 3. Myxomycete spore and amoeboflagellate biology: A review
The spore and amoeboflagellate stages of the heterothallic myxomycete life cycle are generally a uninucleate haploid alternative to the multinucleate diploid plasmodial stage. The spore is produced in a sporangium which develops from the plasmodium, and is a dispersal and resistant stage which has ornamentations that can be used in taxonomy. These small spores have thick pigmented walls and are generally wind dispersed and require water and other biological and physical conditions in order to germinate; this dispersal can occur over long distances and the germination conditions apparently vary between and within a species. The amoeboflagellate stage has three alternative phases: myxamoeba, swarm cell and cyst. The myxamoeba is a typical pleomorphic amoeboid cell that is the major phase, since it is the vegetative phase that ingests bacteria and yeasts, and divides mitotically to form a clonal population of cells. The myxamoeba of heterothallic strains can also, after reaching a certain cell density, become sexually competent and fuse to produce the plasmodial stage. The swarm cell phase develops from the myxamoebal stage when free water is present; it also feeds on bacteria but does not divide unless it reconverts to the myxamoebal phase. The cyst phase develops from the myxamoebal stage, when growth conditions become adverse, by the condensing of the cell and the formation of a resistant wall.
Special Cytology
The second edition of the Fundamentals has appeared (BURNETT, 1976). Symbiotic fungi are described by COOKE (1977) and sexual interactions by VAN DEN ENDE (1976). Electron micrographs of outstanding quality are collected in atlases of fungal ultrastructure (BECKETT et al., 1974) and of biodegradation (OLAH et al., 1978). Behavioral genetics of Phycomyces is reviewed by CERDA-OLMEDO (1977) and the papers of a symposium on nuclear division in fungi are edited by HEATH (1978a)
Morphology, Taxonomy, and Phylogeny
The nuclear reproductive cycle in the myxomycetes: a review
Our understanding of the taxonomy, ecology and population biology of myxomycetes has been enhanced by investigations of the nuclear reproductive cycle of taxa in this group. These studies have involved light microscopy, electron microscopy, DNA cytophotometric reports and genetic investigations. Heterothallism with its associated life cycle events of syngamy and meiosis is extensively reviewed as revealed by light microscopy, genetics and DNA spectrophotometric analysis of nuclear ploidy levels. Non-heterothallism, i.e., homothallism and apogamy, specifically automixis and its genetical and evolutionary significance is discussed. Nuclear division, chromosomal number and polyploidy in the myxomycetes is also detailed.
Heterothallic Mating Systems in the Echinostelium minutum Complex
Six cultures of an Echinostelium sp. slime mold were isolated from cholla cactus detritus collected in Death Valley National Park, California. All six isolates are heterothallic and belong to a single, multiple-allelic mating series with four known mating types. Although the spores, stalks and columella of these isolates resembled a reduced E. minutum, the nearly complete absence of a capillitium prevents a definitive identification. A seventh isolate from cholla collected near Tucson, Arizona and identified as a small desert form of E. minutum, also is heterothallic, but does not cross with the first mating series. This is the first detailed description of a heterothallic mating system in the Echinosteliales.
A study on the amoebo-flagellate transformation in the slime mold Echinostelium minutum de Bary
The structure and behavior of the non-flagellate and flagellate phases of the slime mold Echinostelium minutum de Bary are here described from living cultures examined with phasecontrast microscopy. The ultrastructure of the myxamoebal and swarm cell phases was studied in sectioned material fixed sequentially with glutaraldehyde-acrolein and OsO4. The nearly spherical myxamoeba has two pairs of juxtanuclear centrioles with associated microtubular arrays. During the amoebo-flagellate transformation each pair of centrioles assumes an anterior position in the cell and becomes arranged at right angles to one another within a cone of microtubules. This microtubular cytoskeleton extending under the plasmalemma establishes the twisted, narrowly ovoid form of the swarm cell. Each centriole functions potentially as a basal body. When transformed in phosphate buffer pH 6.8 at 12 °C and a cell concentration of 5×105/ml, the myxamoebae develop 1 to 8 flagella. The average number of flagella per swarm cell is 2.7. After approximately 2 hours the swarm cells begin to revert to myxamoebae by resorption of their flagella. The phylogenetic implications of these light and ultrastructural observations are discussed with regard to possible evolutionary relationships between the Protostelia and Myxomycetes.
Microspectrophotometric nuclear cycle analyses of Armillaria mellea
Absorption microspectrophotometry and fluorescence microspectrophotometry have been compared for their relative abilities to measure Feulgen-stained DNA in post fusion basidial nuclei of the basidiomycete Armillaria mellea. The variance of the fluorescence method is significantly lower than that of the absorption method (P < 0.001), and it is concluded that fluorescence is superior for analysis of small nuclei where data interpretation relies heavily on measuring levels of variability about the mean. F-DNA (Feulgen-stained nuclear DNA) was measured by fluorescence microspectrophotometry in four stages of the nuclear cycle of A. mellea. The nuclei of spores were haploid and unreplicated [mean F-DNA = 53.8, SE = 1.9 arbitrary units (a.u.)], nuclei of unmated, monosporous hyphae were haploid and replicated , SE = 1.6 a.u.), nuclei of prefusion basidial nuclei were haploid and replicated (, SE = 2.0 a.u.), and the nuclei of postfusion basidia were diploid and replicated (, SE = 1.7 a.u.). The basidial data indicated that DNA synthesis occurred during the nuclear cycle prior to fusion of basidial nuclei. There was no evidence of polyploidy in any of the nuclear cycle stages.
Meiosis in protists: Recent advances and persisting problems
This review summarizes the results obtained on meiosis in protists in the last 14 years. Special attention is drawn to the discovery of sexual phenomena in protozoan groups which were earlier considered asexual and to the rather widespread occurrence among the protists of heterophasic life cycles (with “intermediate” meiosis). Synaptonemal complexes are considered markers of early parallel chromosome pairing which is typical of two-divisional meiosis. Two-divisional meiosis (though sometimes achiasmatic) seems to be the general rule among protists, including the Apicomplexa and the dinoflagellates. One-divisional meiosis seems to be rather a rarity having independent and secondary origin (in some flagellates from the gut of Cryptocercus). These cases need reinvestigation with modern methods.
The synaptonemal complexes of Achlya recurva (Oomycetes): karyotype analysis and three-dimensional reconstruction of pachytene nuclei in antheridia and oogonia
Fifteen synaptonemal complexes, as determined by three-dimensional reconstruction of serial, ultrathin sections, were present within both antheridial and oogonial zygotene and pachytene nuclei of the oomyceteous fungus Achlya recurva, thus n = 15. The present study represents the first complete reconstruction of synaptonemal complexes in the genus Achlya. The occurrence of both zygonema and pachynema was simultaneous in antheridia and oogonia. Pachytene nuclei of antheridia and oogonia are small, 13 μm3 in volume, and the average length of the synaptonemal complexes ranged from 1.9 to 4.4 μm. Lateral elements at zygotene ranged from 1.2 to 4.7 μm. Both ends of each synaptonemal complex were attached randomly to the nuclear envelope, so a bouquet formation was not observed at pachytene. In A. recurva, the dimensions of the synaptonemal complex were as follows: overall width = 270 nm; the lateral elements = 75 nm each in width and the central region = 120 nm. There was no central element and associated transverse filaments, which may be associated with development of alternative reproductive strategies other than amphimixis, as in nematodes. Of the 15 synaptonemal complexes present, only the one carrying the nucleolus organizer region could be clearly identified from one nucleus to the next. The nucleolar organizer region was on the average 0.75 μm from the telomere in both zygotene and pachytene nuclei. There were an average of three recombination nodules in each nucleus. Synaptonemal complexes have been reported in over 80 different species of fungi and related protista. Karyotypic evolution in the oomycetes and fungi may be the result of poly-ploidization, followed by cytogenetic diversification involving aneuploidy and differing degrees of polyploidy. Such a sequence of events could explain the apparent polyphyletic formation of this group. Key words: karyotype, Oomycetes, pachytene, synaptonemal complexes, three-dimensional reconstruction.
The nuclear cycle of the myxomyceteEchinostelium minutum: II. Cytophotometric analysis of the nuclear DNA content of the sporangial phase
Nuclei of uncleaved sporangia ofEchinostelium minutum isolate D-3 1971 have a mean Feulgen-DNA content of 1.84. This value does not differ significantly from that recorded for the nuclei of the amoebal and plasmodial phases. No nuclei were found with a DNA content twice that of the nuclei in the amoebae, plasmodia, or uncleaved sporangia. This observation appears to rule out the possibility of zygotic meiosis. A single endosporic nuclear division occurs during the maturation which follows spore cleavage. The mean DNA content of the metaphases measured was 1.99. No metaphases were observed with a DNA content that would be indicative of a second division of meiosis. Also, no 4:2:1 reduction in DNA content was observed. These data confirm our previous hypothesis that this isolate ofE. minutum normally lacks a sexual phase. The single nuclear division in the maturing spore is followed by one of the division products becoming euchromatic and undergoing a single round of DNA replication, while the other division product becomes very pycnotic, eventually degenerating. The mean nuclear DNA values for the euchromatic and pycnotic nuclei are 1.84 and 0.88, respectively. Mature spores normally become uninucleate and have a nuclear DNA content which is equivalent to that of the amoebal and plasmodial phases.
Changes in DNA content of nuclei in apical and intercalary compartments of Polyporus Arcularius during hyphal growth
Cytophotometric analysis of the DNA content of nuclei of P. arcularius after Feulgen staining showed that some nuclei fail to divide during the duplication cycle of apical compartments. DNA synthesis is retarded in some apical nuclei, and consequently mitosis of these nuclei is also delayed. These nuclei have a 2C DNA value and divide during the next cycle of mitosis. Nuclei at the base of the apical compartment do not divide although they also have the 2C DNA value. These nuclei are eventually cut off from the apical compartment by septation, and remain non-dividing in the newly formed intercalary cells. They subsequently divide when the intercalary compartments produce aerial branches.
Reproductive systems in the myxomycetes: a review
| https://www.researchgate.net/publication/229203209_The_nuclear_cycle_of_the_myxomycete_Echinostelium_minutum_I_Cytophotometric_analysis_of_the_nuclear_DNA_content_of_the_amoebal_and_plasmodial_phases |
McDONALD v. UNITED STATES | 507 F.2d 1271 (1974) | 2d127111524 | Leagle.com
ON PLAINTIFF S MOTION FOR PARTIAL SUMMARY JUDGMENT AND DEFENDANT S CROSS MOTION FOR SUMMARY JUDGMENT SKELTON Judge Plaintiff while...2d127111524
McDONALD v. UNITED STATES
No. 396-73.
View Case
Cited Cases
Citing Case
507 F.2d 1271 (1974)
Ronald L. McDONALD
v.
The UNITED STATES.
United States Court of Claims. https://leagle.com/images/logo.png
December 18, 1974.
December 18, 1974.
Attorney(s) appearing for the Case
J. Francis Pohlhaus, Washington, D.C., Atty. of record, for plaintiff; Nathaniel R. Jones, New York City, of counsel.
Alan L. Ferber, Washington, D.C., with whom was Asst. Atty. Gen., Carla A. Hills, New York City, for defendant.
Before LARAMORE, Senior Judge, and SKELTON and KUNZIG, Judges.
United States Court of Claims.
ON PLAINTIFF'S MOTION FOR PARTIAL SUMMARY JUDGMENT AND DEFENDANT'S CROSS MOTION FOR SUMMARY JUDGMENT
SKELTON, Judge:
Plaintiff, while an enlisted man in the United States Marine Corps, was charged and convicted of four counts of assault with intent to commit murder in violation of Article 134, Uniform Code of Military Justice, 10 U.S.C. § 934 (1970). On April 17, 1970, he was sentenced by a general court-martial to a dishonorable discharge, confinement for 80 years at hard labor, and total forfeiture of pay. Subsequent appeals were taken to the convening authority, the Navy Court of Military Review and the United States Court of Military Appeals. At each stage the verdict of the general court-martial was upheld, while at the same time the sentence was reduced. After his final military appeal, the plaintiff's sentence was reduced to 10 years of hard labor, plus discharge and forfeiture of pay. The plaintiff, having served part of his sentence, was granted a parole effective August 24, 1973, under the terms of which his liberty was to be severely reduced until February 5, 1979.
The plaintiff, claiming constitutional defects in his court-martial, brings suit in this court for back pay resulting from the forfeiture provision of his sentence, damages for lost veterans' educational benefits, and an order granting him an honorable discharge. Plaintiff raises three counts in his petition for relief: (1) the inclusion in the record submitted to the authorities reviewing the court-martial of an investigation report made pursuant to Article 32, Uniform Code of Military Justice, 10 U.S.C. § 832 (1970) violated his sixth amendment right of confrontation as well as due process; (2) constitutional due process was violated when the Uniform Code of Military Justice assigns multiple roles to the convening authority; and (3) the statute under which the plaintiff was convicted, 10 U.S.C. § 934, was constitutionally vague and overbroad. Plaintiff moved for and received a suspension of proceedings on the second and third counts in order to await a ruling by the Supreme Court on several pending cases. This case is before us now on plaintiff's motion for summary judgment and defendant's cross motion for summary judgment on count one which deals with the contents of the record made available to the convening authority and the Naval Court of Military Review.
Under Article 32, U.C.M.J., 10 U.S.C. § 832 (1970), it is required that before a charge or specification is referred to a court-martial, a full investigation must be conducted as to the circumstances and truth of the matter set forth in the charge. This article provides:
§ 832. Art. 32. Investigation
(a) No charge or specification may be referred to a general court-martial for trial until a thorough and impartial investigation of all the matters set forth therein has been made. This investigation shall include inquiry as to the truth of the matter set forth in the charges, consideration of the form of charges, and a recommendation as to the disposition which should be made of the case in the interest of justice and discipline.
The plaintiff argues here that the Article 32 investigatory report prepared on the events surrounding this case, was included in the record presented to the convening authority and Military Court of Review and used by them in reviewing the facts and law behind his conviction. In addition to several other allegedly objectionable items, this particular Article 32 report included a statement made by Pfc. Damon L. Johnson as to his suspicions of plaintiff's guilt and placing plaintiff near the scene of the crime. Plaintiff asserts that because Johnson did not testify at the court-martial and thereby subject himself to cross-examination, the consideration of his statement by the convening authority and the Court of Military Review violated both fifth amendment due process and the sixth amendment right of confrontation. In addition, he alleges that consideration of facts such as these, which were not introduced at the court-martial, contravenes federal rules and statutes governing the conduct of such court-martials and that a violation of governmental procedure of this alleged magnitude constitutes a denial of fifth amendment rights.
We note at the outset that under Article 36, U.C.M.J., 10 U.S.C. § 836 (1970), the President is authorized to prescribe rules of procedures for "courts-martial, courts of inquiry, military commissions, and other military tribunals * * *." Pursuant to this authority, the Manual for Courts Martial (MCM) was issued. Under the regulation as thus promulgated by the President, MCM, paragraph 82b(1) and (5), the Article 32 investigation report is required to be appended to the complete set of records submitted to the convening authority and the Court of Military Review. This regulation provides:
b. Contents. (1) General. The record of the proceedings in each case will be separate and complete in itself and independent of any other document. The record will show all the essential jurisdictional facts. It will set forth a verbatim transcript, except as provided below, of all proceedings had in open sessions of the court, all sessions held by the military judge, and hearing held out of the presence of the members. See 74f(1) and Article 39.
* * * * * *
(5) Appendages. Accompanying the original record — securely bound together — will be the original charge sheet and, if not used as exhibits or properly disposed of otherwise, the other papers which accompanied the charges when referred for trial, including the report of investigation under Article 32 and, if the trial was a rehearing or new or other trial of the case, the record of the former hearing or hearings. [Emphasis supplied.]
In deciding whether or not the inclusion of the particular Article 32 report in the record violated any substantive rights as alleged by the plaintiff, the use of the report permitted by the regulations must be considered.
The Uniform Code of Military Justice, 10 U.S.C. §§ 801-940 (1970) requires that a conviction made at a court-martial be reviewed first by the convening authority and then by the Court of Military Review, 10 U.S.C. §§ 860, 866 (1970). It further specifies that, unlike civilian appellate courts, the scope of review may include both the findings of fact and the conclusions of law. As a result, the review authorities are permitted to exercise their own discretion as to the weight that may be given to evidence obtained at the trial, credibility of witnesses, and other issues of fact normally reserved in civilian courts to the initial trier of facts. This discretion to review the factual basis of a conviction is limited, however, by MCM, paragraph 86b(1)(c) to competent evidence established at trial as follows:
b. Matters to be considered on review. (1) When proceedings resulted in findings of guilty. Before he may approve a finding of an offense or the sentence adjudged therefor, the convening authority must determine:
* * * * * *
(c) That the competent evidence of record (87a(3); ch. XXVII) established beyond a reasonable doubt each element found guilty (ch. XXVIII); [Emphasis supplied.]
* * * * * *
The limitation on the scope of review to "competent evidence of record" would appear to exclude hearsay from consideration by the convening authority reviewing a court-martial conviction as to the guilt or innocence of a defendant. Since the Article 32 report is clearly hearsay, containing as it does statements not subjected to cross-examination, under MCM, paragraph 86b(1)(c), it could not be the basis of any decision on guilt or innocence by the convening authority. Thus, although the MCM requires that the Article 32 report be appended to the record, it forbids the reviewing authorities from considering its contents, except for mitigating purposes as stated below, where such contents do not represent competent evidence of record.
Although regulation MCM, paragraph 86b(1)(c) appears to govern only the convening authority and not the Court of Military Review, the Court of Military Appeals has ruled in United States v. Duffy, 3 U.S.C.M.A. 20, 11 C.M.R. 20 (1953) that reviewing authorities, in affirming or reversing a conviction, cannot use evidence that was outside of the trial record. This case, based not on regulation but on the earlier version of Article 64 and 66, U.C.M.J., 10 U.S.C. §§ 864 and 866 (1970), would clearly limit the scope of review open to the Court of Military Review in the same fashion that MCM, paragraph 86b(1)(c) limits the convening authority and prohibits the Article 32 report from being used in any review of the guilt or innocence of the present plaintiff. See also,United States v. Lanford, 6 U.S.C. M.A. 371, 20 C.M.R. 87 (1955).
State and federal courts have long held that a judge sitting in a non-jury case can hear both admissible and inadmissible evidence without reversible error taking place. In such a case, the judge will merely exclude from his consideration the inadmissible evidence and base his decision solely on the evidence that is competent and probative. Chief Judge Marshall in an early Supreme Court case reaffirmed this principle upon which all non-jury cases are based:
[A]s the cause was by consent not tried by a jury, the exception to the admission of evidence was not properly the subject of a bill of exceptions. But if the District Court improperly admitted the evidence, the only effect would be, that this Court would reject that evidence, and proceed to decide the cause, as if it were not in the record. It would not, however, of itself, constitute any ground for a reversal of the judgment. * * * [Field v. United States, 34 U.S. (9 Pet.) 182, 202, 9 L.Ed. 94 (1834).]
See alsoWeems v. George, 54 U.S. (13 How.) 190, 14 L.Ed. 108 (1851). The Court of Military Review, comprised of panels of military judges, all of whom are members of the bar of a federal court or of the highest court of their state as required by 10 U.S.C. § 866(a), is well qualified to exclude the contents of the Article 32 report from its review of a defendant's guilt or innocence as mandated by the regulation. Just as no error or constitutional defect occurs when a judge sitting without jury hears proffered evidence ruled by him to be inadmissible, so, too, no error or constitutional defect occurs when the Court of Military Review sees an Article 32 report but as required by regulation, does not base its decision upon it.
This rule was observed in United States v. Swenson,
165 F.2d 756
(2d Cir. 1948) where evidence not available at trial was placed in the trial record forwarded to the staff judge advocate reviewing a conviction. The judge advocate noted in his affirmance of the conviction that he did not consider the added evidence presented to him. On appeal through a habeas corpus proceeding,
[507 F.2d 1275]
the plaintiff argued that regardless of his intention it would be humanly impossible for the reviewing authority to blot from memory the contents of the new evidence. Judge Swan rejected this argument saying:
[W]e do not think the rule applicable to courts-martial is different in this respect from the rule in civilian courts. Frequently the civilian judge in deciding facts must pass on the competence of evidence, determine to exclude it, and then decide the case as though he had never learned of the excluded evidence. Even in jury cases, it is at times assumed that a jury may disabuse their minds of facts which have been brought to their attention; * *. [Id. at 757.]
Although in Swenson,it is not clear whether the judge actually saw the evidence in question, the holding is broad enough to include the situation where in fact the military judge has seen evidence adjudged incompetent. In the instant case, although we agree that review of the conviction of the plaintiff should not be based on such inadmissible materials as the Article 32 report, there is no evidence that the reviewing authorities ever saw the report, or if they did, that they based their decision to some extent upon its content in violation of regulation and case law.
At oral argument, the plaintiff asserted that although the Court of Military Review is comprised of judges, the convening authority, who represents the first review of a conviction, is neither a judge nor a lawyer and therefore is less able to exclude from his decision the incompetent evidence represented by the Article 32 report. Although this may be true, the Uniform Code of Military Justice provides a second complete review based on both the facts and law of the case in the Court of Military Review. As such, the defendant at a court-martial is given an opportunity to have his conviction reviewed de novo by the Court of Military Review and any prejudice resulting from improprieties in the convening authority's basis for his decision is completely removed.
Although as seen, the Article 32 report cannot be used in considering the guilt or innocence of the defendant at a court-martial, there is no prohibition against using it in reviewing the sentence. SeeUnited States v. Bethea, 22 U.S.C.M.A. 223, 46 C.M.R. 223 (1973), and United States v. Lanford, supra.According to Articles 64 and 66, U.C.M.J., 10 U.S.C. §§ 864, and 866, the reviewing authorities can only reduce a sentence or overturn a conviction, never increase them. As a result, to the extent the Article 32 report is used in a review of a defendant's sentence it serves only as mitigating evidence.
In United States v. Lanford, supra,during a review of the defendant's sentence imposed after a guilty plea, evidence contained in his service record and not introduced at an earlier hearing was utilized by the reviewing authority. The defendant's argument that his service record should not have been considered during the appeal of his sentence was rejected by the Military Court of Appeals when it said:
* * * The sentence imposed by the court is not final. It cannot be increased, but it may be mitigated by the reviewing authorities. The question then arises as to whether the interests of justice require these reviewing authorities to look no further than the trial proceedings for facts which would justify a reduction in the sentence. It seems to us that an accused would be the last person to urge that rule. In any event, we think that the law is less harsh. In our opinion, justice is fostered by giving the reviewing authorities power to go outside the record of trial for information as to the sentence. * * * [6 U.S.C.M.A. at 379.]
In a recent Court of Military Appeals case, United States v. Bethea,
supra,
although the court held that an Article 32 report cannot be used on appeal for deciding the guilt or innocence of a defendant convicted at a court-martial, it did reaffirm the holding of
Lanford
which had permitted the use of evidence
de
[507 F.2d 1276]
horsthe trial record in reviewing the sentence.
Because the only way in which an Article 32 investigative report may be used by the convening authority or the Court of Military Review is to provide mitigating information for the potential reduction of a defendant's sentence, there is no real prejudice resulting from its being seen by those reviewing bodies. In fact, in the instant case where the sentence was substantially lowered at each step of the appeal, being reduced from 80 years of hard labor to only 10, there is no evidence that the inclusion of the report adversely affected the present plaintiff's rights.
Even beyond the consideration of whether inclusion of the Article 32 investigative report violates statute or regulation, the claims of the plaintiff fail to rise to the constitutional levels required before a review of a final decision in a court-martial is allowed in this court. Article 76, U.C.M.J., 10 U.S.C. § 876 (1970), makes final all decisions of courts-martial, as follows:
§ 876. Art. 76. Finality of proceedings, findings, and sentences
The appellate review of records of trial provided by this chapter, the proceedings, findings, and sentences of courts-martial as approved, reviewed, or affirmed as required by this chapter, and all dismissals and discharges carried into execution under sentences by courts-martial following approval, review, or affirmation as required by this chapter, are final and conclusive. Orders publishing the proceedings of courts-martial and all action taken pursuant to those proceedings are binding upon all departments, courts, agencies, and officers of the United States, subject only to action upon a petition for a new trial as provided in section 873 of this title (article 73) and to action by the Secretary concerned as provided in section 874 of this title (article 74), and the authority of the President. Aug. 10, 1956, ch. 1041, 70A Stat. 64.
Under the finality provision of section 876 it would appear that any appealof a court-martial to this court arising in the posture of a suit for back pay would be prohibited. Cases have limited the reach of this statute by excepting collateral review through habeas corpus petitions, Whelchel v. McDonald,340 U.S. 122, 71 S.Ct. 146, 95 L.Ed 141 (1950); Gusik v. Schilder,340 U.S. 128, 71 S.Ct. 149, 95 L.Ed 146 (1950), or by making exceptions for circumstances where a court-martial has so completely denied fifth or sixth amendment rights that the very jurisdiction of the court may be denied. Begalke v. United States,286 F.2d 606, 148 Ct.Cl. 397 (1960), cert. denied, 364 U.S. 865, 81 S.Ct. 108, 5 L.Ed.2d 87; Shapiro v. United States,69 F.Supp. 205, 107 Ct.Cl. 650 (1947).
In the most recent Supreme Court case in which review of a court-martial was sought through a suit here for back pay, United States v. Augenblick,393 U.S. 348, 89 S.Ct. 528, 21 L.Ed.2d 537 (1969), the Court held that where the alleged infirmities at the court-martial fail to rise to a constitutional level, this court has no jurisdiction to collaterally review the conviction. Although what is a sufficient constitutional claim is not precisely clear, the Supreme Court stated in Augenblick:
[A]part from trials conducted in violation of express constitutional mandates, a constitutionally unfair trial takes place only where the barriers and safeguards are so relaxed or forgotten, as in Moore v. Dempsey, supra [261 U.S. 86 [, 43 S.Ct. 265, 67 L.Ed. 543] (1923)], that the proceeding is more a spectacle (Rideau v. Louisiana, 373 U.S. 723, 726 [, 83 S.Ct. 1417, 10 L.Ed.2d 663]) or trial by ordeal (Brown v. Mississippi, 297 U.S. 278, 285 [, 56 S.Ct. 461, 464, 80 L.Ed. 682]) than a disciplined contest. [Id., 393 U.S. at 356, 89 S.Ct. at 534.]
Where, as here, the inclusion of the Article 32 report was in accordance with official regulations, the court-martial cannot be considered a "spectacle" or a
[507 F.2d 1277]
"trial by ordeal." SeeTaylor v. United States, 199 Ct.Cl. 171 (1972); Gallagher v. United States,423 F.2d 1371, 1378, 191 Ct.Cl. 546, 557 (1970), cert. denied, 400 U.S. 849, 91 S.Ct. 58, 27 L.Ed.2d 86. Similarly, since the issue of the Article 32 report was raised at all of the military forums available to the instant plaintiff and dismissed by them, it should not be permitted to be raised again here. SeeBurns v. Wilson,346 U.S. 137, 73 S.Ct. 1045, 97 L.Ed. 1508 (1953), where the court said:
* * * But these provisions [dealing with the finality of courts-martial] do mean that when a military decision has dealt fully and fairly with an allegation raised in that application, it is not open to a federal civil court to grant the writ simply to re-evaluate the evidence. * * * [Id. at 142, 73 S.Ct. at 1049.]
For all of the reasons enumerated above, we hold that since the military reviewing authorities conducted themselves at all times in accordance with the regulations governing court-martials, and since the plaintiff's claims with respect to count one do not rise to a constitutional level, we do not have jurisdiction to decide this portion of the case. United States v. Augenblick,
supra.
We, therefore, deny plaintiff's motion for summary judgment as to count one and grant the defendant's motion for summary judgment as to count one and dismiss plaintiff's petition as to that count, and remand the remainder of the case to the trial judge for further proceedings regarding counts two and three.
[507 F.2d 1278]
[507 F.2d 1279]
[507 F.2d 1280]
| https://www.leagle.com/decision/19741778507f2d127111524 |
Remote Sensing | Free Full-Text | High-Resolution Mapping of Seaweed Aquaculture along the Jiangsu Coast of China Using Google Earth Engine (2016& ndash;2022)
Seaweed aquaculture produces enormous economic and ecological service benefits, making significant contributions to achieving global Sustainable Development Goals (SDGs). However, large-scale development of seaweed aquaculture and the unreasonable use of aquaculture rafts may trigger green tide, bringing negative ecological, social, and economic impacts. Therefore, it is vital to monitor the seaweed aquaculture industry accurately. Here, we mapped 10-m-resolution seaweed aquaculture along the Jiangsu coast of China based on active and passive remote sensing (Sentinel-1/2) and Random Forest using Google Earth Engine. The results demonstrate satisfactory model performance and data accuracy. The square seaweed aquaculture in the Lianyungang Offshore (Mode-I) has gradually expanded to the deep sea since 2016, with a maximum area of 194.06 km2 in 2018. Between 2021 and 2022, the area of the strip-shaped seaweed aquaculture in Subei radiation shoals (Mode-II) was considerably reduced, with most of the reduced land lying on the east side of the Dafeng Elk National Nature Reserve. In general, the area of the seaweed aquaculture in the prohibited breeding area was reduced from 20.32 km2 to 3.13 km2, and the area of the seaweed aquaculture in the restricted breeding area was reduced from 149.71 km2 to 33.15 km2. Results show that under the policy restriction, the scale of unsustainable seaweed aquaculture along the Jiangsu coast has been greatly reduced within seven years. This study can provide an efficient approach for the medium-scale extraction of seaweed aquaculture and provide decision support for the sustainable development of marine aquaculture.
by Jie Cheng 1 , Nan Jia 2 , Ruishan Chen 1,3,* , Xiaona Guo 3 , Jianzhong Ge 4 and Fucang Zhou 4
1
School of Geographic Sciences, East China Normal University, Shanghai 200241, China
2
Center for Systems Integration and Sustainability, Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI 48823, USA
3
School of Design, Shanghai Jiaotong University, Shanghai 200040, China
4
State Key Laboratory of Estuarine and Coastal Research, East China Normal University, Shanghai 200241, China
*
Author to whom correspondence should be addressed.
Remote Sens. 2022 , 14 (24), 6202; https://doi.org/10.3390/rs14246202
Received: 1 November 2022 / Revised: 2 December 2022 / Accepted: 4 December 2022 / Published: 7 December 2022
(This article belongs to the Special Issue Multisource Remote Sensing for Coastal Mapping, Monitoring, and Applications )
Abstract
:
Seaweed aquaculture produces enormous economic and ecological service benefits, making significant contributions to achieving global Sustainable Development Goals (SDGs). However, large-scale development of seaweed aquaculture and the unreasonable use of aquaculture rafts may trigger green tide, bringing negative ecological, social, and economic impacts. Therefore, it is vital to monitor the seaweed aquaculture industry accurately. Here, we mapped 10-m-resolution seaweed aquaculture along the Jiangsu coast of China based on active and passive remote sensing (Sentinel-1/2) and Random Forest using Google Earth Engine. The results demonstrate satisfactory model performance and data accuracy. The square seaweed aquaculture in the Lianyungang Offshore (Mode-I) has gradually expanded to the deep sea since 2016, with a maximum area of 194.06 km
2
2
to 3.13 km
2
, and the area of the seaweed aquaculture in the restricted breeding area was reduced from 149.71 km
2
to 33.15 km
2
. Results show that under the policy restriction, the scale of unsustainable seaweed aquaculture along the Jiangsu coast has been greatly reduced within seven years. This study can provide an efficient approach for the medium-scale extraction of seaweed aquaculture and provide decision support for the sustainable development of marine aquaculture.
Keywords:
seaweed aquaculture
;
sentinel
;
google earth engine
;
SDGs
;
sustainable agriculture
;
random forest
1. Introduction
The scale-up and sustained healthy development of seaweed farming makes a significant contribution to attaining global Sustainable Development Goals (SDGs) (e.g., SDG2 (Zero Hunger), SDG3 (Good Health and Well-Being), SDG13 (Climate Action), SDG14 (Life Below Water) [ 1 ], and SDG15 (Life on Land)). It is also one of the pillar industries of marine aquaculture in China, providing a wide variety of economic and ecological services. In terms of economic value, rich nutrients in seaweed can supplement the needs of the human body, prevent and treat diseases (e.g., goiter and liver cancer), and be processed into industrial products (e.g., food additives and gelling agents) [ 2 , 3 ]. In terms of ecological service value, large-scale seaweed production is a viable option for increasing the ocean carbon sink and achieving carbon neutrality [ 4 ]. At the same time, it has a short production cycle and relatively low labor requirements, so the investment cost of seaweed farming is comparatively low [ 5 ]. Seaweed farming does not occupy terrestrial and freshwater resources. Supplementing terrestrial vegetable production with seaweed production can limit the degradation of terrestrial ecosystems, so it is of great significance for resource conservation and efficient use [ 6 ].
In the past few years, some coastal areas have frequently suffered from green tides [ 7 ]. In 2021, green tides in the Yellow Sea occurred on an unprecedented scale, covering about 1746 km 2 , 2.3 times the historical record in China in 2013 [ 8 ]. Relevant studies have shown that different amounts of Enteromorpha prolifera can be attached to aquaculture facilities. Under the influence of wind and ocean currents, it gradually reached the coast of Shandong, causing a green tide [ 9 ].
Recently, many studies have tried to monitor seaweed cultivation. Traditional survey-based methods may consume a lot of human, material, and financial resources, and cannot understand seaweed aquaculture’s spatial distribution [ 10 ]. In contrast, remote sensing technology has the superiority of low cost, near real-time, and wide monitoring range. As reliable data for information extraction, Multi-spectral Instrument (MSI) and Synthetic-Aperture Radar (SAR) images have been widely used in the field of remote sensing. However, the former is limited by the interference of clouds, fog, and noise limits the latter, so it is difficult to obtain stable and effective images [ 11 ]. The threshold and object-based methods are widely developed for monitoring seaweed farming [ 12 , 13 ]. However, the former cannot apply a wealth of spectral and textural features, and the latter classification results may have many broken patches. Moreover, the current seaweed mapping uses mostly medium-resolution remote sensing satellites such as Landsat [ 14 ]. As an emerging remote sensing image in recent years, the 10-meter resolution Sentinel data provided by the European Space Agency (ESA) is free and open-access. Sentinel data have obvious advantages in terms of imager type, the number of bands, and resolution, providing strong data support for future research [ 11 ]. In addition, deep learning algorithms, such as FCN and U-Net, have been used to extract the seaweed patches [ 15 , 16 ], but these methods have not been applied in large-scale or medium-scale research due to the complexity of the model structure. Therefore, using these deep learning methods is still challenging for accurately mapping seaweed aquaculture on large spatial scales and different geographical environments. Random forest training has fast convergence speed, wide application range, certain robustness, and is suitable for large-scale prediction. Teluguntla et al. used the random forest algorithm to calculate the cultivated land areas of Australia and China based on Google Earth Engine and Landsat 30-meter resolution images [ 17 ]. Xia et al. used random forest classification and Sentinel time series images to successfully map China’s water photovoltaics [ 18 ].
Few studies have used the Google Earth Engine (GEE) platform and active-passive-high-resolution remote sensing to discuss the spatial distribution of seaweed farming areas on large or medium spatial scales, which makes it challenging to identify its scope, development, and impact. GEE is a cloud computing platform that can provide massive geospatial data, making it simple to design algorithms and process time-series imageries in batches lowering the cost and analytical complexity [
19
]. Here we used the Sentinel data and GEE platform to map the seaweed using a machine learning method—random forest. To sum up, the study’s objectives were to: (1) extract the seaweed aquaculture area using the GEE platform and a random forest classification algorithm; (2) analyze the seaweed aquaculture areas, and spatial dynamics in Jiangsu from 2016 to 2022; (3) investigate whether the current seaweed farming areas are distributed in the prohibited and restricted breeding areas, and summarize which policies issued by governments, at all levels, have an impact on its spatial distribution and economic benefits. Our results will provide stakeholders with timely and spatially explicit information to track the development of seaweed aquaculture while providing quantitative support for the sustainable development of marine fisheries and the protection of the ecological environment.
2. Study Area, Data, and Materials
2.1. Study Area
Jiangsu province is located in Eastern China, bordering the Yellow Sea to the east (
Figure 1
(Left)). The cultivation areas of Chinese seaweed are mainly distributed along the southern coast of the Yellow Sea to the north of the Yangtze River Estuary. The coast of Jiangsu province owned more than 99% of Chinese production enterprises [
20
]. Lianyungang, Yancheng, and Nantong are coastal municipalities with a total coastline of 954 km. The tidal flat area is more than 5000 km
2
, which is nearly a quarter of the tidal flat area in China [
21
]. Consequently, we chose the coastal areas of Jiangsu Province as the study area, where seaweed aquaculture is widely distributed and the modes of seaweed cultivation are more typical than that in other regions.
There are two main types of seaweed farming in Jiangsu province ( Figure 1 (Right)): The first is the square-shaped seaweed aquaculture in the Lianyungang Offshore area, where the height of the net screen can be adjusted so that the seaweed can be fully exposed to the sunlight (Mode-I, Figure 1 a). The second is the strip-shaped seaweed aquaculture in Subei radiation shoals (Mode-II, Figure 1 b), with a fixed net-screen height so the exposure time can be affected by the tidal periodicity [ 22 ].
2.2. Data and Materials
2.2.1. Satellite Datasets
Due to the study areas’ complex climate and environmental variables, the GEE platform was used to conduct active and passive remote sensing monitoring of seaweed cultivation areas. This paper’s in-use remote sensing data were from Sentinel-1 and Sentinel-2 satellites, which easily conduct pre-processing and analysis on GEE. The coverage and number of observations for both sensors are given in Figure 2 .
The Sentinel-2 satellites consist of two optical satellites, A and B. Sentinel-2A and Sentinel-2B satellites were launched in June 2015 and March 2017, respectively. By integrating the data from these two satellites, the revisit period can be five days [
23
]. Sentinel-2’s 13 bands provide more support for vegetation classification by creatively dividing the red wave band into three separate bands (B5, B6, B7) in addition to the visible light contained in conventional optical images. Meanwhile, the near-infrared band (B8) can detect the strong reflection of plants. Multiple spectrum indices can be constructed using these abundant bands, which are helpful for data collection and monitoring in seaweed farming. This article uses two levels of Sentinel-2 data, Level-1C, and Level-2A. Level-1C products are Top-of-Atmosphere corrected reflectance products. Level-2A products are Bottom-of-Atmosphere corrected reflectance products that have been ortho-corrected, geometrically corrected, and atmospherically corrected by European Space Agency (ESA) and are available after 28 March 2017.
Sentinel-1 satellites are widely used for land and ocean observations and have all-weather, all-day radar imaging capabilities. Sentinel-1A and Sentinel-1B satellites were successfully launched in April 2014 and April 2016, respectively. The revisit period of the two satellites has been greatly shortened to 6 days. The Sentinel-1 products have been pre-processed using the ESA’s Sentinel-1 toolbox, including orbital reconstruction, thermal noise removal, radiometric calibration, and terrain correction [
24
]. Previous studies have shown that farming rafts are easier to observe in isotropic polarization images [
25
]. Correspondingly, in the Interferometric Wide swath (IW) mode, the image of vertical-horizontal (VH)+ vertical-vertical (VV) polarization in ground range detected (GRD) format was chosen as the data source from ESA’s Copernicus project’s dual polarized C-band SAR. A detailed introduction of the parameters of Sentinel-1/2 data are shown in
Table 1
.
2.2.2. Data from Government Statistics and Reports
In the Tidal Flat Planning for Aquaculture Waters in Jiangsu Province (2020–2030) issued by the Jiangsu Provincial Department of Agriculture and Rural Affairs, three concepts are defined: available breeding areas, restricted breeding areas, and prohibited breeding areas. To identify the rationality of the offshore seaweed aquaculture in Jiangsu, we define the prohibited and restricted breeding areas as the areas of unsustainable development of seaweed aquaculture. Subsequently, the areas of unsustainable development of seaweed aquaculture and the seaweed aquaculture extraction results were overlaid for analysis [
26
]. In addition, for three coastal cities, we applied the Tidal Flat Planning for Aquaculture Waters. To check the accuracy of these results, we collected the China Fisheries Statistical Yearbook from 2016 to 2020 [
27
]. Furthermore, we collected the Jiangsu Province Marine Disaster Bulletin and the China Marine Disaster Bulletin to analyze the dynamics of seaweed farming areas [
28
,
29
].
3. Methods
Our research process is shown in Figure 3 .
3.1. Image Pre-Processing
3.1.1. MISC-OA Marine Mask Extraction
To avoid the interference of the spectral reflectance of the land, we created a high-resolution ocean mask based on Sentinel-2. First, an initial time-series image collection was constructed using 10,440 scenes of surface reflection images in Jiangsu Province from 1 January 2016 to 1 April 2022.
Considering the continuity of the research and the possibility that the coastline may change with factors such as crustal movement and land reclamation, we made year-by-year dynamic marine masks. Due to the limitation of image shooting time, some images often contain exposed tidal flats, so obtaining the maximum water surface area with only one image may not be possible. Jia et al. proposed to use the method of maximum spectral index composite (MSIC) combined with the Otsu algorithm (OA) to obtain the maximum water surface range [ 30 ]. The objectives of the method are: (1) utilize the QA60 band to disguise observations of poor image quality due to opaque and cirrus clouds [ 31 ]; (2) a study shows that modified Normalized Difference Water Index (mNDWI)-MSIC can represent the largest seawater surface extent in coastal information extraction and is the best choice for capturing the highest water level [ 30 ]. The modified Normalized Difference Water Index (mNDWI) is developed from the Normalized Difference Water Index (NDWI), which can enhance open water features, and effectively suppress or remove vegetation and soil noise [ 32 ]. So, on the GEE, we used the qualityMosaic function to implement the MSIC method, and mNDWI was calculated by traversing all images in each year to capture the maximum water surface per year ( Table 2 ); (3) based on image histogram, OA underpinned automatically dividing an optimal threshold for segmenting images into two categories [ 33 ], water and land; (4) convert raster data to vector data for further classification. We finally acquired the mask data in each year using the above steps.
3.1.2. Sentinel Image Pre-Processing
Raft aquaculture facilities are generally placed in the sea from September to October. March and April are the harvest periods of seaweed, and the seaweed facilities are recycled to the shore from the end of May to early June [
34
]. Accordingly, the images were used to extract the seaweed cultivation area before the harvest period. Furthermore, in the Mode-I area, there is no large-scale tidal flat, so there is no need to consider the impact of tidal flat exposure on the binary extraction of seaweed aquaculture. In the Mode-II area located in Subei radiation shoals, the images we chose needed to avoid large areas of tidal flat exposure. Appropriate images helped reduce mixed pixels and distinguish the characteristics of water and seaweed farming areas while avoiding the disturbance caused by tidal flats.
We built the time-series images in the following steps: first, for Sentinel-1,1-month composites were produced with the median values of the effective observations so that noise interference could be minimized to some extent in this manner. Since the quality of the Sentinel-1 monthly median image in 2019 was greatly disturbed by tidal flats, we only used a single image with better quality for subsequent feature selection and extraction; next, for Sentinel-2, cloudless or less than 10% cloudy before the seaweed harvest were filtered. Then it was judged whether the image had been atmospherically corrected, as the L1-C level datasets before 28 March 2017, on the GEE, have not been atmospherically corrected. If no atmospheric correction has been conducted, a SIAC atmospheric correction model based on GEE is required [
35
]; finally, each image band was resampled to 10 m to ensure all the data used in the paper have the same spatial resolutions.
3.2. Feature Selection and Extraction
The Sentinel-2 MSI image contains rich spectral and textural features, while the Sentinel-1 SAR image can penetrate clouds and fog well, offering a multi-dimensional feature space for seaweed agriculture extraction. According to the special geographical environment of the study area, we used the initial bands of Sentinel-2, and dual-polarized features of Sentinel-1 (VV + VH) and constructed commonly used indices (
Table 2
). We selected five spectral indices and one dual-polarized index to assist in the classification of images. Therefore, we utilized the features in
Table 2
to construct the input feature set for the random forest algorithm for seaweed extraction.
According to the features of the study area, we constructed the features of the water index, vegetation index, and soil index, respectively. Currently, Sentinel-1 dual-polarized Water Index (SDWI) and the mNDWI were utilized to capture water. Considering the signal difference between water and other objects in dual-polarized features, SDWI can enhance water information while eliminating the influence of soil and vegetation [ 36 ]. The modified Normalized Difference Water Index (mNDWI) can enhance open water features, and effectively suppress or remove vegetation and soil noise ( Section 3.1.1 ). For vegetation features, we chose the following three representative vegetation indices: Normalized Difference Vegetation Index (NDVI) is one of the most broadly used vegetation indices, which can reflect vegetation’s growth status and distribution density [ 37 ]. Enhanced Vegetation Index (EVI, also known as soil and atmosphere resistant vegetation index (SARVI2)) is improved from NDVI, and after constructing a feedback mechanism developed by Liu et al., the influence of soil and atmospheric environment is simultaneously corrected through the parameters [ 38 , 39 ]. L is the canopy background adjustment parameter. C 1 and C 2 weigh the use of the blue channel in the aerosol correction of the red channel. The value of L (L = 1), C 1 (C 1 = 6.0), and C 2 (C 2 = 7.5) in the EVI formula were first calculated by Huete et al. [ 40 ]. They have been widely accepted as common coefficients. Firstly, these coefficients were calculated for MODIS [ 41 , 42 ], and then the researchers found that the values of these coefficients were also effective for Landsat and Sentinel-2 data [ 43 , 44 ]. Difference Vegetation index (DVI) is sensitive to soil background changes and suitable for vegetation monitoring with low vegetation coverage or in the early and middle stages of vegetation growth [ 45 ]. To extract coastal tidal flats and wetland features, the Normalized Difference Soil Index (NDSI) was introduced as a select metric, which enables us to differentiate the soil, water, and vegetation [ 46 ]. For the Sentinel-2 multispectral bands, we chose the B1–B5, B8, B8A, B11, and B12 bands. B1 is the coastal/aerosol band used to monitor aerosols in near-shore water and the atmosphere. B2, B3, and B4 are visible light bands. B5, B6, and B7 are vegetation red edge bands. B9 and B10 are the water vapor and the cirrus bands, with a resolution of only 60 m. In order to avoid overfitting, model degradation, and long training periods, we removed the low-resolution and abundant bands (B6, B7, B9, and B10) [ 47 ]. Through our observation of images and a previous study [ 25 ], we found that the seaweed rafts in the Mode-I region are easier to observe in the VV band of Sentinel-1. There are more tidal flats in the Mode-II area, and VH of Sentinel-1 has been proven to have a better observation effect [ 11 ], thus, we chose different polarization bands for the two regions.
3.3. Classification with Random Forest
Random forest decision theory was first formally proposed in July 2001 [ 48 ]. Random forest (RF) is a classification algorithm based on decision trees with high computational accuracy, short model training time, and low sensitivity to the quantity and quality of training samples [ 18 ]. It has been successfully applied to remote sensing fields such as water photovoltaic extraction, land cover classification, and mapping of crops [ 18 , 47 , 49 ].
Binary classification (seaweed aquaculture and non-seaweed aquaculture) was conducted derived from the RF algorithm and training samples. We set up the parameters of RF when training the classifiers: (1) number Of Trees (T): Previous studies have shown that T can effectively improve the classification accuracy of random forests [
49
]. After the T exceeds 100, the model will reduce the sensitivity to the number Of Trees, and the classification results tend to be stable. The T in our study was set to 500 through multiple experiments. (2) Five other parameters including the number of variables per split, the fraction of input to bag per tree, the minimum number of samples required to be at a leaf node, random seed, and the maximum number of leaf nodes in each tree, were set by default.
3.4. Post-Classification
3.4.1. Integrated Updating
Update methods are increasingly used for land cover classification and variation analysis [ 50 ]. Xia et al. used the integrated update method to modify the classification results of each year by using the pixel values of the classification results of water body types (aquaculture ponds and other water bodies) for many years as a reference map [ 23 ]. This method can reduce the “false changes” in the classification process and improve classification accuracy. Considering that the rafts for seaweed farming will be in that location for several years once they are placed, it is suitable to apply the integrated update method to remove misclassified pixels outside the scale of seaweed aquaculture. Therefore, we used the binary map of the classification results over the years as a reference map and improved the performance.
3.4.2. Fill and Smooth Edges
Considering the challenges of pixel-based classification, the extracted results need to be filled with empties and smoothed edges. For example, the edges of the extracted results were misclassified, and the interiors of the extracted results were spatially discontinuous (empties). We can fill empties and smooth edges through clumping. Clumping is a method of clustering and merging adjacent similarly classified regions using mathematical morphological operators (erosion and dilation). Most speckles will disappear in the resulting maps via filling empties, while jagged edge information will be alleviated via smoothing edges.
3.4.3. Remove Noise and Debris
Pixel-based classification is prone to pixel islanding problems. To address this problem, we used the eight-connection method of the connectedPixelCount function in GEE to extract the seaweed aquaculture from small areas.
3.4.4. Remove Offshore Wind Power
According to the microwave scattering principle, the echo intensity is mainly determined by the ground objects’ complex permittivity and surface roughness. Due to the unique side-view imaging method of SAR images, very few reflected electromagnetic waves are received by the sensor in the water where specular reflection occurs, resulting in a low backscattering coefficient of the water. However, the echo intensity of small-scale offshore wind turbines in Subei radiation shoals was relatively large, which had a certain impact on the correct analysis of the images. Although we selected many windmill samples, there are still mis-extractions of windmill edge information (e.g., windmill wings). We also used the connectedPixelCount function to remove the wrong pixels.
3.5. Convex Hull Algorithm
Convex Hull is a classical and commonly used algorithm in computational geometry. It is mathematically defined as: in the vector space V, the intersection S of all convex sets containing X is named the convex hull of X. The problem solved by the convex hull algorithm is: given a bunch of discrete points in space, calculate a convex polygon containing all the points. We conducted it to obtain the circumscribed polygon of the seaweed cultivation area, which is beneficial to grasp the direction and scale of its spatial expansion intuitively.
3.6. Validation
To evaluate the classification accuracy from 2016 to 2022, 30% of the samples were used as a validation sample to reckon the user’s overall accuracy (OA) and Kappa coefficients. The samples were generated by expert visual interpretation based on free satellite images such as Landsat, Sentinel, and Google Earth historical images. Moreover, we utilized the China Fisheries Statistical Yearbook to verify the reliability further.
4. Results and Analysis
4.1. Accuracy Assessment
The accuracy assessment showed that our results have high accuracy (OA > 88% and Kappa coefficient > 0.74) ( Table 3 ). We found that there were still variations in some years ( Figure 4 c). Compared with the statistical yearbook, the area of seaweed aquaculture in 2016 was high, while the area of seaweed aquaculture in 2017 was low. We considered that multiple hazards (e.g., sea ice disaster, sargasso disaster, wave disaster) might cause bias in our observations, which we will discuss in Section 5.2 .
4.2. Spatiotemporal Dynamics in Seaweed Aquaculture
The seaweed aquaculture areas in Jiangsu Province are mainly distributed in the Haizhou Bay (Mode-I) in Lianyungang and Subei radiation shoals (Mode-II). The total area of seaweed aquaculture in Jiangsu has reduced by half from 507.96 km 2 (2016) to 242.95 km 2 (2022) ( Figure 4 c). We used the convex hull algorithm to enclose the range of the seaweed farming areas ( Figure 5 and Figure 6 ). From 2016 to 2020, the area of Mode-II was always larger than that of Mode-I, with a maximum difference of 351.47 km 2 in 2016. However, Mode-I’s area exceeded Mode-II’s area in 2021, with a maximum difference of 29.55 km 2 in 2022. The spatial expansion trend was ( Figure 4 a,b): the area of Mode-I gradually expanded from nearshore to the deep eastern sea, and some nearshore areas had a reduction in the breeding density and the reduction of the aquaculture areas ( Figure 7 c,d). The area of Mode-II was not significantly expanded in space, but in 2017, the seaweed aquaculture area near Yangkou Port was partially reduced compared to 2016, and no seaweed farming has been installed in this region since then ( Figure 7 a). In 2021, the breeding area near the tidal flat in the eastern sea area of Dafeng Elk National Nature Reserve significantly decreased ( Figure 7 b). Compared with 2020, the area of Mode-II decreased by 94.36 km 2 .
4.3. Spatial Distribution of Diverse Modes of Seaweed Aquaculture
Seaweed was grown and matured on rafts’ net screens as an artificial large-scale cultured algae. The seaweed rafts are mainly composed of net screens, floating ropes, rafts, buoys, and so on. The buoy has the function of floating, the raft supports the net screen, and seaweed is distributed on the net screen, which can make the laver float on the seawater surface ( Figure 8 ) [ 51 ].
Through remote sensing observations, it was discovered that there were a few strip-shaped seaweed aquaculture areas near the coast and in the deep sea in Haizhou Bay of Lianyungang. Most areas of Haizhou Bay have square-shaped seaweed aquaculture areas with adjustable raft heights (Mode-I) (
Figure 9
). Data collection and field investigation found that the aquaculture area mainly adopts the stay-pole raft aquaculture method (
Figure 8
(Left)). It is a method that directly inserts bamboo poles, wooden stakes, or FRP (Fiberglass Reinforced Plastics) poles into the seabed as pillars, and hangs a net screen on the pillars so that the net screen floats or dries out with the rise and fall of the tide. During the breeding period, farmers constantly adjust the tightness of the floating ropes of the rafts at regular time intervals to avoid the rafts being completely submerged in water due to the impact of wind, waves, and tides. The spacing of each seaweed farming unit is used to provide a channel for picking. With the continuous development of aquaculture technology, seaweed aquaculture will gradually expand from near-shore shallow-water areas to offshore deep-water areas.
It was discovered that the seaweed aquaculture areas in Subei radiation shoals were all strip-shaped seaweed aquaculture areas with fixed raft heights affected by the tide (Mode-II). The unique geographical condition in Subei radiation shoals has created a semi-floating raft aquaculture method that is unique in China and is suitable for the intertidal zone with a large tidal range ( Figure 8 (Right)). In this way, the net screen and the raft are suspended in the sea when the tide rises. When the tide falls, the net screen and raft are exposed on the beach [ 22 ].
4.4. Analysis of Unsustainable Development of Seaweed Aquaculture
In recent years, the government of Jiangsu Province has gradually realized the seriousness of green tide. It has successfully issued various policies and plans, such as Jiangsu Province’s “14th Five-Year” Marine Economic Development Plan and the Planning of Tidal Flats in Aquaculture Waters in Jiangsu Province (2020–2030) [ 26 , 52 ]. These policies and plans aim to achieve marine aquaculture’s sustainable and healthy development, reduce the pressure on the marine environment, and build a blue space for a new development pattern.
The overlay analysis of the mariculture planning map and the extraction results of the seaweed aquaculture area in 2022 shows that the Xuwei port waterway of Lianyungang and the Yangkou port waterway of Nantong, the core area and buffer area of the national nature reserve in Jiangsu, and the core areas and buffer zones of China’s territorial sea bases are setting as prohibited or restricted breeding areas ( Figure 10 ).
We calculated the area of seaweed aquaculture in prohibited and restricted breeding areas in 2016 and 2022. In general, the area of the seaweed aquaculture in the prohibited breeding area was reduced from 20.32 km
2
to 3.13 km
2
, and the area of the seaweed aquaculture in the restricted breeding area was reduced from 149.71 km
2
to 33.15 km
2
. In addition, the area of Mode-I in the prohibited breeding area was reduced from 4.84 km
2
to 2.69 km
2
, but the area of Mode-I in the restricted breeding area was increased from 2.39 km
2
to 9.69 km
2
. The area of Mode-II in the prohibited breeding area and the restricted breeding area was reduced from 15.48 km
2
to 0.44 km
2
and 147.32 km
2
to 23.46 km
2
. This shows that in the past seven years, due to the improvement of government planning and laws, the area of unsustainable development of seaweed aquaculture tends to decrease, and the unsustainable development area of seaweed aquaculture in Mode-II has decreased more significantly. In the future, the supervision of unsustainable farming behaviors in the northwest of Haizhou Bay should be strengthened.
5. Discussion
5.1. Model Performance and Data Accuracy
Although previous studies used remote sensing images to extract seaweed aquaculture, most did not obtain higher resolution mapping of seaweed aquaculture, which brought certain challenges to area estimation [
14
]. Our research used high-resolution Sentinel time-series imagery and machine learning methods to correctly identify small, easily overlooked farming units and reduce misclassification caused by edge-confused pixels. Therefore, it was a favorable attempt to accurately map the medium-scale seaweed cultivation areas along the coast of Jiangsu. Meanwhile, our framework is also a very active application of GEE in extracting seaweed aquaculture, which can quickly retrieve long-time series images and map the latest vintage of seaweed aquaculture (2022). In addition, to avoid the impact of land reclamation on coastline changes, this paper proposed to use annual time series remote sensing images for coastline measurements, rather than utilizing fixed vector data. The overall accuracy can reach higher than 0.88, and the Kappa coefficient can reach higher than 0.74. Concurrently, the comparison with statistical data was added, which showed that our model had high accuracy for extracting seaweed cultivation areas.
As more and more machine learning methods, remote sensing datasets, and socioeconomic data are integrated into the Google Earth Engine cloud computing platform, it has become easier to extract information from remote sensing images and analyze hot issues. This framework is an active application of rapid mapping of seaweed aquaculture areas based on Google Earth Engine, which can provide a reference for other coastal information extraction.
5.2. Development and Impact of Seaweed Aquaculture
In recent years, the demand for seaweed in various countries in the world has increased, and the development of China’s seaweed industry has taken the lead in the world [
53
]. This paper indicated that from 2016 to 2022, the seaweed cultivation area in Mode-I first increased and then decreased, and there was a trend of expanding to the deep-sea area. In 2018, it reached a maximum area of 194.06 km
2
. Since then, Mode-I has reduced the breeding scale and breeding density in the nearshore area, and the area has gradually decreased. The area in Mode-II showed a trend of decreasing year-by-year, of which the area in 2017 and 2021 decreased by 25.43% and 41.75%, respectively, compared with the previous year. In 2021, the scale of aquaculture in the Dongsha area (radial sand ridges) of Subei radiation shoals reduced significantly.
With the influence of climate warming, unstable marine environment, and human factors, the seaweed aquaculture industry will face huge disaster risks (e.g., sea ice expansion, sargassum invasion, typhoons, and higher waves) and bring potential ecological impacts. Affected by the extremely cold weather, the main seaweed-producing area (Mode-I) of Haizhou Bay in Lianyungang reached the lowest temperature in 46 years in early January 2016. The sea ice expansion caused severe damage to tens of thousands of hectares of fresh seaweed [ 54 ]. Our results indicated that the area of seaweed cultivation in 2016 was 78.24 km 2 , but the actual yield may be lower than that measured and mapped from remote sensing because the seaweed was damaged by freezing. From December 2016 to early 2017, large-scale golden tides occurred on the Subei radiation shoals [ 55 ]. A large amount of sargassum accumulated on the breeding rafts, and almost all the seaweed rafts on the edge of the tidal flat collapsed, resulting in a large-scale reduction in seaweed production and a major economic loss of about 500 million yuan [ 56 ]. Our results indicated that the aquaculture area of Mode-II in 2017 decreased by 25.43% compared with 2016, and in the following years did not return to the scale of 2016 ( Figure 6 ). In addition, the extreme wave disasters in 2016, 2017, and 2020 also caused a large-scale reduction in aquaculture production, and the coastal aquaculture rafts were seriously damaged and washed away by the waves [ 29 ]. Compared with 2019, the total area of seaweed aquaculture decreased by 16.59% in 2020. Therefore, the compounding of multiple extreme events may be responsible for the bias in our extraction results and statistical yearbooks.
In 2007, the green tide was first detected along the coast of Qingdao, Shandong Province, in the northeastern part of Jiangsu province [
13
]. Since then, the Green Tide Control Department has adopted measures such as reducing the area of seaweed cultivation to support the control of green tides. However, in 2021, the Yellow Sea still ushered the largest green tides in 15 years [
7
]. Relevant studies have shown that some damaged bamboo poles may become the attachment base of prolifera, triggering the green tide [
9
]. Currently, the Chinese government has incentives and subsidies to encourage the early harvest of seaweed and the use of new raft materials [
57
]. Therefore, raft fixing technology and raft materials (e.g., FRP) should be fundamentally improved, then seaweed farming should be controlled at a reasonable scale.
In addition, attention to the impact of seaweed aquaculture on biodiversity is crucial. Subei radiation shoals are also an important area on the migration route of East Asian-Australian migratory birds. However, the large-scale expansion of the seaweed farming industry may lead to a reduction in the area of biological habitats. The Enteromorpha disaster caused by the unsustainable development of seaweed aquaculture may lead to the death of marine organisms due to hypoxia.
While extracting seaweed, we unexpectedly found that the offshore wind power projects in Subei radiation shoals have been further expanded in recent years. We should realize synergies between offshore wind energy and Integrated Multi-trophic Aquaculture (IMTA) systems to improve ocean resource utilization and avoid energy shortages in coastal cities [ 58 ].
5.3. Recent Policy Restrictions on Seaweed Aaquaculture
Since 1994, China’s national and local governments have issued five relevant laws, three regulations, twelve plans, and two policy suggestions related to the seaweed aquaculture industry ( Table S1 ). Especially since 2018, policies related to the seaweed aquaculture industry in Jiangsu have emerged.
Therefore, the development of marine aquaculture has been restricted by some policies. The Opinions on Accelerating the Healthy Development of the Seaweed Industry, released in 2018, proposed that in the future, Lianyungang City will reduce the high-density breeding of seaweed, guide farmers to control the breeding density within a reasonable range, and centrally treat and use the waste generated by aquaculture. It is also proposed that it is planned to gradually withdraw seaweed farming from offshore tidal flats in 2025, to speed up the healthy development of the seaweed industry in Lianyungang. From our results, we can see that compared with other years, Lianyungang actively reduced the area of seaweed aquaculture and the density of seaweed rafts in some areas in 2022 (
Figure 7
c,d). In the Tidal Flat Plan for Aquaculture Waters in Jiangsu Province (2020–2030) released in 2022, and Planning of the National Ecological Protection Red Line in Jiangsu Province, released in 2018, coastal wetlands, national nature reserves, and their buffer zones, territorial sea bases and their buffer zones, and port waterways were all regarded as key ecological protection and restricted development areas, which restrict the direction and speed of seaweed aquaculture expansion. Results also showed that the scale of seaweed aquaculture in the regions mentioned above is decreasing. The Opinions of the General Office of the Jiangsu Provincial Government on Accelerating the Promotion of High-quality Development of Fisheries released in 2020 emphasizes the promotion of ecologically healthy farming, requires research on aquaculture capacity in coastal waters, and reasonably controls the scale of aquaculture. Our research can provide quantitative data support for formulating healthy ecological aquaculture policies [
59
].
5.4. Applicability and Limitations of Research Methods
This research could be applied to other multispectral and SAR images to accurately create the distribution map of seaweed aquaculture and comprehend its spatiotemporal distribution variations using the methods of sea and land mask extraction and seaweed extraction. Additionally, using the GEE platform, our methodology can be used for the quick and precise extraction of seaweed farming in various coastal areas and for mastering diverse kinds of aquaculture. Furthermore, we can assess the seaweed industry’s future output and carbon sequestration capacity, and then provide quantitative support for ocean blue carbon, sustainable aquaculture development, and disaster prevention.
Researchers should pay attention to the phenological aspects of seaweed aquaculture, the data and procedure uncertainties to implement this technology, and the importance of filtering appropriate images in other places. To begin with, different harvest periods apply to different places. The raft’s installation and recuperation times, as well as the seedling and harvest phases, must all be considered, otherwise unclear spectral characteristics may be introduced, resulting in missing extractions. Due to the tides and the growth environment of shallow seabed algae (coral reefs, seagrass, macroalgae), water column correction should be considered in the future to improve the accuracy of algae extraction below the sea surface [
60
]. Furthermore, our results may overestimate the actual seaweed aquaculture area due to the gap between the seaweed raft unit and the resolution of remote sensing photos.
6. Conclusions
Few studies have connected active and passive remote sensing on the GEE platform to map seaweed aquaculture and analyze their spatiotemporal dynamics. This study aimed to bridge this gap using the above-mentioned methodologies and the random forest classification algorithm. According to our findings, the seaweed aquaculture industry in Jiangsu experienced significant fluctuations between 2016 and 2022 due to laws and regulations. Since 2016, Mode-I has gradually expanded to the deep eastern sea, while reducing the breeding density and range in the nearshore area, and it reached a maximum area of 194.06 km
2
in 2018. The expansion of Mode-II was not apparent in space, and the area was greatly reduced in 2021 and 2022. Its reduced area was mainly located in the eastern part of the Dafeng Elk National Nature Reserve. In addition, we studied the area change of unsustainable seaweed aquaculture in 2016 and 2022. We found that in the last seven years, the area of unsustainable development of seaweed aquaculture has decreased, especially Mode-II has decreased obviously. In 2022, the areas of seaweed aquaculture in the prohibited and restricted breeding areas are 3.13 km
2
and 33.15 km
2
, respectively, and there is more unsustainable development of seaweed aquaculture in the northwest of Haizhou Bay. In the future, the government of Jiangsu Province needs to vigorously develop the marine aquaculture industry, pay attention to the innovation of marine aquaculture technology, make efficient use of marine resources, and explore a sustainable development path for marine aquaculture. This will help the world to develop ocean blue carbon better, achieve carbon neutrality, and adapt to and mitigate climate change.
The extraction method of seaweed aquaculture areas in this research can be easily deployed to map seaweed farming areas in other extensive places. Rapid, precise, and timely mapping of seaweed aquaculture can be an important source of data for evaluating carbon sequestration capacity and potential impact on marine ecosystems.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/rs14246202/s1 , Table S1: Policies, regulations and materials related to seaweed aquaculture.
Author Contributions
Conceptualization, R.C. and J.G.; Methodology, J.C. and N.J.; software and data curation, J.C.; validation, J.C. and N.J.; resources, F.Z.; writing—original draft preparation, J.C.; writing—review and editing, N.J., X.G. and R.C.; visualization, J.C.; supervision and project administration and funding acquisition, R.C. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by the Key Technologies Research and Development Program (2017YFC1503001), the National Social Science Fund of China (20ZDA085), and the National Natural Science Foundation of China [grant number 41771119].
Data Availability Statement
All data created in this study are publicly available. Our research relies on the Google Earth Engine cloud computing platform jointly developed by Google, Carnegie Mellon University and the US Geological Survey ( https://earthengine.google.com/ (accessed on 20 January 2022)). The Sentinel datasets are openly available in Google Earth Engine. The download path of processed data can be found in Zenodo repository with the identifier https://doi.org/10.5281/zenodo.7053911 (accessed on 6 September 2022). The Chinese fishery Statistical Yearbooks from 2016 to 2020 and The Planning of Tidal Flats in Aquaculture Waters in Jiangsu Province (2020–2030) are also downloaded and placed in the Zenodo repository. Requests for raw data should be made to [email protected] .
Acknowledgments
Thanks to the GEE platform for providing Sentinel-1 and Sentinel-2 data.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. The scope of the study area ( Left ) and seaweed aquaculture on Google Earth Pro ( Right , a , b ).
Figure 1. The scope of the study area ( Left ) and seaweed aquaculture on Google Earth Pro ( Right , a , b ).
Figure 2. Spatial distribution of Sentinel-1/2 data: ( a ) total number of Sentinel-1 SAR images; ( b ) total number of Sentinel-2 optical images.
Figure 2. Spatial distribution of Sentinel-1/2 data: ( a ) total number of Sentinel-1 SAR images; ( b ) total number of Sentinel-2 optical images.
Figure 3. Process flow for extracting seaweed aquaculture area.
Figure 3. Process flow for extracting seaweed aquaculture area.
Figure 4. Spatial change of seaweed aquaculture (2016–2022) ( a , b ) and comparison of extraction results and statistical data of seaweed aquaculture and culturing raft from 2016 to 2022 ( c ) the data for 2021–2022 has not been announced yet.
Figure 4. Spatial change of seaweed aquaculture (2016–2022) ( a , b ) and comparison of extraction results and statistical data of seaweed aquaculture and culturing raft from 2016 to 2022 ( c ) the data for 2021–2022 has not been announced yet.
Figure 5. Spatiotemporal dynamics of seaweed aquaculture in mode-I (2016–2022).
Figure 5. Spatiotemporal dynamics of seaweed aquaculture in mode-I (2016–2022).
Figure 6. Spatiotemporal dynamics of seaweed aquaculture in mode-II (2016–2022).
Figure 6. Spatiotemporal dynamics of seaweed aquaculture in mode-II (2016–2022).
Figure 7. Spatial performance of policy restrictions (the reduction of the breeding scale of Mode-II is in the Yangkou Port waterway ( a ) and the east of the nature reserve ( b ); Mode-I’s reduction in breeding scale ( c ) and breeding density ( d )).
Figure 7. Spatial performance of policy restrictions (the reduction of the breeding scale of Mode-II is in the Yangkou Port waterway ( a ) and the east of the nature reserve ( b ); Mode-I’s reduction in breeding scale ( c ) and breeding density ( d )).
Figure 8. Diagram of different types of seaweed rafts (Stay-pole raft aquaculture in the shallow sea ( Left ), Semi-floating raft in the intertidal zone ( Right )).
Figure 8. Diagram of different types of seaweed rafts (Stay-pole raft aquaculture in the shallow sea ( Left ), Semi-floating raft in the intertidal zone ( Right )).
Figure 9. Display of amplified extraction results and related pictures of seaweed aquaculture (square seaweed aquaculture (Mode-I, image source: http://jingzhou.cjyun.org/p/33094.html (accessed on 8 May 2022)) and strip-shaped seaweed aquaculture (Mode-II, photograph is from field surveys)).
Figure 9. Display of amplified extraction results and related pictures of seaweed aquaculture (square seaweed aquaculture (Mode-I, image source: http://jingzhou.cjyun.org/p/33094.html (accessed on 8 May 2022)) and strip-shaped seaweed aquaculture (Mode-II, photograph is from field surveys)).
Figure 10. Distribution of unsustainable development of seaweed aquaculture (( a ): Seaweed farming in prohibited/restricted breeding areas in 2022; ( b , c ): Scope of Mode-I and Mode-II distributed in prohibited/restricted breeding areas in 2016; ( d , e ): Scope of Mode-I and Mode-II distributed in prohibited/restricted breeding areas in 2022).
Table 1. Various parameters of satellite sensors.
Table 1. Various parameters of satellite sensors.
Satellite Sensor Format or Level Spatial Resolution (m) Time Resolution (Day) Duration of This Study (Year) Sentinel-1 SAR IW/Level-1 10 6 2016–2022 Sentinel-2 MSI L1-C/L2-A 10 5 2016–2022
Table 2. Input feature set for the random forest algorithm for seaweed extraction.
Table 2. Input feature set for the random forest algorithm for seaweed extraction.
Feature Type Formulation/Band Spectrum Sentinel-2 (B1-B5, B8, B8A, B11, B12) Radar Sentinel-1 (VV + VH) Water indices mNDWI = ( b G − b SWIR ) / ( b G + b SWIR ) SDWI = ln ( 10 × VH × VV ) − 8 Vegetation indices EVI = G × ( b NIR − b R ) / ( b NIR + C 1 × b R − C 2 × b B + L ) DVI = b NIR − b R NDVI = ( b NIR − b R ) / ( b NIR + b R ) Soil index NDSI = ( b SWIR − b NIR ) / ( b SWIR + b NIR )
b + band name means the reflectance of the specific band. In the EVI formula, L is the canopy background adjustment parameter ( L = 1 ) and G is the gain factor ( G = 2.5 ). C 1 , C 2 are the coefficients of the aerosol resistance term ( C 1 = 6.0 , C 2 = 7.5 ), which are used to correct the aerosol influences on the red band through the blue band.
Table 3. Accuracy assessment.
Table 3. Accuracy assessment.
Time/Breeding Mode Mode-I Mode-II Overall Accuracy Kappa Overall Accuracy Kappa 2016 0.95 0.90 0.94 0.89 2017 0.97 0.94 0.95 0.89 2018 0.96 0.92 0.98 0.96 2019 0.98 0.95 0.88 0.74 2020 0.93 0.86 0.95 0.90 2021 0.98 0.95 0.96 0.91 2022 0.97 0.94 0.96 0.92
MDPI and ACS Style
Cheng, J.; Jia, N.; Chen, R.; Guo, X.; Ge, J.; Zhou, F. High-Resolution Mapping of Seaweed Aquaculture along the Jiangsu Coast of China Using Google Earth Engine (2016–2022). Remote Sens. 2022, 14, 6202.
https://doi.org/10.3390/rs14246202
AMA Style
Cheng J, Jia N, Chen R, Guo X, Ge J, Zhou F. High-Resolution Mapping of Seaweed Aquaculture along the Jiangsu Coast of China Using Google Earth Engine (2016–2022). Remote Sensing. 2022; 14(24):6202.
https://doi.org/10.3390/rs14246202
Chicago/Turabian Style
Cheng, Jie, Nan Jia, Ruishan Chen, Xiaona Guo, Jianzhong Ge, and Fucang Zhou. 2022. "High-Resolution Mapping of Seaweed Aquaculture along the Jiangsu Coast of China Using Google Earth Engine (2016–2022)" Remote Sensing14, no. 24: 6202.
https://doi.org/10.3390/rs14246202
Article Metrics
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Architecture of a TensorFlow graph for training a deep neural network,... | Download Scientific Diagram
Download scientific diagram | Architecture of a TensorFlow graph for training a deep neural network, generated with TensorBoard. from publication: A Comparison Study of Classifier Algorithms for Cross-Person Physical Activity Recognition | Physical activity is widely known to be one of the key elements of a healthy life. The many benefits of physical activity described in the medical literature include weight loss and reductions in the risk factors for chronic diseases. With the recent advances in wearable... | Activity Recognition, Physical Activity and Classifier | ResearchGate, the professional network for scientists.
<here is a image c87d0c54884467bd-c13657244dc97d06>
Architecture of a TensorFlow graph for training a deep neural network, generated with TensorBoard.
Source publication
A Comparison Study of Classifier Algorithms for Cross-Person Physical Activity Recognition
<here is a image 063a2862d71d286f-53765ca07251fa92> Yago Sáez
<here is a image f7b367a938dece91-c10afe33a07bb769> Alejandro Baldominos
<here is a image 6d1f092a3e6140db-3abae9e22dc31789> Pedro Isasi
Physical activity is widely known to be one of the key elements of a healthy life. The many benefits of physical activity described in the medical literature include weight loss and reductions in the risk factors for chronic diseases. With the recent advances in wearable devices, such as smartwatches or physical activity wristbands, motion tracking...
Context in source publication
Context 1
... both configurations, we used a logistic regression as the cost function, 10,000 iterations with the Adam optimizer, a dropout probability of 0.5 and a learning rate of 0.001. The computational graph for training such a deep neural network, as generated by TensorBoard, is shown in
Figure 5
. Table 4 shows the parameters used when running each of the classifiers. ...
Citations
... With the advancements in technology, new deep learning classification models have become more applicable.
Saez et al. (2016)
reported that the use of CNN is possible with 280 nodes as input. These nodes were from six sensors: two accelerometers, one gyroscope, GPS, and one magnetometer. ...
... Each one provided a minimum of three features based on x,y,z-coordinates from each sensor system. CNN has also provided an increase in accuracy for activity recognition in medical health (DiPietro et al., 2016), physical activity
(Saez et al., 2016)
, and genetics (Ijjina & Chalavadi, 2016). ...
... Table 1 shows the anonymized information about the users of our experiments from PAMAP2, providing information about gender, age, height, weight, resting HR, maximum HR (calculated value), and dominant hand. Player1 Male 27 182 83 75 193 right Player2 Female 25 169 78 74 195 right Player3 Male 31 187 92 68 189 right Player4 Male 24 194 95 58 196 right Player5 Male 26 180 73 70 194 right Player6 Male 26 183 69 60 194 right Player7 Male 23 173 86 60 197 right Player8 Male 32 179 87 66 188 left Player9 Male 31 168 65 54 189 right For the ML algorithm feasibility test, we used synthetic generated datasets and anonymized sample datasets
[28]
. It has collected the minimum data threshold for a specific data science project. ...
Background:
One of the most critical topics in sports safety today is the reduction in injury risks through controlled fatigue using non-invasive athlete monitoring. Due to the risk of injuries, it is prohibited to use accelerometer-based smart trackers, activity measurement bracelets, and smart watches for recording health parameters during performance sports activities. This study analyzes the synergy feasibility of medical radar sensors and tri-axial acceleration sensor data to predict physical activity key performance indexes in performance sports by using machine learning (ML). The novelty of this method is that it uses a 24 GHz Doppler radar sensor to detect vital signs such as the heartbeat and breathing without touching the person and to predict the intensity of physical activity, combined with the acceleration data from 3D accelerometers.
Methods:
This study is based on the data collected from professional athletes and freely available datasets created for research purposes. A combination of sensor data management was used: a medical radar sensor with no-contact remote sensing to measure the heart rate (HR) and 3D acceleration to measure the velocity of the activity. Various advanced ML methods and models were employed on the top of sensors to analyze the vital parameters and predict the health activity key performance indexes. three-axial acceleration, heart rate data, age, as well as activity level variances.
Results:
The ML models recognized the physical activity intensity and estimated the energy expenditure on a realistic level. Leave-one-out (LOO) cross-validation (CV), as well as out-of-sample testing (OST) methods, have been used to evaluate the level of accuracy in activity intensity prediction. The energy expenditure prediction with three-axial accelerometer sensors by using linear regression provided 97-99% accuracy on selected sports (cycling, running, and soccer). The ML-based RPE results using medical radar sensors on a time-series heart rate (HR) dataset varied between 90 and 96% accuracy. The expected level of accuracy was examined with different models. The average accuracy for all the models (RPE and METs) and setups was higher than 90%.
Conclusions:
The ML models that classify the rating of the perceived exertion and the metabolic equivalent of tasks perform consistently.
... Therefore, a novel method is made possible by the picture representation of time series, allowing for the extraction of characteristics that are unavailable in the conventional 1D time series signals. Consequently, TSC issues can be seen as texture image recognition projects as well [7],
[8]
[44]
[7]
[7]
| https://www.researchgate.net/figure/Architecture-of-a-TensorFlow-graph-for-training-a-deep-neural-network-generated-with_fig5_311985317 |
draft-bradner-rfc3979bis-08
Intellectual Property Rights in IETF Technology (Internet-Draft, 2016)
Network Working Group Scott Bradner
Internet-Draft Harvard University
Intended status: BCP
Obsoletes:
3979
4879
Jorge Contreras
Updates:
2026
University of Utah
Expires: October 21, 2016 March 21, 2016
Intellectual Property Rights in IETF Technology
draft-bradner-rfc3979bis-08.txt
Abstract
The IETF policies about Intellectual Property Rights (IPR), such as
patent rights, relative to technologies developed in the IETF are
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to technology worked on within the IETF. It also describes the
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RFC 2026
and obsoletes
RFC 3979
and
RFC 4879
.
Status of this Memo
This Internet-Draft is submitted in full conformance with the
provisions of
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BCP 79
.
Internet-Drafts are working documents of the Internet Engineering
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This document is subject to
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and the IETF Trust's Legal
Bradner & Contreras [Page 1]
Internet-Draft RFC 3979 bis March 2016 Provisions Relating to IETF Documents
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Table of Contents 1 . Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Participation in the IETF . . . . . . . . . . . . . . . . . . . .
3.1. General Policy . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Rights and Permissions in Contributions. . . . . . . . . . . . .
3.3. Obligations on Participants . . . . . . . . . . . . . . . . . .
4. Actions for Documents for which IPR Disclosure(s)
Have Been Received . . . . . . . . . . . . . . . . . . . . . . .
5. IPR Disclosures . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Who Must Make an IPR Disclosure? . . . . . . . . . . . . . . . .
5.1.1. A Contributor's IPR in his or her Contribution . . . . . . .
5.1.2. An IETF Participant's IPR in Contributions by Others . . . .
5.1.3. IPR of Others . . . . . . . . . . . . . . . . . . . . . . . .
5.2. The Timing of Providing Disclosure . . . . . . . . . . . . . . .
5.2.1. Timing of Disclosure Under Section 5.1.1 . . . . . . . . . . .
5.2.2. Timing of Disclosure Under Section 5.1.2 . . . . . . . . . . .
5.3. How Must an IPR Disclosure be Made? . . . . . . . . . . . . . .
5.4. What Must be in an IPR Disclosure? . . . . . . . . . . . . . . .
5.4.2. Updating IPR Disclosures . . . . . . . . . . . . . . . . . . .
5.4.3. Blanket IPR Statements . . . . . . . . . . . . . . . . . . . .
5.5. Licensing Information in an IPR Disclosure . . . . . . . . . . .
5.6. Level of Control over IPR requiring Disclosure . . . . . . . . .
5.7. Disclosures for Oral Contributions . . . . . . . . . . . . . . .
5.8. General Disclosures . . . . . . . . . . . . . . . . . . . . . .
6. Failure to Disclose . . . . . . . . . . . . . . . . . . . . . . .
7. Evaluating Alternative Technologies in IETF Working Groups . . . .
8. Change Control for Technologies . . . . . . . . . . . . . . . . .
9. Licensing Requirements to Advance Standards Track IETF Documents .
10. No IPR Disclosures in IETF Documents . . . . . . . . . . . . . .
11. Application to non-IETF Stream Documents . . . . . . . . . . . .
12. Security Considerations . . . . . . . . . . . . . . . . . . . .
13. Changes Since RFC 3979 and RFC 4879 . . . . . . . . . . . . . . .
14. References . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.1. Normative References . . . . . . . . . . . . . . . . . . . . .
14.2. Informative References . . . . . . . . . . . . . . . . . . . .
15. Editor's Addresses . . . . . . . . . . . . . . . . . . . . . . . Bradner & Contreras [Page 2]
Internet-Draft RFC 3979 bis March 2016 1 . Definitions The following definitions are for terms used in the context of this
document. Other terms, including "IESG," "ISOC," "IAB," and "RFC
Editor," are defined in [ RFC2028 ].
a. "Alternate Stream": the IAB Document Stream, the IRTF Document
Stream and the Independent Submission Stream, each as defined in Section 5.1 of [RFC4844] .
b. "Contribution": any submission to the IETF intended by the
Contributor for publication as all or part of an Internet-Draft or
RFC and any statement made within the context of an IETF activity,
in each case that is intended to affect the IETF Standards Process
or that is related to the activity of an Alternate Stream that has
adopted this definition.
Such statements include oral statements, as well as written and
electronic communications, which are addressed to:
o the IETF plenary session,
o any IETF working group or portion thereof,
o any IETF "birds of a feather" (BOF) session or portion thereof,
o any IETF-sanctioned design team or portion thereof,
o the IESG, or any member thereof on behalf of the IESG,
o the IAB or any member thereof on behalf of the IAB,
o any IETF mailing list, web site, chat room or discussion board,
operated by or under the auspices of the IETF, including the
IETF list itself,
o the RFC Editor or the Internet-Drafts function.
Statements made outside of an IETF session, mailing list or other
function, or that are clearly not intended to be input to an IETF
activity, group or function, are not Contributions in the context
of this document. For example, the presentations made by invited
speakers at IETF plenary sessions to discuss advances in Internet
technology generally, or to describe their existing products or
technologies, are not Contributions.
Throughout this memo, the term "written Contribution" is used.
For purposes of this memo, "written" means reduced to a written or
visual form in any language and any media, permanent or temporary,
including but not limited to traditional documents, e-mail
messages, discussion board postings, slide presentations, text
messages, instant messages, and transcriptions of oral statements.
c. "Contributor": an individual submitting a Contribution Bradner & Contreras [Page 3]
Internet-Draft RFC 3979 bis March 2016 d. "Covers" or "Covered" mean that a valid claim of a patent or a
patent application (including a provisional patent application) in
any jurisdiction , or any other Intellectual Property Right, would
necessarily be infringed by the exercise of a right (e.g., making,
using, selling, importing, distribution, copying, etc.) with
respect to an Implementing Technology. For purposes of this
definition, "valid claim" means a claim of any unexpired patent or
patent application which shall not have been withdrawn, cancelled
or disclaimed, nor held invalid by a court of competent
jurisdiction in an unappealed or unappealable decision.
e. "IETF": In the context of this document, the IETF includes all
individuals who participate in meetings, working groups, mailing
lists, functions and other activities which are organized or
initiated by ISOC, the IESG or the IAB under the general
designation of the Internet Engineering Task Force or IETF, but
solely to the extent of such participation.
f. "IETF Documents": RFCs and Internet-Drafts that are published as
part of the IETF Standards Process. These are also referred to as
"IETF Stream Documents" as defined in Section 5.1.1 of RFC 4844 .
g. "IETF Standards Process": the activities undertaken by the IETF in
any of the settings described in the above definition of
Contribution. The IETF Standards Process may include
participation in activities and publication of documents that are
not directed toward the development of IETF standards or
specifications, such as the development and publication of
informational documents.
h. "IPR" or "Intellectual Property Rights": means a patent, utility
model, or similar right that may Cover an Implementing Technology,
whether such rights arise from a registration or renewal thereof,
or an application therefore, in each case anywhere in the world.
See [ RFC5378 ] for a discussion of Trademarks.
i. "Implementing Technology": means a technology that implements an
IETF specification or standard.
j. "Internet-Draft": a temporary document used in the IETF and RFC
Editor processes, as described in [ RFC2026 ].
k. "Participating in an IETF discussion or activity": means making a
Contribution, as described above, or in any other way acting in
order to influence the outcome of a discussion relating to the
IETF Standards Process. Without limiting the generality of the
foregoing, acting as a working group chair or Area Director
constitutes "Participating" in all activities of the relevant Bradner & Contreras [Page 4]
Internet-Draft RFC 3979 bis March 2016 working group or area. "Participant" and "IETF Participant" mean
any individual Participating in an IETF discussion or activity.
l. "Reasonably and personally known": means something an individual
knows personally or, because of the job the individual holds,
would reasonably be expected to know. This wording is used to
indicate that an organization cannot purposely keep an individual
in the dark about patents or patent applications just to avoid the
disclosure requirement. But this requirement should not be
interpreted as requiring the IETF Contributor or Participant (or
his or her represented organization, if any) to perform a patent
search to find applicable IPR.
m. "RFC": the basic publication series for the IETF. RFCs are
published by the RFC Editor and once published are never modified.
(See [RFC2026] Section 2.1 ) 2 . Introduction The IETF policies about Intellectual Property Rights (IPR), such as
patent rights, relative to technologies developed in the IETF are
designed to ensure that IETF working groups and Participants have as
much information about any IPR constraints on a technical proposal as
possible as early in the development process as possible. The
policies are intended to benefit the Internet community and the
public at large, while respecting the legitimate rights of IPR
holders. This memo details the IETF policies concerning IPR related
to technology worked on within the IETF. It also describes the
objectives that the policies are designed to meet. This memo updates RFC 2026 [ RFC2026 ] and obsoletes RFC 3979 [ RFC3979 ] and RFC 4879 [ RFC4879 ]. Section 1 defines the terms used in this document. Sections 3 through 11 set forth the IETF's policies and procedures relating to
IPR. Section 13 lists the changes between this document and RFCs
3979 and 4879. A separate document [ RFC5378 ] deals with rights (such
as copyrights and Trademarks) in Contributions, including the right
of IETF and its Participants to publish and create derivative works
of those Contributions. This document is not intended to address
those issues. See RFC 6702 [ RFC6702 ] for a discussion of "Promoting
Compliance with Intellectual Property Rights (IPR) Disclosure Rules".
This document is not intended as legal advice. Readers are advised
to consult their own legal advisors if they would like a legal
interpretation of their rights or the rights of the IETF in any
Contributions they make. 3 . Participation in the IETF Bradner & Contreras [Page 5]
Internet-Draft RFC 3979 bis March 2016 3.1 . General Policy In all matters relating to Intellectual Property Rights, the intent
is to benefit the Internet community and the public at large, while
respecting the legitimate rights of others. 3.2 . Rights and Permissions in Contributions By submission of a Contribution, each person actually submitting the
Contribution, and each named co-Contributor, is deemed to agree to
the following terms and conditions, on his or her own behalf, and on
behalf of the organizations the Contributor represents or is
sponsored by (if any) when submitting the Contribution. 3.3 . Obligations on Participants By Participating in IETF, each Participant is deemed to agree to
comply with all requirements of this RFC that relate to Participation
in IETF activities.
A. The Contributor represents that he or she has made or will
promptly make all disclosures required by Section 5.1.1 of this
document.
B. The Contributor represents that there are no limits to the
Contributor's ability to make the grants, acknowledgments and
agreements herein that are reasonably and personally known to the
Contributor. 4 . Actions for Documents for which IPR Disclosure(s) Have Been Received A. The IESG, IAB, ISOC and IETF Trust disclaim any responsibility for
identifying the existence of or for evaluating the applicability
of any IPR, disclosed or otherwise, to any IETF technology,
specification or standard, and will take no position on the
validity or scope of any such IPR.
B. When the IETF Secretariat has received a notification under Section 5.1.3 of the existence of non-participant IPR that
potentially Covers a technology under discussion at IETF or which
is the subject of an IETF Document, the IETF Secretariat shall
promptly publish such notification and will request that the
identified third party make an IPR disclosure in accordance with
the provisions of Section 5 .
C. When an IPR disclosure has been made as provided in Section 5 of
this document, the IETF Secretariat may request from the purported Bradner & Contreras [Page 6]
Internet-Draft RFC 3979 bis March 2016 holder of such IPR a written assurance that upon approval by the
IESG for publication of the relevant IETF specification(s) as one
or more RFCs, all persons will be able to obtain the right to
implement, use, distribute and exercise other rights with respect
to Implementing Technology under one of the licensing options
specified in Section 5.5 .A below unless a statement identifying
one of the licensing options described in Section 5.5 .A has
already been received by the IETF Secretariat. The working group
proposing the use of the technology with respect to which the
Intellectual Property Rights are disclosed may assist the IETF
Secretariat in this effort.
The results of this procedure shall not, in themselves, block
publication of an IETF Document or advancement of an IETF Document
along the standards track. A working group may take into
consideration the results of this procedure in evaluating the
technology, and the IESG may defer approval when a delay may
facilitate obtaining such assurances. The results will, however,
be recorded by the IETF Secretariat, and be made available online.
D. Determination of Provision of Reasonable and Non-discriminatory
Terms
The IESG will not make any determination that any terms for the
use of an Implementing Technology has been fulfilled in practice. 5 . IPR Disclosures This document refers to the IETF Participant making disclosures,
consistent with the general IETF philosophy that Participants in the
IETF act as individuals. A Participant's obligation to make a
disclosure is also considered satisfied if the IPR owner, which may
be the Participant's employer or sponsor, makes an appropriate
disclosure in place of the Participant doing so. 5.1 . Who Must Make an IPR Disclosure? 5.1.1 . A Contributor's IPR in his or her Contribution Any Contributor who reasonably and personally knows of IPR meeting
the conditions of Section 5.6 which the Contributor believes Covers
or may ultimately Cover his or her written Contribution (other than a
Contribution that is not intended to be used as an input into the
IETF Standards Process), or which the Contributor reasonably and
personally knows his or her employer or sponsor may assert against
Implementing Technologies based on such written Contribution, must
make a disclosure in accordance with this Section 5 . Bradner & Contreras [Page 7]
Internet-Draft RFC 3979 bis March 2016 5.1.2 . An IETF Participant's IPR in Contributions by Others If an individual Participates relative to a written Contribution
(other than a Contribution that is not intended to be used as an
input into the IETF Standards Process) made by another person and
such Participant reasonably and personally knows of IPR meeting the
conditions of Section 5.6 which the Participant believes Covers or
may ultimately Cover that Contribution, or which the Participant
reasonably and personally knows his or her employer or sponsor may
assert against Implementing Technologies based on such written
Contribution, then such Participant must make a disclosure in
accordance with this Section 5 . 5.1.3 . IPR of Others If any person has information about IPR that may Cover a written
Contribution, but such person is not required to disclose such IPR
because it does not meet the criteria in Section 6.6 (e.g., the IPR
is not owned or controlled by the person or his or her employer or
sponsor, or such person is not an IETF Participant), such person is
encouraged to file a third party disclosure as described in Section 5.3 below. Such a notice should be filed as soon as reasonably
possible after the person realizes that such IPR may Cover a
Contribution. 5.2 . The Timing of Providing Disclosure Timely IPR disclosure is important because working groups need to
have as much information as they can while they are evaluating
alternative solutions. 5.2.1 . Timing of Disclosure Under Section 5.1.1 A. The IPR disclosure required pursuant to section 5.1.1 must be made
as soon as reasonably possible after the Contribution is submitted
or made unless the required disclosure is already on file. For
example, if the Contribution is an update to a Contribution for
which an IPR disclosure has already been made and the
applicability of the disclosure is not changed by the new
Contribution, then no new disclosure is required. But if the
Contribution is a new one, or is one that changes an existing
Contribution such that the revised Contribution is no longer
Covered by the disclosed IPR or would be Covered by new or
different IPR, then a new disclosure must be made.
B. If a Contributor first learns of IPR in its Contribution that
meets the conditions of Section 5.6 , for example a new patent
application or the discovery of a relevant patent in a patent Bradner & Contreras [Page 8]
Internet-Draft RFC 3979 bis March 2016 portfolio, after the Contribution is published in an Internet-
Draft, a disclosure must be made as soon as reasonably possible
after the IPR becomes reasonably and personally known to the
Contributor. 5.2.2 . Timing of Disclosure Under Section5.1.2 The IPR disclosure required pursuant to section 5.1.2 must be made as
soon as reasonably possible after the Contribution is made, unless
the required disclosure is already on file.
Participants who realize that IPR meeting the conditions of Section 5.6 will be or has been incorporated into a Contribution, or is
seriously being discussed in a working group, are strongly encouraged
to make a preliminary IPR disclosure. That IPR disclosure should be
made as soon after coming to the realization as reasonably possible,
not waiting until the Contribution is actually made.
If an IETF Participant first learns of IPR that meets the conditions
of Section 5.6 in a Contribution by another party, for example a new
patent application or the discovery of a relevant patent in a patent
portfolio, after the Contribution was made, an IPR disclosure must be
made as soon as reasonably possible after the Contribution or IPR
becomes reasonably and personally known to the Participant. 5.3 . How Must an IPR Disclosure be Made? IPR disclosures must be made by following the instructions at http://www.ietf.org/ipr-instructions . IPR disclosures and other IPR-
related information, including licensing information, must not be
included in RFCs or other IETF Contributions. The RFC-Editor will
remove any IPR-related information from Contributions prior to
publication as an RFC. 5.4 . What Must be in an IPR Disclosure? 5.4.1 . Content of IPR Disclosures An IPR disclosure must list the numbers of any issued patents or
published patent applications or indicate that the disclosure is
based on unpublished patent applications. The IPR disclosure must
also list the name(s) of the inventor(s) (with respect to issued
patents and published patent applications) and the specific IETF
Document(s) or activity affected. If the IETF Document is an
Internet-Draft, it must be referenced by specific version number. In
addition, if the IETF Document includes multiple parts and it is not
reasonably apparent which part of such IETF Document is alleged to be Bradner & Contreras [Page 9]
Internet-Draft RFC 3979 bis March 2016 Covered by the IPR in question, it is helpful if the discloser
identifies the sections of the IETF Document that are alleged to be
so Covered. 5.4.2 . Updating IPR Disclosures. Those who disclose IPR should be aware that as drafts evolve, text
may be added or removed, and it is recommended that they keep this in
mind when composing text for disclosures.
A. An IPR disclosure must be updated or a new disclosure made
promptly after any of the following has occurred: (1) the
publication of a previously unpublished patent application,
(unless sufficient information to identify the published
application was disclosed when the unpublished application was
disclosed), (2) the abandonment of a patent application (3) the
issuance of a patent on a previously disclosed patent application
(unless sufficient information to identify the issued patent was
disclosed when the patent application was disclosed), (4) a
material change to the IETF Document covered by the Disclosure
that causes the Disclosure to be covered by additional IPR. If a
patent has issued, then the new IPR disclosure must include the
patent number and, if the claims of the granted patent differ from
those of the application in manner material to the relevant
Contribution, the IPR disclosure must describe any differences in
applicability to the Contribution. If the patent application was
abandoned, then the new IPR disclosure must explicitly withdraw
any earlier IPR disclosures based on the application. IPR
disclosures against a particular Contribution are assumed to be
inherited by revisions of the Contribution and by any RFCs that
are published from the Contribution unless the disclosure has been
updated or withdrawn.
B. If an IPR holder files patent applications in additional countries
which refer to, and the claims of which are substantially
identical to, the claims of a patent or patent application
previously disclosed in an IPR disclosure, the IPR holder is not
required to make a new or updated IPR disclosure as a result of
filing such applications or the issuance of patents on such
applications.
C. New or revised IPR disclosures may be made voluntarily at any
other time, provided that licensing information may only be
updated in accordance with Section 5.5 .C.
D. Any person may submit to IETF an update to an existing IPR
disclosure. If such update is submitted by a person other than
the submitter of the original IPR disclosure (as identified by Bradner & Contreras [Page 10]
Internet-Draft RFC 3979 bis March 2016 name and e-mail address), then the Secretariat shall attempt to
contact the original submitter to verify the update. If the
original submitter responds that the proposed update is valid, the
Secretariat will update the IPR disclosure accordingly. If the
original submitter responds that the proposed update is not valid,
the Secretariat will not update the IPR disclosure. If the
original submitter fails to respond after the Secretariat has made
three separate inquiries and at least 30 days have elapsed since
the initial inquiry was made, then the Secretariat will inform the
submitter of the proposed update that the update was not
validated, and that the updater must produce legally sufficient
evidence that the submitter (or his/her employer) owns or has the
legal right to exercise control over the IPR subject to the IPR
disclosure. If such evidence is satisfactory to the Secretariat,
after consultation with legal counsel, then the Secretariat will
make the requested update. If such evidence is not satisfactory,
then the Secretariat will not make the requested update. 5.4.3 . Blanket IPR Statements The requirement to make an IPR disclosure is not satisfied by the
submission of a blanket statement that IPR may exist on every
Contribution or a general category of Contributions. This is the
case because the aim of the disclosure requirement is to provide
information about specific IPR against specific technology under
discussion in the IETF. The requirement is also not satisfied by a
blanket statement of willingness or commitment to license all
potential IPR Covering such technology under fair, reasonable and
non-discriminatory terms for the same reason. However, the
requirement for an IPR disclosure is satisfied by a blanket statement
of the IPR discloser's commitment to license all of its IPR meeting
the requirements of Section 5.6 (and either Section 5.1.1 or 5.1.2)
to implementers of an IETF specification on a royalty-free (and
otherwise reasonable and non-discriminatory) basis as long as any
other terms and conditions are disclosed in the IPR disclosure. 5.5 . Licensing Information in an IPR Disclosure A. Since IPR disclosures will be used by IETF working groups during
their evaluation of alternative technical solutions, it is helpful
if an IPR disclosure includes information about licensing of the
IPR in case Implementing Technologies require a license.
Specifically, it is helpful to indicate whether, upon approval by
the IESG for publication as an RFC of the relevant IETF
specification(s), all persons will be able to obtain the right to
implement, use, distribute and exercise other rights with respect
to an Implementing Technology a) under a royalty-free and
otherwise reasonable and non- discriminatory license, or b) under Bradner & Contreras [Page 11]
Internet-Draft RFC 3979 bis March 2016 a license that contains reasonable and non-discriminatory terms
and conditions, including a reasonable royalty or other payment,
or c) without the need to obtain a license from the IPR holder
(i.e., a covenant not to sue).
B. The inclusion of a licensing declaration is not mandatory but it
is encouraged so that the working groups will have as much
information as they can during their deliberations. If the
inclusion of a licensing declaration in an IPR disclosure would
significantly delay its submission then the discloser may submit
an IPR disclosure without a licensing declaration and then submit
a new IPR disclosure when the licensing declaration becomes
available. IPR disclosures that voluntarily provide text that
includes licensing information, comments, notes, or URL for other
information may also voluntarily include details regarding
specific licensing terms that the IPR holder intends to offer to
implementers of Implementing Technologies, including maximum
royalty rates
C. It is likely that IETF will rely on licensing declarations and
other information that may be contained in an IPR disclosure and
that implementors will make technical, legal and commercial
decisions on the basis of such commitments and information. Thus,
when licensing declarations and other information, comments,
notes, or URLs for further information are contained in an IPR
disclosure, the persons making such disclosure agree and
acknowledge that the commitments and information contained in such
disclosure shall be irrevocable, and will attach to the associated
IPR, and all implementers of Implementing Technologies will be
justified and entitled to rely on such materials in relating to
such IPR, whether or not such IPR is subsequently transferred to a
third party by the IPR holder making the commitment or providing
the information. IPR holders making IPR disclosures that contain
licensing declarations or providing such information, comments,
notes or URLs for further information must ensure that such
commitments are binding on any subsequent transferee of the
relevant IPR.
D. Licensing declarations must be made by people who are authorized
to make such declarations. 5.6 . Level of Control over IPR requiring Disclosure IPR disclosures under Sections 5.1.1 . and 5.1.2 are required with
respect to IPR that is (a) owned, directly or indirectly, by the
individual or his/her employer or sponsor (if any) or (b) that such
persons otherwise have the right to license or assert or (c) that Bradner & Contreras [Page 12]
Internet-Draft RFC 3979 bis March 2016 such persons derive a direct or indirect pecuniary benefit from such
IPR, or (d) in the case of an individual, the individual is listed as
an inventor on a patent or patent application. 5.7 . Disclosures for Oral Contributions. If a Contribution is oral and is not followed promptly by a written
disclosure of the same material, and if such oral Contribution would
be subject to a requirement that an IPR Disclosure be made had such
oral Contribution been written, then the Contributor must accompany
such oral Contribution with an oral declaration that he/she is aware
of relevant IPR in as much detail as reasonably possible, or file an
IPR Declaration with respect to such oral Contribution that otherwise
complies with the provisions of Sections 5.1 to 5.6 above. 5.8 . General Disclosures. The IETF may make available a public facility (e.g., a web page and
associated database) for the posting of IPR-related information and
disclosures that do not conform to the requirements of Sections 5.1 to 5.6 ("General Disclosures"). General Disclosures may include,
among other things, "blanket disclosures" described in Section 5.4.3 (other than blanket disclosures accompanied by royalty-free licensing
commitments, as permitted by Section 5.4.3 ), disclosures of IPR that
do not identify the specific IETF Documents Covered by the disclosed
IPR, and licensing statements or commitments that are applicable
generally and not to specific IPR disclosures. All of this
information may be helpful to the IETF community, and its disclosure
is encouraged. However, General Disclosures do not satisfy an IETF
Participant's obligation to make IPR disclosures as required by this
policy.
In some cases, if an IPR disclosure submitted by an IETF Participant
does not meet the requirements of this policy, the IETF may elect to
post the non-conforming IPR disclosure as a General Disclosure, in
order to provide the greatest amount of information to the IETF
community. This action does not excuse the IETF Participant from
submitting a new IPR disclosure that conforms with the requirements
of Sections 5.1 to 5.6 . The IETF reserves the right to decline to
publish General Disclosures that are not relevant to IETF activities,
that are, or are suspected of being, defamatory, false, misleading,
in violation of privacy or other applicable laws or regulations, or
that are in a format that is not suitable for posting on the IETF
facility that has been designated for General Disclosures. 6 . Failure to Disclose There may be cases in which individuals are not permitted by their Bradner & Contreras [Page 13]
Internet-Draft RFC 3979 bis March 2016 employers or by other factors to disclose the existence or substance
of patent applications or other IPR. Since disclosure is required
for anyone making a Contribution or participating in IETF activities,
a person who is not willing or able to disclose IPR for this reason,
or any other reason, must not contribute to or participate in IETF
activities with respect to technologies that he or she reasonably and
personally knows to be Covered by IPR which he or she will not
disclose, unless that person knows that his or her employer or
sponsor will make the required disclosures on his or her behalf.
Contributing to or participating in IETF activities about a
technology without making required IPR disclosures is a violation of
IETF process.
In addition to any remedies the IESG may consider other actions. See
[ RFC6701 ] for details. 7 . Evaluating Alternative Technologies in IETF Working Groups In general, IETF working groups prefer technologies with no known IPR
claims or, for technologies with claims against them, an offer of
royalty-free licensing. However, to solve a given technical problem,
IETF working groups have the discretion to adopt a technology as to
which IPR claims have been made if they feel that this technology is
superior enough to alternatives with fewer IPR claims or free
licensing to outweigh the potential cost of the licenses. To assist
these working groups, it is helpful for the IPR claimants to declare,
in their IPR Declarations, the terms, if any, on which they are
willing to license their IPR Covering the relevant IETF Documents.
When adopting new technologies, the participants in an IETF working
group are expected to evaluate all the relevant tradeoffs from their
perspective. Most of the time these considerations are based purely
on technical excellence, but IPR considerations may also affect the
evaluation and specific licensing terms may affect the participants'
opinion on the desirability of adopting a particular technology.
The IETF has no official preference among different licensing terms
beyond what was stated at the beginning of this section. However, for
information and to assist participants in understanding what license
conditions may imply, what follows are some general observations
about some common types of conditions. This paragraph is provided for
information only:
When there is no commitment to license patents covering the
technology, this creates uncertainty that obviously is concerning.
These concerns do not exist when there is a commitment to license,
but the license terms can still differ greatly. Some common Bradner & Contreras [Page 14]
Internet-Draft RFC 3979 bis March 2016 conditions include 1) terms that are fair, reasonable and non-
discriminatory, and which may bear royalties or other financial
obligations (FRAND or RAND); 2) royalty-free terms that are otherwise
fair, reasonable and non-discriminatory (RAND-z); and 3) commitments
not to assert declared IPR. Open source projects, for instance, often
prefer the latter two. However, licenses often come with complex
terms that have to be evaluated in detail, and this crude
classification may not be sufficient to make a proper evaluation. For
instance, licenses may also include reciprocity and defensive
suspension requirements that require careful evaluation.
The level of use of a technology against which IPR is disclosed is
also an important factor in weighing IPR encumbrances and associated
licensing conditions against technical merits. For example, if
technologies are being considered for a mandatory-to-implement change
to a widely deployed protocol, the hurdle should be very high for
encumbered technologies, whereas a similar hurdle for a new protocol
could conceivably be lower.
Over the last few years the IETF has adopted stricter requirements
for some security technologies. It has become common to have a
mandatory-to-implement security technology in IETF technology
specifications. This is to ensure that there will be at least one
common security technology present in all implementations of such a
specification that can be used in all cases. This does not limit the
specification from including other security technologies, the use of
which could be negotiated between implementations. An IETF consensus
has developed that no mandatory-to-implement security technology can
be specified in an IETF specification unless it has no known IPR
claims against it or a royalty-free license is available to all
implementers of the specification unless there is a very good reason
to do so. This limitation does not extend to other security
technologies in the same specification if they are not listed as
mandatory-to-implement.
It should also be noted that the absence of IPR disclosures at any
given time is not the same thing as the knowledge that there will be
no IPR disclosure in the future, or that no IPR Covers the relevant
technology. People or organizations not currently involved in the
IETF or people or organizations that discover IPR they feel to be
relevant in their patent portfolios can make IPR disclosures at any
time.
It should be noted that the validity and enforceability of any IPR
may be challenged for legitimate reasons outside the IETF. The mere
existence of an IPR disclosure should not be taken to mean that the
disclosed IPR is valid or enforceable or actually Covers a particular Bradner & Contreras [Page 15]
Internet-Draft RFC 3979 bis March 2016 Contribution. Although the IETF can make no actual determination of
validity, enforceability or applicability of any particular IPR, it
is reasonable that a working group or the IESG will take into account
on their own views of the validity, enforceability or applicability
of IPR in their evaluation of alternative technologies. 8 . Change Control for Technologies The IETF must have change control over the technology described in
any standards track IETF Documents in order to fix problems that may
be discovered or to produce other derivative works.
In some cases the developer of patented or otherwise controlled
technology may decide to hand over to the IETF the right to evolve
the technology (a.k.a., "change control"). The implementation of an
agreement between the IETF and the developer of the technology can be
complex. (See [ RFC1790 ] and [ RFC2339 ] for examples.)
Note that there is no inherent prohibition against a standards track
IETF Document making a normative reference to proprietary technology.
For example, a number of IETF Standards support proprietary
cryptographic transforms. 9 . Licensing Requirements to Advance Standards Track IETF Documents RFC 6410 [RFC6410] Section 2.2 states: "If the technology required to
implement the specification requires patented or otherwise controlled
technology, then the set of implementations must demonstrate at least
two independent, separate and successful uses of the licensing
process. " A key word in this text is "requires." The mere
existence of disclosed IPR does not necessarily mean that licenses
are actually required in order to implement the technology. 10 . No IPR Disclosures in IETF Documents IETF Documents must not contain any mention of specific IPR. All
specific IPR disclosures must be submitted as described in Section 5 .
Readers should always refer to the on-line web page to get a full
list of IPR disclosures received by the IETF concerning any
Contribution. ( http://www.ietf.org/ipr/ ) 11 . Application to non-IETF Stream Documents This memo has been developed for the benefit and use of the IETF
community. As such, the rules set forth herein apply to all
Contributions and IETF Documents that are in the "IETF Document
Stream" as defined in Section 5.1.1 of RFC 4844 (i.e., those that are
contributed, developed, edited and published as part of the IETF Bradner & Contreras [Page 16]
Internet-Draft RFC 3979 bis March 2016 Standards Process). The IAB Document Stream, the IRTF Document
Stream and the Independent Submission Stream, each as defined in Section 5.1 of RFC 4844 are referred to collectively herein as
"Alternate Streams".
The legal rules that apply to documents in Alternate Streams are
established by the managers of those Alternate Streams as defined in
[ RFC 4844 ]. (i.e., the Internet Architecture Board (IAB), Internet
Research Steering Group (IRSG) and Independent Submission Editor).
These managers may elect, through their own internal processes, to
cause this memo to be applied to documents contributed to them for
development, editing and publication in their respective Alternate
Streams. If an Alternate Stream manager elects to adopt this memo,
they must do so in a manner that is public and notifies their
respective document contributors that this memo applies to their
respective Alternate Streams. In such case, each occurrence of the
term "Contribution," and "IETF Document" in this memo shall be read
to mean a contribution or document in such Alternate Stream, as the
case may be. It would be advisable for such Alternate Stream manager
to consider adapting the definitions of "Contribution," and other
provisions in the memo to suit their particular needs. 12 . Security Considerations This memo relates to IETF process, not any particular technology.
There are security considerations when adopting any technology,
whether IPR-protected or not. A working group should take those
security considerations into account as one part of evaluating the
technology, just as IPR is one part, but there are no known issues of
security with IPR procedures. 13 . Changes Since RFC 3979 and RFC 4879 [this section will be revised before publication to list the actual
changes that are approved]
This document combines RFC 3979 and RFC 4879 .
Reordered the defined terms
Boilerplate -- since the document boilerplate formerly in BCP79 Sec.
5 has been moved to the Trust Legal Provisions since 2009, deleted
the boilerplate requirements from this document.
Foreign Counterparts -- don't need to file a new IPR disclosure
Provisional Apps -- suggest that these be required to be disclosed
when covering the technology in question. Bradner & Contreras [Page 17]
Internet-Draft RFC 3979 bis March 2016 Inventor names -- added words requiring that inventors be listed
along with patent numbers as result of WG discussion.
Oral statements -- the existing text is internally contradictory.
Some places say that disclosures must be made for oral statements,
but others talk about disclosures only being required following
publication as an ID. Proposed that oral statements don't trigger
the normal IPR disclosure obligations, as oral statements are
inherently imprecise and it's hard to know when they describe
something covered by the technical terms of a patent claim.
However, if an oral contribution is made and it is not followed by
a written contribution, then the oral discloser must either make a
concurrent oral IPR disclosure or file a formal written
disclosure.
Other Contribution Clarification -- suggested a number of other
clarifications to the definition of Contribution that have come up
over the years, including the addition of BOFs.
WG Consideration of Patents -- this is mostly in the existing
language, but added a sentence saying that WGs should not engage
in collective licensing negotiation.
Disclosure of licensing terms is ok -- added a sentence.
Licensing commitments are irrevocable -- added a paragraph.
Participation -- this is a complicated issue that runs throughout the
document. At a high level, suggested that anyone who says
something on a list or in a WG meeting is required to make IPR
disclosures
Updating Disclosures - added a number of clauses to address issues
that have come up over the years, including updating obligations
if an employee changes jobs or his/her employer buys another
company.
Alternate Streams - borrowed and adapted the copyright language used
in the Trust Legal Provisions. Each alternate stream
(Independent, IRTF and IAB) would need to take some action
(preferably issuing an RFC) to adopt BCP 79 for its stream. This
was done with copyright already, and pretty smoothly.
IETF Exec Dir -- flagged the various places where the IETF Exec
Director is supposed to do something under this policy. Not sure
whether these things are getting done today or by whom. Need to
rationalize and update these procedures based on the current admin
structure. Bradner & Contreras [Page 18]
Internet-Draft RFC 3979 bis March 2016 Generally, also tried to cut back some of the historical and
explanatory text that seemed outdated 14 . References 14.1 . Normative References [ RFC2026 ] Bradner, S., "The Internet Standards Process -- Revision
3", BCP 9 , RFC 2026 , October 1996.
[ RFC2028 ] Hovey, R. and S. Bradner, "The Organizations Involved in
the IETF Standards Process", BCP 11 , RFC 2028 , October 1996.
[ RFC4844 ] Daigle, L. Ed. and Internet Architecture Board, "The RFC
Series and RFC Editor", RFC 4844 , July 2007.
[ RFC6410 ] Housley, R., D. Crocker, and E. Burger, "Reducing the
Standards Track to Two Maturity Levels", RFC 6401 , October 2011. 14.2 . Informative References [ RFC1790 ] Cerf, V., "An Agreement between the Internet Society and
Sun Microsystems, Inc. in the Matter of ONC RPC and XDR
Protocols", RFC 1790 , April 1995.
[ RFC2339 ] The Internet Society and Sun Microsystems, "An Agreement
Between the Internet Society, the IETF, and Sun Microsystems, Inc.
in the matter of NFS V.4 Protocols", RFC 2339 , May 1998.
[ RFC5378 ] Bradner, S. Ed, J. Contreras, Ed, "Rights Contributors
Provide to the IETF Trust", RFC 5378 , November 2008
[ RFC6701 ] Farrel, A., and P. Resnick, "Sanctions Available for
Application to Violators of IETF IPR Policy", RFC 6702 , August
2012
[ RFC6702 ] Polk, T. and P. Saint-Andre, "Promoting Compliance with
Intellectual Property Rights (IPR)Disclosure Rules", RFC 6702 ,
August 2012
IANA Considerations
This memo requires no action by the IANA. [this section should be
removed for publication] 15 . Editor's Addresses Scott Bradner Bradner & Contreras [Page 19]
Internet-Draft RFC 3979 bis March 2016 Harvard University
8 Story St.
Cambridge MA, 02138
Phone: +1 617 495 3864
EMail: sob@harvard.edu
Jorge Contreras
University of Utah
S.J. Quinney College of Law
383 South University St.
Salt Lake City, UT 84112
Email: cntreras@gmail.com
Changes in revisions of this document
[this section should be removed for publication]
version 00 -> version 01
many clean ups suggested by Russ Housley
removed "informational" from section 5.1.1 version 01 -> version 02
change RFC 2026 reference in section 9 to RFC 6410 fixed multiple references to (old) section 6 revised section 5.5 to clarify the intention, as suggested by David
Rudin
version 02 -> version 03
created a definition of "participation" in the definitions section as
suggested by multiple people
A number of changes suggested by Adrian Farrel
expanded introduction by including a copy of the abstract
fixed reference to RFC 6701 add mention of RFC 6702 to the introduction and added RFC 6702 to
the references
removed last sentence of section 5.4.2 B
removed discussion of asking for info on non-US patents from section 13 revised 5.4.2.C
added 5.4.2 D based on a suggestion by Alexa Morris
add note about inheritance to section 5.4.2 .A
revise list of bullets for definition of contribution - section 1 .b
added 5.5.D Bradner & Contreras [Page 20]
Internet-Draft RFC 3979 bis March 2016 fixed wording problem in 5.2.2 noted by SM
version 03 -> version 04
revised definition of "Participating in an IETF discussion or
activity" section 1 .k
changed language re "foreign" patents - section 5.4.2 B
removed mention of claims in provisional applications in section 1 .d
version 04 -> version 05
revised section 1 .k based on list discussion
tightened up section 4 .B and removed the last sentence which
describes a function that does not seem to be done - suggested by
Fabian Gonell
change the requirement in section 5.1.1 .B to a request - - suggested
by Fabian Gonell
replaced "withdraw" with "update" in 5.1.1.B since the disclosure is
still valid against the older Contribution
remove section 5.2.1 .C as redundant - suggested by Fabian Gonell
added text from the mailing list discussion to Section 5.4.2 revised section 5.4.2 .D to have the licensing information
requirements in one place. - suggested by Fabian Gonell
version 05 -> version 06
revised 1.k based on BOF and list discussion, added assumptive
participation for WG chairs & ADs
changed "should" in 4.C to reflect current practice
removed 5.1.1 B since the topic is covered in 5.4.3
added "with respect to issued patents and published patent
applications" in 5.4.1 based on BOF discussion
revised 5.4.2 A based on BOF discussion
removed 5.4.2 C since it was redundant
added parenthetical at the end of 5.5 A
added additional clause to 5.6 based on issue that came up
added 5.8 on general disclosures based on BOF discussion
revised 7 based on suggestions by Stephen Wegner and mailing list
discussions
removed the last sentence of 7 since the legal picture is changing
version 06 -> version 07
5.3 -- clarify that extraneous IPR disclosures should not be made in
Contributions, only in IPR Disclosures
in 5.4.1 went from "must" disclose section of document affected to
"it is helpful" to disclose this, at AD request (restore to 3979)
6 -- removed list of potential non-compliance penalties and instead
refer to RFC 6701 .
7 -- removed order of preference for licensing terms and replaced
with AD suggested language Bradner & Contreras [Page 21]
Internet-Draft RFC 3979 bis March 2016
version 07 -> version 08
added ToC
revised
section 5.1.2
changed "working group" to "implementor" in
section 5.5
c
Bradner & Contreras [Page 22]
draft-bradner-rfc3979bis-08 Internet-Draft
Info
Document Document type This is an older version of an Internet-Draft that was ultimately published as RFC 8179 . Select version 00 01 02 03 04 05 06 07 08 09 10 11 12 13 RFC 8179 Compare versions RFC 8179 draft-bradner-rfc3979bis-13 draft-bradner-rfc3979bis-12 draft-bradner-rfc3979bis-11 draft-bradner-rfc3979bis-10 draft-bradner-rfc3979bis-09 draft-bradner-rfc3979bis-08 draft-bradner-rfc3979bis-07 draft-bradner-rfc3979bis-06 draft-bradner-rfc3979bis-05 draft-bradner-rfc3979bis-04 draft-bradner-rfc3979bis-03 draft-bradner-rfc3979bis-02 draft-bradner-rfc3979bis-01 draft-bradner-rfc3979bis-00 RFC 3979 draft-bradner-rfc3979bis-07 RFC 8179 draft-bradner-rfc3979bis-13 draft-bradner-rfc3979bis-12 draft-bradner-rfc3979bis-11 draft-bradner-rfc3979bis-10 draft-bradner-rfc3979bis-09 draft-bradner-rfc3979bis-08 draft-bradner-rfc3979bis-07 draft-bradner-rfc3979bis-06 draft-bradner-rfc3979bis-05 draft-bradner-rfc3979bis-04 draft-bradner-rfc3979bis-03 draft-bradner-rfc3979bis-02 draft-bradner-rfc3979bis-01 draft-bradner-rfc3979bis-00 RFC 3979 draft-bradner-rfc3979bis-08 Side-by-side Inline Authors Scott O. Bradner , Jorge Contreras RFC stream Other formats txt pdf bibtex Report a datatracker bug
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Polymers | Free Full-Text | Antibacterial Activity of Polymer Nanocomposites Incorporating Graphene and Its Derivatives: A State of Art
The incorporation of carbon-based nanostructures into polymer matrices is a relevant strategy for producing novel antimicrobial materials. By using nanofillers of different shapes and sizes, and polymers with different characteristics, novel antimicrobial nanocomposites with synergistic properties can be obtained. This article describes the state of art in the field of antimicrobial polymeric nanocomposites reinforced with graphene and its derivatives such as graphene oxide and reduced graphene oxide. Taking into account the vast number of articles published, only some representative examples are provided. A classification of the different nanocomposites is carried out, dividing them into acrylic and methacrylic matrices, biodegradable synthetic polymers and natural polymers. The mechanisms of antimicrobial activity of graphene and its derivatives are also reviewed. Finally, some applications of these antimicrobial nanocomposites are discussed. We aim to enhance understanding in the field and promote further work on the development of polymer-based antimicrobial nanocomposites incorporating graphene-based nanomaterials.
10.3390/polym13132105
Antibacterial Activity of Polymer Nanocomposites Incorporating Graphene and Its Derivatives: A State of Art
by Ana M. Díez-Pascual * and José A. Luceño-Sánchez
Universidad de Alcalá, Facultad de Ciencias, Departamento de Química Analítica, Química Física e Ingeniería Química, Ctra. Madrid-Barcelona, Km. 33.6, 28805 Alcalá de Henares, Madrid, Spain
Author to whom correspondence should be addressed.
Polymers 2021 , 13 (13), 2105; https://doi.org/10.3390/polym13132105
Received: 9 June 2021 / Revised: 22 June 2021 / Accepted: 23 June 2021 / Published: 26 June 2021
Abstract
:
Keywords:
antimicrobial activity
polymer nanocomposites
graphene
graphene oxide
reactive oxygen species
synergic effects
1. Introduction
1
Pseudomonas aeruginosa
P. aeruginosa
Staphylococcus aureus
S. aureus
2
Escherichia coli (E. coli)
E. coli
Contamination by microorganisms is a critical parameter in diverse areas, such as medical devices, dental equipment, healthcare products and hygienic applications, hospital surfaces/furniture, dental restoration, water purification systems, food packaging and storage, and so forth. To solve this issue, several types of thermoplastic materials are sterilized and antisepsis by different methods, including dry or wet heating and ionic radiation, are employed. However, microorganisms can pollute these polymers when exposed to the environment. Therefore, there is an urgent need for novel polymeric material with antibacterial activity [ 3 ]. Thermoplastics are strong and able to resist repeated sterilization, high severe temperatures and chemical environments. Consequently, antimicrobial polymer composites can be employed as a strategy to circumvent hospital-acquired infections, and can be prepared either by inserting a biocide agent into the polymer bulk, i.e., during their processing or by applying surface coatings [ 4 , 5 ]. Furthermore, three main groups of polymer nanocomposites have been reported depending on how the nanoparticles and polymers are combined [ 6 ]: (1) non-polymer coated nanoparticles distributed in a polymer matrix, (2) nanoparticles attached to polymeric micro/nanostructures, (3) polymer-grafted nanoparticles, which form a core shell structure, dispersed inside a polymer matrix. Hybrid structures with carbon cores and polymer brushes can be formed via controlled/living polymerization as a result of “grafting to” or “grafting from” methods [ 7 , 8 ].
Up until now, a wide number of antimicrobial agents, including metal nanoparticles, metal-oxide nanoparticles [ 9 ] and carbon nanomaterials [ 3 ], have been used as fillers to reinforce polymeric matrices. Recently, graphene (G) and its derivatives ( Scheme 1 ), graphene oxide (GO), reduced graphene oxide (rGO) and graphene quantum dots (GQDs) have arisen as effective antimicrobial agents on pathogens, fungi, and bacteria [ 10 ].
Graphene is an atomically thin, 2D layer of sp 2 carbon atoms in a honeycomb structure. It possesses a unique combination of properties including high stiffness and strength, elevated thermal and electrical conductivity, very high electron mobility, molecular barrier capability, low toxicity and so forth [ 11 ]. For these reasons, a lot of effort has been devoted to integrating G into polymeric matrices to design polymer-based nanocomposites with outstanding properties due to synergistic effects. Nonetheless, the use of pristine G has been limited due to its insolubility in aqueous media, and strong agglomeration tendency, owing to van der Waals interactions among sheets. To solve this issue, several graphene derivatives, including GO, rGO and GQDs have been used as nanofillers in polymer nanocomposites.
13
Scheme 1
Over the last years, a vast number of reviews dealing with polymeric materials with antimicrobial activity have been published [ 14 , 15 , 16 ]. Furthermore, a few articles have reviewed the antimicrobial properties of G-based materials [ 17 , 18 , 19 ]. In this article, the antimicrobial properties of polymeric composites comprising G or its derivatives are reviewed. Due to the large number of articles in the field, only some representative examples are described. The idea is to provide the reader with a panoramic of the current state of art in this exciting and lively field, and to promote further work on the development of polymer-based antimicrobial nanocomposites. Additionally, some applications of these antimicrobial nanocomposites are discussed.
2. Mechanisms of Antimicrobial Activity of Graphene and Its Derivatives
Hu et al. [ 20 ] in 2010 reported for the first time that GO possessed excellent antimicrobial activity. Since then, numerous studies have reported the antimicrobial activity of G and its derivatives [ 21 , 22 , 23 , 24 ]. Their antibacterial action can be ascribed to several mechanisms, including chemical and physical processes, as depicted in Scheme 2 .
2.1. Chemical Mechanisms of Antibacterial Action
Among the chemical mechanism of bactericide activity is oxidative stress, which is defined as excess production of reactive oxygen species (ROS) relative to antioxidant defense. ROS are oxygen-based molecules and free radicals with high reactivity. Examples of ROS include peroxides (H 2 O 2 ), superoxide ( • O − 2 ), hydroxyl radical ( • OH), hydroxyl ion (OH − ), and singlet oxygen ( 1 O 2 ) ( Scheme 3 ). ROS can be harmful to cells due to oxidative damage to lipids, proteins, and DNA. Moreover, ROS are extremely destructive to organisms at high concentrations causing peroxidation of lipids, oxidation of proteins, and damage to nucleic acids, enzyme inhibition, activation of programmed cell death (PCD) pathway, and ultimately leading to the death of the cells [ 25 ].
21
E. coli
26
27
2
2
2
2
Nonetheless, the antibacterial activity of G derivatives does not arise only from ROS-mediated damage, but through electron transfer interaction from microbial membrane to graphene [ 28 ]. Thus, the physical contact of microorganisms with G will result in Schottky barrier formation and Fermi level alignment based on the band theory, which enables the facile transfer of electrons from bacterial membranes to graphene materials that are good electron acceptors. In this regard, functionalities also influence the electron transfer processes, particularly because GO shows more insulating character compared to pristine G (metallic) and rGO (semiconductor).
2.2. Physical Mechanisms of Antibacterial Action
Scheme 2
23
E. coli
S. aureus
29
30
31
32
Another possible mechanism that causes antibacterial activity was proposed by Luan et al. [ 33 ], who reported that the lipophilic flat surface of G disrupted the protein-protein bonding in the cell membrane and led to functional failure.
34
35
11
3. Antimicrobial Polymeric Nanocomposites Incorporating Graphene-Based Nanomaterials
Polymeric nanocomposites are materials with polymers as a matrix and nanofillers as reinforcing material. Polymeric nanocomposites incorporating graphene can be prepared via different techniques such as melt compounding, solution blending, in situ polymerization, latex mixing, and electropolymerization [ 36 ]. Furthermore, different methods have been used to modify graphene and other carbon nanomaterials with polymers via covalent and non-covalent approaches such as hydrophobic interactions, π–π stacking, and van der Waals forces [ 37 ]. Taking into account the polymer matrix, different polymer/graphene nanocomposites with antibacterial activity have been developed, as will be described in the following sections.
3.1. Nanocomposites Based on Acrylic and Methacrylic Polymers
38
39
S. aureus, E. coli
S. mutans.
39
Fiber meshes of PMMA containing GO have also been developed via pressurized gyration, and their antibacterial potential against E. coli was investigated [ 40 ]. Average bacterial reduction ranged from 46 to 85%, and the optimal bactericide action was found for the nanocomposite containing 8 wt% of GO. Bacterial toxicity of the nanocomposites was analyzed in terms of ROS formation.
2
N
N
41
42
43
E. coli
S. aureus
5
6
Figure 1
PNIPAM-based hydrogels containing GO and GO/CNT nanocomposites have also been prepared via dispersion of GO (or GO-CNT) in a solution of monomers followed by free radical polymerization [ 44 ]. The agar diffusion test demonstrates the good antimicrobial activity against P. aeruginosa .
3.2. Nanocomposites Based on Biocompatible Synthetic Polymers
45
E. coli
C. metallidurans
B. subtilis
R. opacus
E. coli
S. aureus
46
E. coli
47
E. coli
S. aureus
48
Furthermore, the antibacterial properties of PVA/GO/Ag nanocomposite films prepared via solution blending followed by film casting were found to be time- and GO-Ag loading-dependent [ 49 ]. Composites with GO-AgNPs loadings of 0.5, 1, 2 and 5 wt% were prepared. For the antibacterial tests, S. aureus and E.coli bacteria were cultured on a plate count agar for 24 h at 37 °C, following the disk diffusion method [ 43 ]. The antibacterial activity was tested in 96-well microliter plates with an initial bacterial concentration of 5 × 10 6 CFU/mL, using a microplate reader at 450 nm. Samples with GO-Ag concentration ≤ 1 wt% showed no inhibition of S. aureus cells over 72 h ( Figure 2 a). By increasing their loading up to 2 wt%, a drop in bacterial growth was found after 24 h of exposure, and with 5 wt% GO-Ag, a complete inhibition was attained after 24 h of exposure. In contrast, the incorporation of 0.5 and 1 wt% GO-Ag results in a small reduction in E. coli bacterial growth upon 24 h of exposure, and beyond that time, no inhibitory effect is observed ( Figure 2 b). The growth of E. coli is completely suppressed after 24 and 48 h of exposure of PVA films filled with 5 wt% GO-AgNPs. After 72 h this sample shows reduced antibacterial activity. Overall, it is found that the E. coli strain is systematically more resistant than S. aureus to these PVA/GO-AgNPs hybrid nanocomposites, in agreement with the results reported by other authors [ 45 ].
Another strategy consisted of the addition of starch and GO combined with Ag nanoparticles [ 50 ]. Starch acted as a reducing agent, reducing GO to rGO, from an exfoliated state to intercalated state in PVA, hence leading to an improved distribution into the PVA matrix. Thus, the antibacterial effect was a result of the synergistic effects of GO and Ag into PVA in the presence of starch.
PLA is one of the most commonly used synthetic biodegradable polymer for medical applications, though it has some shortcomings such as poor barrier properties. It has been combined with different G-based nanomaterials and their mixtures with nanoparticles, resulting in nanocomposites with higher antibacterial activity against S. aureus and E. coli [ 51 , 52 , 53 , 54 ]. Various factors, such as the nanocomposite preparation method, nanofiller concentration, morphology as well as degree of dispersion of the nanofiller into PLA matrix, had an influence on the final properties. Nanocomposites of PLA with either GO or thermally reduced GO have been prepared by melt mixing [ 51 ]. Both types of composites inhibited the attachment and proliferation of both bacteria, the efficiency increasing with increasing loading, and it was significantly improved by applying an electrical stimulus. GO loaded with ZnO nanoparticles was also prepared and mixed with PLA by the solution-blending method [ 52 ]. UV-visible spectra and antibacterial testing results showed that the nanocomposite films had strong UV-resistance and antimicrobial activity at very low GO-ZnO loading. Shen et al. [ 54 ] used GO/Ag hybrids as nanofillers in a PLA matrix. Nanocomposites were prepared via two processes: in situ polymerization and direct mechanical blending, and the effects of the nanofiller content and preparation method on the antibacterial properties were explored. The antibacterial efficiency increased from 0 to 99% as the loading increased up to 2.0 wt%, and composites prepared by the in situ polymerization method showed better efficiency. It was reported that GO improved the antibacterial activity of Ag nanoparticles into PLA due to better Ag-cell wall interactions, due to the good distribution of Ag onto GO surfaces, and the good dispersibility of the hybrids, which was improved by in situ polymerization method.
55
E. coli
S. aureus
6
Figure 3
+
56
E. coli
Figure 3
E. coli
S. aureus
57
PCL is another biodegradable synthetic polymer that does not show antibacterial activity, but, upon blending with rGO/Ag, it shows biocide action. PLC/rGO/Ag (94:5:1) hybrids prepared via solution casting yielded better performance than binary PLA/Ag or PLA/rGO [ 58 ], attributed to direct contact killing by mechanical rupture of the bacterial cells via well-dispersed rGO/Ag mixtures together with the slow and steady release of Ag ions.
Polyethylene glycol (PEG), a biocompatible and biodegradable polymer widely used for the development of tissue engineering scaffolds, has great potential for functionalizing G and its derivatives for medical applications. A few studies have assessed the biological activity and cytotoxicity of G and GO covalently modified with PEG and its derivatives [ 59 , 60 ]. For instance, ternary hybrids of PEG-functionalized GO with Ag nanoparticles have been prepared by a simple, fast and green microwave irradiation route [ 61 ], at different irradiation times and their bactericide properties were investigated against S. aureus and E. coli bacteria as model organisms, following the disk diffusion method [ 43 ]. The initial bacterial concentration was set at 10 5 CFU/mL. After incubation at 37 °C for 25 h, the inhibition zones were measured.
E. coli
Figure 4
E. coli
62
36
6
control
composite
S. aureus, S. epidermidis, P. aeruginosa
E. coli
Figure 5
S. aureus
S. epidermidis
E. coli
P. aeruginosa
•
co
co
co
63
E. coli
S. aureus
S. aureus
S. aureus,
E. coli
3.3. Nanocomposites Based on Natural Polymers
64
co
65
E. coli
P. aeruginosa
S. aureus
66
2
A. niger
B. subtilis
67
In another study, CS was combined with polyvinylpyrrolidone (PVP) and GO nanosheets to yield nanocomposites in which GO and CS can interact via covalent and non-covalent bonding [ 68 ]. Thus, the epoxy groups of GO can react with the amino groups of CS via nucleophilic substitution reaction, similar to the cross-linking and curing reaction of epoxy resins ( Scheme 4 a). Additionally, they can interact via H bonding between the OH and COOH groups of GO and the NH 2 and OH groups of CS ( Scheme 4 b).
69
S. aureus
E. coli
68
2
GO can improve CS antibacterial activity through a synergistic effect on bacterial inhibition by damaging the membrane cell. The mechanism of this could be related to an improvement of the surface roughness and hydrophobic character, which increases the interaction between CS and the bacteria. The nanocomposites can adsorb on the cell wall surface and bind to metals of the nutrient needed for the bacterial growth, provoking the death of the microorganism. The antibacterial action of CS-GO is somewhat more vigorous against Gram-positive bacteria.
d
d
d
70
71
3
−
2
Figure 6
Figure 6
S. aureus
E. coli
43
8
E. coli
S. Aureus
Alginates (AG) are ionic-block copolymers of polysaccharides that occur in the cell wall of brown algae. They comprise regions of successive β- d -mannuronic acid monomers (M-blocks), regions of α- l -guluronic acid (G blocks), and regions of scattered M and G units [ 72 ]. The physical properties of alginates depend on the M/G ratio and the distribution of M and G units across the polymer chain. Owing to their hydrophilicity, biocompatibility, biodegradability, nontoxicity and low-cost in comparison with other biopolymers, they show great potential for the fabrication of nanocomposites with G-derivatives [ 73 ].
Marti et al. [ 74 ] crosslinked AG with Ca 2+ cations and GO by mixing ZnCl 2 aqueous solution with GO/AG aqueous solution under stirring followed by solvent casting. The incorporation of 1% GO into AG-based films provided strong antibacterial activity against S. aureus and S. epidermidis , and no cytotoxicity for human cells. A similar approach was applied to synthetize sodium alginates with GO, which exhibited higher antibacterial action against the two indicated bacteria for the same GO content [ 75 ].
β-
d
76
+
S. aureus
E. coli
77
Agar or agar-agar is another polysaccharide with gel-forming properties widely employed in the food industry. It is a mixture of two components: the linear polysaccharide agarose, and a heterogeneous mixture of smaller molecules called agaropectin. To provide antibacterial activity, nanofillers can be incorporated in the agar matrix. Thus, an agar/rGO-PEG-Ag-ZnO nanocomposite hybrid was developed [ 78 ] via room temperature solution processing, leading to ZnO and Ag-NPs being distributed uniformly over rGO nanosheets. This nanocomposite showed high biocide activity (about 95%) against S. aureus and P. aeruginosa bacteria, attributed to a synergistic effect of rGO, Ag and ZnO nanoparticles. The higher contributor to the antimicrobial action was Ag, which prevented nutrient transportation to the cells.
Furcellaran (FUR) is a group of sulfated high molecular weight polysaccharides with gel-forming properties, obtained from red algae Furcellaria lumbricalis, that shows antibacterial activity against S. enterica . To expand its range of antimicrobial activity, nanocomposite films based on FUR, GO, carbon quantum dots (CQDs) and maghemite nanoparticles (MAN), have been prepared by the solution casting method [ 79 ]. The nanocomposites showed a strong inhibitory effect on the growth of S. aureus and E. coli.
80
81
co
PHBV films with 1 wt% GO nanosheets or carbon nanofibers (CNFs) were prepared by solution casting with the aim of enhancing thermal behavior, wettability and antibacterial activity against S. aureus . The results showed that both nanomaterials produced similar enhancements of the physical properties. However, PHBV/GO exhibited higher antibacterial activity than that of PHBV/CNFs [ 82 ]. Gouvea et al. [ 83 ] reported the preparation of PHBV/rGO-ZnO hybrid material at 3, 6 and 9 wt% nanofiller content by melt extrusion. GO-ZnO composite was first synthesized by the simultaneous reduction of zinc diacetate and GO, at 20:1 ratio. Significant antimicrobial surface property against E. coli was found because of direct contact between bacteria cells and the hybrid’s surface.
84
Figure 7
6
0
0
0
E. coli
S. aureus
A summary of the properties of polymeric nanocomposites with graphene-based nanomaterials is provided in Table 1 .
4. Applications for Polymeric Nanocomposites with Graphene Materials
Currently, graphene-based polymeric nanocomposites designed to inhibit bacterial growth are being explored for numerous technological applications. For example, they are being investigated for water purification, for the fabrication of antibacterial food packaging, protective clothing, as antifouling agents, as well as several biomedical applications including bandages and wound dressing, tissue engineering, drug delivery and for the prevention of biofilm formation on medical equipment and implantable devices. Some of these applications are briefly described below.
4.1. Water Purification
85
86
87
88
For instance, GO/polyether sulfone (PES), reduced GO (rGO)/PES and polyethyleneimine (PEI)-coated GO membranes have been developed via a facile blending method for wastewater filtration [ 89 ]. Zeng et al. prepared PVDF membranes that were covalently functionalized GOQDs by a hydrothermal reaction. They displayed excellent antibacterial activity against E. coli and antibiofouling performances [ 90 ].
Maio et al. [ 91 ] used a one-step wet electrospinning method for the fabrication of polycaprolactone (PCL)/GO membranes for wastewater treatment. Chen et al. [ 92 ] recently developed an ultrafiltration membrane based on GO and polysulfone coated with polydiacetylene that exhibited strong antibacterial activity against E. coli . A composite elastic membrane based on G-rubber silicone has also been developed for water treatment [ 93 ], and it efficiently inhibited bacterial attachment. More complex membranes comprising GO, Ag, and a metal-organic framework (MOF) incorporated in PES have also been prepared with excellent antibacterial properties due to synergistic effects [ 94 ].
4.2. Antibacterial Food Packaging
95
66
E. coli
96
97
98
S. aureus
E. coli
99
S. aureus
E. coli
C. albicans
4.3. Protective Textiles
Graphene polymeric nanocomposites have also been used in the textile industry [ 100 ]. Their addition to fabrics has been reported to improve antibacterial activity as well as other key properties such as mechanical strength, conductivity, flame resistance, UV protection and gas barrier. Owing to these characteristics, they are good candidates for the fabrication of personal protective equipment. A few works have shown that G-based fabrics inhibit bacterial metabolism. For instance, cotton and cotton/nylon fabrics mixed with small amounts of GO or rGO showed noteworthy antibacterial activity against Gram-positive (100% and 98.4% versus S. aureus and E. faecalis , respectively) and Gram-negative bacteria (84.8% and 96.4% inhibition against E. coli and P. aeruginosa , respectively) [ 101 ]. Synthetic fabrics such as polyester, polyester doped with rGO/Ag nanocomposites and GO/PVA prevented bacterial growth [ 102 ].
4.4. Wound Dressings
N
N
41
103
4.5. Tissue Engineering
Polymeric nanocomposites with G have been successfully employed in many tissue engineering investigations due to their mechanical stability. For instance, a 3D scaffold has been prepared by combining GO with CS to analyze the potential of bone tissue engineering [ 104 ]. These scaffolds showed excellent biocompatibility. The presence of GO improved the mechanical characteristics, pore formation, and bioactivity of the scaffold, and thus promoted the possibilities for in vitro and in vivo bone tissue engineering. A similar scaffold was prepared by mixing gelatin with GO and CS via a freeze-drying approach, and showed better physiochemical properties when tested for properties such as biodegradation, wettability, protein adsorption, and biomineralization, which all favored application toward bone tissue engineering [ 105 ].
4.6. Drug Delivery
Strong effort has been focused on using G for drug delivery. The extremely high surface area (2600 m 2 /g), and flexible structure of G enable bioconjugation and molecular loading [ 106 ]. Thus, GO is very effective for cancer therapy, including insoluble drugs [ 58 ]. For instance, Ma et al. [ 107 ] fabricated a hybrid of GO/polysebacic anhydride (GO/PSA) nanocomposite and explored its drug release efficacy for levofloxacin, a bactericidal drug. The GO/PSA hybrids exhibited a considerable increase in the release time of the drug compared to the neat polymer, as well as outstanding biocidal efficacy without any cytotoxic effect. Additionally, a PCL-based fiber containing an antibacterial agent (chlorhexidine) (CHX) and G nanoplatelets was prepared by melt spinning. The ternary fibers displayed outstanding antimicrobial activity and played a key role in minimizing the risk of infections after surgery [ 108 ]. Similarly, a ternary biocomposite with PLA, ciprofloxacin (a biocide) and G nanoplatelets was prepared, and the results showed that the incorporation of GNP increased the stiffness of the matrix and decreased the burst release outcome [ 109 ].
co
co
110
E. coli
S. aureus
111
Figure 8
112
5. Conclusions
In most cases, the antimicrobial properties have been tested against E. coli and S. aureus as model pathogens. Taking into account the growing spread of antibiotic-resistant bacteria related to their danger towards public health worldwide, it is crucial to explore other pathogenic species to illustrate the comprehensive range of bactericidal properties of graphene-based nanomaterials. Despite a few studies on P. aeruginosa and B. subtilis being published, a deeper understanding is necessary to obtain accurate knowledge about the antibacterial ability of this family of nanomaterials. Moreover, a more detailed and consistent understanding of the mechanisms of antimicrobial action is essential, as well as an understanding of how different parameters, such as the nanomaterial synthesis method, its defect content, lateral dimensions, shape, number of layers as well as amount of functional groups, influence the nanomaterial antibacterial properties.
On the other hand, approaches to synthesize G on a large scale and at a relatively low fee are in high demand. Despite noteworthy efforts having been carried out in this direction, current methods are seriously limited by their low efficiencies, which should be addressed for commercial applications. A reliable method for meeting the strong demand for G or its derivatives through an environmentally friendly approach and with high yield is still lacking. Another issue is that the real specific surface area of G-based nanomaterials is significantly lower than the predictions due to the strong agglomeration tendency of the sheets via hydrophobic interactions, and this limits their antibacterial activity. In this regard, novel strategies to effectively exfoliate G in a green way are pursued.
While the connection to the biomedical market is still missing, researchers are continuously proposing different graphene-based materials as antibacterial agents. Thus, some works on the antibacterial properties of graphene quantum dots (GQDs) have been highlighted. GQDs display lower toxicity than GO and cause no apparent toxicity in vivo. Further GQDs suspensions can produce ROS upon photo-excitation, hence can be used for the photodynamic treatment of pathogens, a strategy scarcely developed up to date.
Overall, the development and use of antimicrobial polymeric nanocomposites with G is hindered by the lack of techniques to provide simple, reproducible, and cost-effective nanomaterials at a large scale. The research in this field is still in its infancy. The combination between these carbon nanostructures and the polymers has opened new properties and applications due to their synergistic effects. Nonetheless, more work is needed to ensure that the developed nanocomposites are easy to manufacture and have no toxicity. It can be envisaged that after wide-ranging research in the field and continuous innovative efforts, nanocomposites incorporating polymers and G-based nanomaterials could provide a new outlook for the development of antimicrobial agents. This milestone can be reached via collaboration between different disciplines and technologies (i.e., nanotechnology and polymer science).
Author Contributions
J.A.L.-S. performed the literature review and drew the figures. A.M.D.-P. designed the work and wrote the article. All authors have read and agreed to the published version of the manuscript.
Funding
Financial support from the Community of Madrid within the framework of the Multi-year Agreement with the University of Alcalá in the line of action “Stimulus to Excellence for Permanent University Professors”, Ref. EPU-INV/2020/012, is gratefully acknowledged.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
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Scheme 1. Chemical structure of graphene and its derivatives, graphene oxide (GO), reduced graphene oxide (rGO) and graphene quantum dots (GQDs).
Scheme 1. Chemical structure of graphene and its derivatives, graphene oxide (GO), reduced graphene oxide (rGO) and graphene quantum dots (GQDs).
Scheme 2. Representation of the mechanisms of antibacterial activity of G and its derivatives.
Scheme 2. Representation of the mechanisms of antibacterial activity of G and its derivatives.
Scheme 3. Structures of reactive oxygen species (ROS).
Scheme 3. Structures of reactive oxygen species (ROS).
Figure 1. Photographs showing the antibacterial activity of PNIPAM-based hydrogels with different Ag:G weight ratios (0.5:1, 1:1 and 5:1) are denoted as Ag0.5G1, Ag1G1 and Ag5G1, respectively, against E. coli ( a ) and S. aureus ( b ). Reprinted with permission from ref. [ 41 ]. Copyright 2021 Advanced Functional Materials.
Figure 1. Photographs showing the antibacterial activity of PNIPAM-based hydrogels with different Ag:G weight ratios (0.5:1, 1:1 and 5:1) are denoted as Ag0.5G1, Ag1G1 and Ag5G1, respectively, against E. coli ( a ) and S. aureus ( b ). Reprinted with permission from ref. [ 41 ]. Copyright 2021 Advanced Functional Materials.
Figure 2. Absorbance vs. time curves for S. aureus ( a ) and E. coli ( b ) after exposure to PVA/GO-AgNPs composite films. Viable counts of S. aureus ( c ) and E. coli ( d ). Samples are labelled as PVA/GO-AgNPsx, where x denotes the wt% of the Go-AgNPs filler. Reprinted with permission from ref. [ 49 ]. Copyright 2021 MDPI.
Figure 2. Absorbance vs. time curves for S. aureus ( a ) and E. coli ( b ) after exposure to PVA/GO-AgNPs composite films. Viable counts of S. aureus ( c ) and E. coli ( d ). Samples are labelled as PVA/GO-AgNPsx, where x denotes the wt% of the Go-AgNPs filler. Reprinted with permission from ref. [ 49 ]. Copyright 2021 MDPI.
Figure 3. ( a ) Photograph and ( b ) diameter of the zone of inhibition of electrospun PVDF/Ag/GO nanocomposite membranes with different Ag-GO loading exposed to E. coli . GO content was fixed at 1 wt% while the AgNPs contents were kept at 0.5, 1 and 2 wt%. Reprinted with permission from ref. [ 55 ]. Copyright 2021 Express Polymer Letters.
Figure 3. ( a ) Photograph and ( b ) diameter of the zone of inhibition of electrospun PVDF/Ag/GO nanocomposite membranes with different Ag-GO loading exposed to E. coli . GO content was fixed at 1 wt% while the AgNPs contents were kept at 0.5, 1 and 2 wt%. Reprinted with permission from ref. [ 55 ]. Copyright 2021 Express Polymer Letters.
Figure 4. Antibacterial activity of PEG/GO/Ag nanocomposites. ( A ) Bacterial colony formation of E. coli under different treatments. ( B ) Bacterial cell viability of E. coli exposed to nanocomposites with different sizes of Ag nanoparticles: GO-Ag1 (8 nm) GO-Ag2 (50 nm). Reprinted with permission from ref. [ 61 ]. Copyright 2021 Springer Nature.
Figure 4. Antibacterial activity of PEG/GO/Ag nanocomposites. ( A ) Bacterial colony formation of E. coli under different treatments. ( B ) Bacterial cell viability of E. coli exposed to nanocomposites with different sizes of Ag nanoparticles: GO-Ag1 (8 nm) GO-Ag2 (50 nm). Reprinted with permission from ref. [ 61 ]. Copyright 2021 Springer Nature.
Figure 5. Antibacterial activity of PPF and PPF/PEG-GO composites with GO loadings of 0.1, 0.5, 1, 2, and 3 wt% against S. aureus, S. epidermidis, P. aeruginosa and E. coli . Antibacterial activity was calculated as: log(viable cell count control /viable cell count composite ). Reprinted with permission from ref. [ 36 ]. Copyright 2016 American Chemical Society.
Figure 5. Antibacterial activity of PPF and PPF/PEG-GO composites with GO loadings of 0.1, 0.5, 1, 2, and 3 wt% against S. aureus, S. epidermidis, P. aeruginosa and E. coli . Antibacterial activity was calculated as: log(viable cell count control /viable cell count composite ). Reprinted with permission from ref. [ 36 ]. Copyright 2016 American Chemical Society.
Scheme 4. Representation of the interactions between graphene oxide (GO) and chitosan (CS): covalent ( a ) and non-covalent ( b ).
Scheme 4. Representation of the interactions between graphene oxide (GO) and chitosan (CS): covalent ( a ) and non-covalent ( b ).
Figure 6. ( A ) Schematic representation of the synthesis of starch-reduced GO (SRGO)–polyiodide nanocomposite. ( B ) UV-vis spectra and ( C ) XRD pattern of GO, SRGO and the nanocomposite. Reprinted with permission from ref. [ 71 ]. Copyright 2021 Elsevier.
Figure 6. ( A ) Schematic representation of the synthesis of starch-reduced GO (SRGO)–polyiodide nanocomposite. ( B ) UV-vis spectra and ( C ) XRD pattern of GO, SRGO and the nanocomposite. Reprinted with permission from ref. [ 71 ]. Copyright 2021 Elsevier.
Figure 7. Schematic representation of the interactions between GO and cellulose nanocrystals via covalent and non-covalent bonds. Reprinted with permission from ref. [ 84 ]. Copyright 2019 American Chemical Society.
Figure 7. Schematic representation of the interactions between GO and cellulose nanocrystals via covalent and non-covalent bonds. Reprinted with permission from ref. [ 84 ]. Copyright 2019 American Chemical Society.
Figure 8. Schematic representation of the synthesis of HPG-GO hydrogel. Reprinted with premission from ref. [ 112 ]. Copyright 2021 Elsevier.
Figure 8. Schematic representation of the synthesis of HPG-GO hydrogel. Reprinted with premission from ref. [ 112 ]. Copyright 2021 Elsevier.
Table 1. Characteristics of polymer nanocomposites with G-based nanomaterials.
Table 1. Characteristics of polymer nanocomposites with G-based nanomaterials.
Matrix Nanofiller Processing Method Bacteria Inhibition Comments Reference (wt%) (%) PMMA GO-Ag (1) GO-Ag (2) SN + curing E. coli - Synergistic effect of both nanofillers [ 38 ] S. aureus S. mutans PMMA fibers GO (8) Pressurized gyration E. coli 85 GO well distributed across fiber [ 40 ] PNIPAM Ag/G (0.5:1) In situ polymerization E. coli S. aureus - Synergistic effect: G prevented Ag aggregation [ 41 ] Ag/G (1:1) Ag/G (5:1) PNIPAM GO/CNT (1:1) FRP P. aeruginosa - Strong interaction GO-PNIPAM [ 44 ] PVK GO (3) Bulk polymerization B. subtilis 89 Better properties than raw GO [ 45 ] R. opacus 89 E. coli 89 C. metallidurans 91 PVA G (1) SN+ solution casting E. coli 92 5 wt% G is the optimal nanofiller ratio [ 46 ] G (5) E.coli 95.8 G (10) E.coli 97.1 G (1) S. aureus 92.3 G(5) S. aureus 99.6 G(10) S. aureus 99.7 PLA GO/Ag (2) In situ polymerization E. coli 99 Improved Ag dispersion with GO [ 54 ] S. aureus 99 PVDF fibers GO/Ag (1:0.5) ES E. coli S. aureus - GO promotes release of Ag + [ 55 ] GO/Ag (1:1) GO/Ag (1:2) PCL GO/Ag (5:1) SN+ solution casting E. coli 59 Rupture of the cells by rGO-Ag [ 58 ] PPF PEG-GO (3) SN+ curing S. aureus 97 Strong interaction between PEG-GO and PPF [ 36 ] S. epidermidis 94 P. aeruginosa 85 E. coli 81 CS GO/TiO 2 (4/16) SA A. niger 99 Synergistic effect of all components [ 67 ] B. subtilis 99 AG GO (1) SN+ solution casting S. aureus 99 Strong AG-GO interactions [ 74 ] S. epidermis 99 AGAR rGO/Ag/ZnO solution casting S. aureus 95 Uniform distribution of Ag and ZnO over rGO [ 78 ] P. aeruginosa 95 PHBV CNC/GO (1:1) solution casting E. coli 99.7 Synergistic effect by chemical grafting [ 84 ] S. aureus 99.8
SN: sonication; FRP: free radical polymerization; ES: electrospinning; SA: self assembly.
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MDPI and ACS Style
Díez-Pascual, A.M.; Luceño-Sánchez, J.A. Antibacterial Activity of Polymer Nanocomposites Incorporating Graphene and Its Derivatives: A State of Art. Polymers 2021, 13, 2105.
https://doi.org/10.3390/polym13132105
AMA Style
Díez-Pascual AM, Luceño-Sánchez JA. Antibacterial Activity of Polymer Nanocomposites Incorporating Graphene and Its Derivatives: A State of Art. Polymers. 2021; 13(13):2105.
https://doi.org/10.3390/polym13132105
Chicago/Turabian Style
Díez-Pascual, Ana M., and José A. Luceño-Sánchez. 2021. "Antibacterial Activity of Polymer Nanocomposites Incorporating Graphene and Its Derivatives: A State of Art" Polymers13, no. 13: 2105.
https://doi.org/10.3390/polym13132105
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Neil Kinnock
by Jeff Overs
resin print, January 1994
NPG x76178
© Jeff Overs
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FISHING LEVY (BASS STRAIT SCALLOP FISHERY) REGULATIONS (AMENDMENT) 1996 NO.53
EXPLANATORY STATEMENT
STATUTORY RULES 1996 No. 53
Issued by the Authority of the Minister for Resources and Energy
Fishing Levy Act 1991
Fishing Levy (Bass Strait Scallop Fishery) Regulations (Amendment)
Section 8 of the Fishing Levy Act 1991
(the Levy Act) empowers the
Governor-General to make regulations for the purposes of section 6 of the Levy
Act.
Section 5 of the Levy Act imposes levy in respect of a fishing concession.
Section 6 of the Levy Act provides that the amount of levy imposed on the
fishing concession is the amount prescribed by the Regulations. Sections 5 and
6 of the Levy Act commenced prior to the issue of the fishing concessions, in
respect of which the levy is imposed.
Section 168 of the Fisheries Management Act 1991
(the Management Act)
empowers the GovernorGeneral to make regulations for the purposes of the
Management Act. Section 110 of the Management Act provides that the levy
imposed by the Levy Act is due and payable at a time or times ascertained in
accordance with regulations made under the Management Act.
"Fishing concession" is defined under the Levy Act and the Management Act to
mean, among other things, a fishing permit.
The Fishing Levy (Bass Strait Scallop Fishery) Regulations (the principal
Regulations) specify the amount of levy imposed in respect of fishing permits
granted for the Bass Strait Scallop Fishery (the fishery). The previous effect
of the principal Regulations was to:
* require the payment of levy in the amount of $1,100
for each fishing permit granted for the fishery during the period 1 January
1996 to 31 December 1996; and
* specify the research component of the levy, to be
payable to the Fisheries Research and Development Corporation, to be $60.
As discussed below, collection of levy for the fishery has usually been carried
out in arrears.
The Fishing Levy (Bass Strait Scallop Fishery) Regulations (Amendment) (the
Regulations) effect a "catch-up" in the collection of levy (as discussed
below), by requiring payment of levy in the amount of $2,200 in 2 instalments
as follows:
* a first instalment of levy of $1,100 and in
practice payable in about late June 1996, to cover the actual costs of managing
the fishery's 1995 fishing season (and other estimated management and research
costs of the fishery for the 1995/1996 financial year); and
* a second instalment of levy, also of $1,100 and in
practice payable at the end of November 1996, to cover the estimated costs of
managing the fishery's 1996 fishing season (and other management and research
costs of the fishery for the 1996/1997 financial year).
The Regulations also specify the research component of the levy, payable to the
Fisheries Research and Development Corporation, to be $120.
The Australian Fisheries Management Authority (AFMA) usually collects levies
from other fisheries in advance of expenditure on a financial year basis, to
cover its estimated recoverable management costs and research costs relating to
each fishery. It is current Government policy that these costs be recovered
from operators in Commonwealth managed fisheries.
Levy for the fishery has previously been collected in arrears, due to the
timing of the fishery's season, which typically runs from about June or July to
December in each year. Such an "arrears" arrangement for the 1995/1996
financial year was previously reflected in the principal Regulations, under
which levy of $1,100 was to have been collected from holders of fishing permits
for the 1996 fishing season at about the end of the 1995/1996 financial year,
to cover management and research costs relating to management and research in
the fishery during the 1995/1996 financial year and in particular the fishery's
1995 fishing season.
The Regulations effect a "catch-up" in levy collection by providing for
collection of levy for the 1995/1996 financial year in arrears and also for
collection of levy for the 1996/1997 financial year, mostly in advance.
The Regulations only apply this "catch-up" to fishing permits that are granted
in 1996. Due to the nature of the principal Regulations, which currently set
levy for fishing permits granted in a defined period (namely 1996), a further
amendment to the principal Regulations would be required to implement levy for
fishing permits that are granted after the end of 1996. In future years, it is
intended that levy only be collected to cover estimated recoverable management
and research costs for the fishery that relate to the financial year and
fishing season in which the levy is collected.
The "catch-up" brings forward levy collection to take place as early as
possible in the financial year to which the levy relates, rather than at about
the end of the financial year, or even after the financial year has ended. As a
result of the "catch up", it is intended that levy collection for the fishery
would in future years occur in about September, which is early in the financial
year and is also mid-season, thus coinciding with times when operators who pay
the levy have a revenue stream coming from the fishery.
The "catch-up" has been agreed to by the Bass Strait Scallop Consultative
Committee, which provides advice to AFMA about management of the fishery. The
amounts of levy to be collected are based on budgets that have been agreed to
by the Committee.
Under the Regulations, levy is due and payable in respect of fishing permits
for the fishery as follows:
* If a fishing permit is granted in the period 1
January 1996 to 31 October 1996 inclusive, the levy is payable as
instalments:
- the first instalment of $1,100 is due and payable
before the end of 28 days after the grant of the fishing permit, and
- the second instalment, also of $1,100 is due and
payable on or before 29 November 1996.
Fishing permits for the fishery are typically granted just prior to the season
commencing, so in fact no fishing permits for the fishery's 1996 season were
granted before May 1996.
* If a fishing permit is granted on or after 1
November 1996, all of the levy, that is $2,200 is due and payable before the
end of 28 days after the grant of the fishing permit.
Details of the Regulations, which commenced on gazettal, are set out below:
Regulation 1
provides that the Regulations amend the principal
Regulations.
Regulation 2
amends regulation 3 of the principal Regulations to
implement the new rate of levy for fishing permits and to specify the research
component of the levy.
Regulation 3
amends regulation 4 of the principal Regulations to
set new dates for when the new rate of levy is due and payable.
[Index] [Related Items] [Search] [Download] [Help] | http://www.austlii.com/au/legis/cth/num_reg_es/flssfr1996n53634.html |
(PDF) MOOCs in Indian Higher Education: A Study of Library and Information Sciences courses
PDF | Purpose: This study examines the Massive Open Online Courses(MOOCs) concept, characteristics, and availability of library and information science... | Find, read and cite all the research you need on ResearchGate
Conference Paper
PDF Available
MOOCs in Indian Higher Education: A Study of Library and Information Sciences courses
April 2023
Conference: National Conference on Knwolege Transaction in Digital Scholarship(KTDS) 2023
At: BHU, Varanisi
Authors:
<here is a image d9cce059a7f19cd3-daf3c597d9904bbf>
Pramod Kumar
Banaras Hindu University
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Shri Ram Pandey
Shri Ram Pandey
Abstract
Purpose: This study examines the Massive Open Online Courses(MOOCs) concept, characteristics, and availability of library and information science courses(LIS) in the Indian higher education system. The MOOC platform offers various free online courses, including school/vocational lessons, university courses, postgraduate courses, engineering courses, and professional courses. MOOCs provide knowledge to students, researchers, and faculty members from ‘Anytime, Anyone, Anywhere’. During the COVID-19 pandemic, e-learning and distance education has played vital roles in accessing quality education among students, researchers, and faculty members in the Indian higher education system.
Method: MOOCs are educational tools that convert traditional teaching methods into ICT-based holistic learning methods. Literature research is adopted based on the study's objectives to elicit the needed literature. Reviewing scholarly literature from the past ten years on MOOCs which discussed MOOCs' role in the Indian higher education scenario.
Result: The study found that in India, out of 1074 universities, only 662 institutes(LIS degree 459, LIS Diploma 81 and LIS certificates 32 institutes) offered LIS courses. In India, 11 courses on SWAYAM and 14 LIS courses on MOOCs are available. The NPTEL, IIT Mumbai,
mooKIT, agMOOCS, IIMBx, SWAYAM and INLIBNET are popular platforms that provide education through MOOCs in India. MOOCs are available to students, researchers, and teachers 24x7 hours. With the success of MOOCs, e-learning may become more convenient and accessible to everyone.
Discussion: This study examines how MOOCs influence teaching and knowledge in the Indian higher education system. In the Indian higher education system, out of 662 LIS institutes, only 25 LIS courses are offered through MOOCs. MOOCs are currently being developed for all subject areas so that students at different locations can access the materials prepared by experts. Today implication of MOOCs is a big challenge in the Indian education system, especially in backward, mountain, and village areas, to promote quality education through MOOCs. Due to a lack of digital literacy, a vast population must be aware of adopting ICT technology in education. The Indian government should provide digital literacy, remove internet issues, and distribute smartphones, tablets, and laptops among students. Then MOOCs could help to achieve the goal of the New Education Policy(NEP) 2020. NEP 2020 aims to increase the Gross Enrollment Ratio(GER) in preschool to secondary education to 100% by 2030 and 50% in higher education by 2035, including vocational education. Higher education needed to adopt more digital technology platforms for teaching, learning, and creating innovative environments associated with the transformations to achieve the goal of NEP.
Conclusion: Massive Open Online Courses have revolutionised education in the 21st century, offering free online resources for strengthening content across various academic disciplines. The SWAYAM platform is an in-house education platform that provides a wide range of high-quality courses. Everybody has access to the internet, no matter where they are or what time it is. Using this method, many people can access interactive teaching materials. Through MOOCs, students, researchers, and faculty members access knowledge anytime, anywhere.
National
Conference
on
Knowledge
Transaction
in
Digital
Scholarship
April
10-11,
2023
ICSSR
Indian
Councl
of
Social
Science
Research
Organised
by:
Department
of
Library
&
Information
Science
Varanasi
Banaras
Hindu
University
KTDS
2023
Azadl
ka
Amrit
Mahotsav
MOOCs
in
Indian
higher
education:
A
study
of
Library
and
Information Science courses
Pramod
Kumar
62
4
hstracts
Senior Research Fellow
Department
of
Library
and
Information
Science
Banaras
Hindu
University.
Varanasi-221005
E-mail
ld:
pramodjnvbhuS@gmail.com
Shri
Ram
Pandey
Associate
Professor
Department
of
Library
and
Information
Science
Central
University
of
Haryana,
Mahendragarh,
India
(Department
of
Library
and
Information
Science
Banaras
Hindu
University,
Varanasi-22
1005)
E-mail
ld: shriram.lib@bhu.ac.
in
This
study
examines
the
Massive
Open
Online
Courses(MOOCs)
concept,
characteristics,
and
availability
of
library
and
information
science
courses(LIS)
in
the
Indian
higher
education
system.
The
MOOC
platform
offers
various
free
online
courses,
including
school/vocational
lessons,
university
courses,
postgraduate
courses,
engineering
courses,
and
professional
courses.
MO0Cs
provide
knowledge
to
students,
researchers,
and
faculty
members
from
'Anytime,
Anyone,
Anywhere."
During
the
COVID-19
pandemic,
e-learming
and
distance
education
has
played
vital
roles
in
accessing
quality
education
among
students,
researchers,
and
faculty
members
in
the
Indian
higher
education
system.
MOOCs
are
educational
tools
that
convert
traditional
teaching
methods
into
ICT-based
holistic
learning
methods.
Literature
research
is
adopted
based
on
the
study's
objectives
to
elicit
the
needed
literature.
Reviewing
scholarly
literature
from
the
past
ten
years
on
MOOCs
which
discussed
MOOCs'
role
in
the
Indian
higher
education
scenario.
The
study
found
that out
of
1074
Diploma
81,
and
LIS
459,
LIS
courscs on
SWAYAM
and
14
LIS
courses
on
MOOCs
are
available.
The
NPTEL,
IIT
Mumbai,
that provide
mooKIT,agMOOCS,
IIMBx.
rescarchers,
universities
in
India,
only
662
institutes(LIS
degree
certificates
32
institutes)
offered
LIS
courses.
In
India,
1|
education
through
and
teachers 24x7
cducation
system,
SWAYAM,
and
INLIBNET
are
popular
platforms
MOOCs
in
India.
MOOCs
are
available
to
students,
hours.
With
the
success
of
MOOCs,
e-learning
may
become
more
convenient
and
accessible
to
everyone.
This
study
examincs
how
MOOCs
influence
tcaching
and
knowledge
in
the
Indian
higher
education
system.
In
the
Indian
higher
out
of
KTDS-2023
662
LIS
institutes,
only
25
LIS
courses
are
offered
through
MOOCs.
MOOCs
are
currently
being
developed
for
all
subject
areas
so
that
students
at
different
locations
can
access
the
materials
prepared
by
experts.
Today
MOOCs
is
a big
challenge
in
the
Indian
education
implication
of
system,
especially
in
rard
mountain,
and
village
areas,
to
promote
quality
education
through
MOOCs.
Due
..lack
of
digital
literacy,
a
vast
population
must
be
aware
of
adopting
ICT
technology
in
adcation.
The
Indian
govermment
should
provide
digital
literacy,
remove
internet
issues,
and
Aistribute
smartphones,
tablets,
and
laptops
among
students.
Then
MOOCs
could
help
to
hieve
the
goal
of
the
New
Education
Policy(NEP)
2020.
NEP
2020
aims
to
increase
the
Cross
Enrollment
Ratio(GER)
in
preschool
to
secondary
education
to
100%
by
2030
and
s0%
in
higher
education
by
2035,
including
vocational
education.
Higher
education
needed
to
adopt
more
digital
technology
platforms
for
teaching,
learning,
and
creating
innovative
environments
associated
with
the
transformations
to
achieve
the
goal
of
NEP.
Massive
Open
Online
Courses
have
revolutionized
education
in
the
21st
century,
offering
free
online
resources
for
strengthening
content
across
various
academic
disciplines.
The
SWAYAM
platform
is
an
in-house
education
platform
that
provides
a
wide
range
of
high-quality
courses.
Everybody
has
access
to
the
internet,
no
matter
where
they
are
or
what
time
it
is.
Using
this
method,
many
people
can
access
interactive
teaching
materials.
Through
MOOCs,
students,
researchers,
and
faculty
members
access
knowledge
anytime,
anywhere.
Keyword:
Massive
Open
Online
Courses
(MO0Cs):
MO0Cs;
Library
and
Information
Science(LIS);
New
Education
PolicyNEP)
and
India
Where
we
stand?
An
analysis
of
school
library
facilities
in
light
of
NEP
2020
Navneet
Kumar
Sharma
Professional
Assistant
Kamala
Nehru
College.
University
of
Delhi
Email:
navneet@knc.
du.ac.
in
Abstracts
| https://www.researchgate.net/publication/371313693_MOOCs_in_Indian_Higher_Education_A_Study_of_Library_and_Information_Sciences_courses |
Materials | Free Full-Text | Bitumen Binders Modified with Sulfur/Organic Copolymers
With the continuing growth of waste sulfur production from the petroleum industry processes, its utilization for the production of useful, low-cost, and environmentally beneficial materials is of primary interest. Elemental sulfur has a significant and established history in the modification of bitumen binders, while the sulfur-containing high-molecular compounds are limited in this field. Herein, we report a novel possibility to utilize the sulfur/organic copolymers obtained via the inverse vulcanization process as modifiers for bitumen binders. Synthesis and thermal characterization (TGA-DSC) of polysulfides derived from elemental sulfur (S8) and unsaturated organic species (dicyclopentadiene, styrene, and limonene) have been carried out. The performance of modified bitumen binders has been studied by several mechanical measurements (softening point, ductility, penetration at 25 & deg;C, frass breaking point, adhesion to glass and gravel) and compared to the unmodified bitumen from the perspective of normalized requirements concerning polymer-modified bitumen. The interaction of bitumen binder with sulfur/organic modifier has been studied by means of FTIR spectroscopy and DSC measurements. The impact of the modification on the performance properties of bitumen has been demonstrated. The bitumen binders modified with sulfur/organic copolymers are in general less sensitive to higher temperatures (higher softening point up to 7 & deg;C), more resistant to permanent deformations (lower penetration depth), and more resistant to aging processes without intrusive deterioration of parameters at lower temperatures. What is more, the modification resulted in significantly higher adhesion of bitumen binders to both glass (from 25% up to 87%) and gravel surfaces in combination with a lower tendency to form permanent deformations (more elastic behavior of the modified materials).
Bitumen Binders Modified with Sulfur/Organic Copolymers
by
Jakub Wręczycki 1,* ,
Yuriy Demchuk 2,* ,
Dariusz M. Bieliński 1 ,
Michael Bratychak 2 ,
Volodymyr Gunka 2 ,
Rafał Anyszka 1 and
Tomasz Gozdek 1
1
Institute of Polymer and Dye Technology, Faculty of Chemistry, Lodz University of Technology, 16 Stefanowskiego Street, 90-537 Lodz, Poland
2
Department of Chemical Technology of Oil and Gas Processing, Institute of Chemistry and Chemical Technologies, Lviv Polytechnic National University, 12 Bandery Street, 79013 Lviv, Ukraine
*
Authors to whom correspondence should be addressed.
Materials 2022 , 15 (5), 1774; https://doi.org/10.3390/ma15051774
Received: 5 January 2022 / Revised: 11 February 2022 / Accepted: 23 February 2022 / Published: 26 February 2022
Versions Notes
Abstract
:
With the continuing growth of waste sulfur production from the petroleum industry processes, its utilization for the production of useful, low-cost, and environmentally beneficial materials is of primary interest. Elemental sulfur has a significant and established history in the modification of bitumen binders, while the sulfur-containing high-molecular compounds are limited in this field. Herein, we report a novel possibility to utilize the sulfur/organic copolymers obtained via the inverse vulcanization process as modifiers for bitumen binders. Synthesis and thermal characterization (TGA-DSC) of polysulfides derived from elemental sulfur (S
8
) and unsaturated organic species (dicyclopentadiene, styrene, and limonene) have been carried out. The performance of modified bitumen binders has been studied by several mechanical measurements (softening point, ductility, penetration at 25 °C, frass breaking point, adhesion to glass and gravel) and compared to the unmodified bitumen from the perspective of normalized requirements concerning polymer-modified bitumen. The interaction of bitumen binder with sulfur/organic modifier has been studied by means of FTIR spectroscopy and DSC measurements. The impact of the modification on the performance properties of bitumen has been demonstrated. The bitumen binders modified with sulfur/organic copolymers are in general less sensitive to higher temperatures (higher softening point up to 7 °C), more resistant to permanent deformations (lower penetration depth), and more resistant to aging processes without intrusive deterioration of parameters at lower temperatures. What is more, the modification resulted in significantly higher adhesion of bitumen binders to both glass (from 25% up to 87%) and gravel surfaces in combination with a lower tendency to form permanent deformations (more elastic behavior of the modified materials).
Keywords:
polysulfides
;
sulfur polymers
;
inverse vulcanization
;
polymer-modified bitumen
1. Introduction
The utilization of sulfur excess, mainly manufactured as a side product of the petroleum industry processes, constitutes an important and challenging problem for the chemical industry and related branches [ 1 , 2 ]. Exploration of low-cost, high-sulfur content organic or polymeric materials fabricated from elemental sulfur (S 8 ) and its further utilization pathways should be therefore of primary interest to sustain the proper cycle of sulfur conversion [ 2 , 3 ]. Recently, remarkable progress and renewed interest have been observed in elemental sulfur-based polymer chemistry. The scope of possibilities, accurate comparisons of the polysulfides synthesis methods as well as the green aspects of inclusion of elemental sulfur to polymer chemistry was summarized in exemplary comprehensive reviews [ 4 , 5 , 6 ].
The addition of high-molecular materials to a raw bitumen binder constitutes a very promising trend in the modification of its properties nowadays. The modification makes fatigue resistance of bitumen extended, its stiffness at higher temperatures increased, or cracking resistance at lower temperatures higher [ 7 , 8 , 9 ]. The rapidly growing pavement industry in the last few decades and, consequently, increased vehicular traffic load, forced the attempts of quality improvement of the most sensitive component of asphalt concrete [ 7 , 10 ]. Therefore, various polymers have been utilized over the years as bitumen binder modifiers with an example of thermoplastic polymers (polyethylene [ 11 ], polypropylene [ 12 ], ethylene vinyl acetate or ethylene butyl acrylate [ 13 ]), thermoplastic elastomers (styrene-butadiene-styrene triblock copolymers (SBS) [ 13 , 14 ]), polycondensation resins (phenol-cresol-formaldehyde resins and phenol-formaldehyde resins with labile peroxy bonds or methacrylic components [ 10 , 15 ]), petroleum resins with epoxy, hydroxy or carboxy groups [ 16 ], low-molecular organic compounds (formaldehyde and maleic anhydride) [ 17 , 18 ], or recycled elastomers in the form of ground tire rubber [ 19 ].
Historically speaking, a combination of bitumen binders with elemental sulfur as modifier started in the 19th century, but the first practical tests had been carried out and described later on, at the end of the 1930s by Bencowitz and Boe [ 20 ]. Although, the results were relatively successful, the costs of sulfur-overpriced bitumen binder resulted in discontinuing the research for the next decades. The real interest in the utilization of sulfur in asphalt paving materials was recognized in the 1970s and 1980s as a result of the growing generation of recovered sulfur from secondary sources and, consequently, a sulfur price decrease [ 21 , 22 , 23 ]. Primarily, the addition of large amounts of sulfur to asphalt concrete was intended to partially replace bitumen binder and decrease the costs of asphalt concrete. The formed materials were so-called “sulfur-extended asphalts” (SEA) and offered generally comparable or even superior properties compared to conventional asphalt concrete [ 23 , 24 ]. The upgraded technology of SEA is constantly in use and development under the name of Shell Thiopave ® (Shell Brands International AG, Baar, Switzerland), offering a pelleted form of plasticized sulfur, which significantly reduces the hydrogen sulfide and sulfur dioxide emissions during mixing, and enables asphalt production at lower temperatures [ 24 ].
Sulfur as a modifier in smaller quantities also was investigated in the absence [ 25 , 26 , 27 ] or the presence of other additives, predominantly of rubbers such as natural or synthetic rubbers [ 8 , 28 ] or SBS [ 8 , 29 ]. In the latter case, the presence of sulfur in the rubber-modified bitumen may enable interconnections through sulfide or polysulfide links between polymer and bitumen via vulcanization of both unsaturated rubber and functionalized bitumen components improving its storage stability and rheological properties such as resistance to deformation [ 7 , 8 ].
Surprisingly, not enough attention has been focused on using a polymerized form of sulfur and other high-molecular sulfur-containing compounds in bitumen binder modification. Besides the work of Elkholy et al. [
30
], who used the polysulfides derived from elemental sulfur thermally modified with a mixture of residual olefinic hydrocarbons (distillate fractions of C
5
) and bituminous residue as a modifier of bitumen binders and the work of Liang et al. [
31
], concerning the effect of polymerized sulfur on SBS-modified asphalt, no other reports are present in the literature. This conceives a new potential area to utilize sulfur/organic copolymers.
In order to fulfill this research gap as well as encourage by successful application of sulfur/organic copolymers obtained via the “inverse vulcanization” process as curing agents for rubber in our previous work [
32
], herein we report the application of selected polysulfides of this type as modifiers for bitumen binder. The thermal properties of sulfur/organic copolymers as well as their content optimization from the point of their performance as bitumen modifiers were evaluated. The characteristics of unmodified and modified bitumen samples were compared in terms of mechanical parameters and adhesive properties of bitumen binders.
2. Materials and Methods
2.1. Materials
Elemental sulfur (S 8 ), in a form of powder, was received from Siarkopol Tarnobrzeg (Tarnobrzeg, Poland). Dicyclopentadiene (DCPD) (≥95%) was purchased from Merck KGaA (Darmstadt, Germany), styrene (ST) (99%) from Acros Organics (Geel, Belgium), while the limonene (LIM) was synthesized (extracted from orange peel skin) from the Institute of Organic Chemistry (Lodz University of Technology, Lodz, Poland). The bitumen binder amenable to modification BND 60/90 was produced by PJSC “Transnational financial and industrial oil company Ukrtatnafta” (Kremenchuk, Ukraine).
2.2. Structure of the Experimental Work
The research framework including particular experimental steps has been presented in Scheme 1 . The comprehensive descriptions of selected steps and methods are presented below in Section 2.3 , Section 2.4 , Section 2.5 , Section 2.6 , Section 2.7 , Section 2.8 , Section 2.9 and Section 2.10 .
2.3. Synthesis of Sulfur/Organic Copolymers
The synthesis of the sulfur/organic copolymers was carried out in a glass reaction flask (250 mL volume), covered with a four-necked glass lid. The glass lid was equipped with a condenser, dropping funnel, mechanical stirrer, and a thermocouple. The reaction vessel with sulfur inside was immersed in a silicone oil bath and heated up to the temperature of 140 °C. While heating, at a temperature point around 120 °C, the sulfur started to melt down, and the mechanical stirrer was launched. After the temperature hit the final temperature setpoint, the molten sulfur was stirred for approximately 30 min. Afterward, the organic comonomers were dripped into the liquid sulfur within 30 min each time. Due to the exothermic reaction, the temperature was supervised to not exceed 160 °C. The copolymerization process in a bulk (known in this case as an “inverse vulcanization”) was carried out under the air atmosphere and atmospheric pressure. The obtained products were poured out into silicone molds at room temperature and solidified. Before its application, the copolymers were crushed with the use of mortar and pestle to obtain the powdery materials used further as bitumen binder modifiers. Copolymerization conditions and composition of the sulfur/organic copolymers are summarized in
Table 1
.
2.4. Thermal Analysis of Sulfur/Organic Copolymers
The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of the sulfur/organic copolymers were carried out using Netzsch TG 209 and Netzsch DSC 204 instruments (Netzsch, Selb, Germany), respectively. Both analyzers were connected with a Netzsch TASC 414/3A heat controller (Netzsch, Selb, Germany). The TGA tests were performed under nitrogen (N
2
) atmosphere in aluminum crucibles on a small powder sample (9–11 mg). The tested temperature range was 40–450 °C, applying heating mode and a rate of 10 °C/min. The DSC analyses were performed only in a heating mode under nitrogen (N
2
) atmosphere in the temperature range from 40 to 200 °C. The samples were tested in aluminum crucibles with variable heating rates. In the temperature range from 40 to 80 °C and from 140 to 200 °C, the heating rate was set to 7.5 °C/min, while in the temperature range from 80 to 140 °C, the heating rate was set to 2.5 °C/min. The lower heating rate in this temperature range was applied to provide better peaks resolution that occurred in this range.
2.5. Modification of the Bitumen Binders
Modifications of the bitumen were carried out in a glass modification vessel equipped with a mechanical stirrer and a thermometer, placed on a laboratory hotplate. The definite amount of bitumen BND 60/90 was heated up to the appropriate temperature (190 °C), and afterward, the particular modifier (sulfur/organic copolymer) was added. The amount of sulfur/organic copolymers as a modifier (1.0; 2.5 wt %) was pre-investigated experimentally. The mixture was stirred for 1 h at 1000 rpm.
2.6. Analysis of Physical Properties of Bitumen Binders
Analysis of the unmodified (raw) bitumen binder and the bitumen binders modified with sulfur/organic copolymers (BBMSOC) were investigated according to the European standard test methods dedicated to the bitumen and the asphalt binders (PN-EN) as well as to the Ukrainian national standard test procedures (DSTU). The BBMSOC were compared either with unmodified (raw) bitumen BND 60/90 as well as with the requirements for the performance of oil-oxidized polymer-modified bitumen binder (used as a reference) with softening point equal at least to 53 °C for 60/90-53 bitumen, regulated by the Ukrainian national standard DSTU B V.2.7-135:2014 [ 33 ]. The softening point of unmodified and modified bitumen binders was determined with the use of the ring and ball method, according to the PN-EN 1427:2015 European standard test method [ 34 ]. The needle penetration at 25 °C and the penetration index were investigated according to the PN-EN 1426:2015 [ 35 ] and PN-EN 12591:2009 [ 36 ] European standard test methods, respectively. Ductility at 25 °C was measured according to the PN-EN 13587:2010 [ 37 ] standard and the Fraas breaking point of prepared bitumen binders, as stated in the PN-EN 12593:2015 standard [ 38 ]. Adhesion to the surface of the glass was assessed according to the Ukrainian standard test method DSTU B V.2.7-81-98 [ 39 ] with a supplement according to the point 8.6 of the DSTU 4044-2001 standard [ 40 ], while adhesion to the gravel surface according to point 28 of the DSTU B V.2.7-89-99 standard [ 41 ]. Homogeneity was determined as follows: the sample of 300 ÷ 350 g of BBMSOC was heated up to the temperature of 160 ± 5 °C and stirred for 10 ÷ 15 min. After that, the bitumen binder was decanted to the porcelain vessel and a glass rod was immersed in the bitumen at the depth of 6 ÷ 8 cm and pulled out afterward. The organoleptic assessment of bitumen downflow was done; if the surface of the rod is homogenously coated without particles of unsolved modifier, the homogeneity of bitumen would be accepted (+). The following procedure was repeated at least 3 times for each bitumen sample. Short-term aging was simulated using the RTFOT (Rolling Thin Film Oven Test). In this study, the test was carried out in accordance with the PN-EN 12607-1 European standard test method for 75 min, at 163 °C [ 42 ].
2.7. FTIR Measurements of Bitumen Binders
The Fourier transform infrared (FTIR) spectroscopy studies were performed at room temperature by using a Thermo Scientific Nicolet 6700 FTIR spectrometer equipped with a diamond Smart Orbit ATR sampling accessory (Thermo Fisher Scientific, Waltham, MA, USA). The FTIR absorbance spectra were investigated in the absorption mode (64 scans) within the wavenumber range of 4000–400 cm −1 with the spectral resolution set to 4 cm −1 .
2.8. Thermal Analysis of Bitumen Binders
The differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of bitumen binders were carried out by using a Mettler Toledo TGA/DSC 1 STARe System (Mettler Toledo, Greifensee, Switzerland) equipped with a Gas Controller GC10 (Mettler Toledo, Greifensee, Switzerland). The DSC samples were firstly cooled from room temperature to −90 °C with a cooling rate of 10 °C/min and afterward heated up and investigated in a temperature range from −80 °C to 200 °C, with a heating rate of 10 °C/min. The TGA tests were carried out with a heating rate of 10 °C/min in a temperature range from 25 °C to 600 °C under an argon atmosphere.
2.9. Nanoindentation Test of Bitumen Binders
The microhardness characteristic of the composites was tested with a NanoTest 600 instrument (Micromaterials Ltd., Wrexham, UK) equipped with a Berkovich indenter, using depth controlled (3000 nm) mode with the loading/unloading speed of dP/dt = 0.05 mN/s. The measurements were carried out under controlled conditions: temperature 20 ± 2 °C and relative humidity of 60 ± 5%. The characteristic of the composite surface was calculated based on the unloading curve, using the procedure proposed by Olivier and Pharr [ 43 ].
2.10. Surface Free Energy of Bitumen Binders
The sessile drop method was applied for contact angle measurements in order to calculate the surface free energy (SFE) of bitumen binders. The samples were poured onto glass plates. Two liquids differing in polarity: distilled water and 1,4-dioodomethane were applied in a form of 2 µL droplets under ambient conditions. An OCA 15EC goniometer (DataPhysics Instruments GmbH, Filderstadt, Germany) equipped with a single direct dosing system (0.01–1 mL B. Braun syringe, Melsungen, Germany) was used. To calculate SFE of the bitumen binders, the Owens–Wendt–Rabel–Kaelble method was utilized [
44
] according to the formulas presented below:
The surface free energy is the sum of two components: (1) dispersive (
γ d s
) and polar components (
γ p s
), Equation (1).
γ
s
=
d
+
γ
s
p
(1)
The dispersive component can be determined from the formula below, Equation (2):
γ
s
d
=
[
γ
1
p
⋅
γ
2
⋅
(
cos
d
−
⋅
While the value of the polar component can be determined from the formula below, Equation (3):
s
where:
γ p
1,
γ d
1,
γ
1
—consecutively: polar and dispersion components and their sum for a polar liquid;
γ p
2,
γ d
2,
γ
2
—consecutively: polar and dispersion components and their sum for a non-polar liquid;
θ
1
,
contact angle of a polar and non-polar liquid, respectively.
The surface tensions and their components for low molecular weight liquids (mJ/m
2
), which were used for the Owens–Wendt calculations: water (polar liquid) (
γ p
= 51.0,
γ d
= 21.6,
γ
= 72.6), diiodomethane (non-polar liquid) (
γ p
= 2.3,
γ d
= 48.5,
γ
= 50.8)
3. Results and Discussion
3.1. Thermal Behaviour of Sulfur/Organic Copolymers (TGA-DSC)
The investigation of sulfur/organic copolymers using differential scanning calorimetry (DSC) and thermogravimetry (TGA) was aimed to analyze their behavior at the temperatures required in the bitumen modification process (190 °C). The calorimetry provided information concerning their phase structure, while the thermogravimetric studies determined the thermal stability of the copolymers. Elemental sulfur (S
8
) curves were added for comparison. The onset decomposition temperature was established as a temperature required for 5% mass loss during decomposition (T
5%
). The results are presented in
Figure 1
a,b and summarized in
Table 2
.
The DSC curve of elemental sulfur is represented by three distinct peaks with a maximum at 108 °C, 120 °C, and 170 °C, corresponding, respectively, to (i) the transition of crystalline structure, namely from orthorhombic sulfur to monoclinic sulfur, (ii) melting of the sulfur crystals and (iii) the latter to the ring-opening polymerization of sulfur molecules. Non-purified sulfur/organic copolymers are composed of macromolecules (polymeric phase) and elemental sulfur unreacted in the (co)polymerization process (crystalline phase). In this case, the DSC curve reveals one broader peak in the temperature interval from c.a. 90 °C to 110 °C. It may be ascribed to the melting of the residual low-molecular crystalline sulfur disrupted by sulfur/organic macromolecules existing in solid solution mixture (fused melting) [
45
,
46
]. The enthalpy values of this effect significantly diversify depending on the copolymer type. Also, the peaks are shifted into lower temperatures in the case of S/DCPD/LIM and S/DCPD/LIM/ST copolymers. According to our previous investigation [
32
], purification of copolymers by solvent extraction, from elemental sulfur, should lead to these peaks disappearing. Generally, the lower enthalpy of the melting peak, the lower elemental sulfur (crystalline) content in sulfur/organic copolymers, and simultaneously the higher polymeric phase (amorphous) content [
45
]. Following this rule, the highest polymeric phase content, and the lowest content of S
8
possess S/DCPD/LIM/ST copolymer (ΔH = 14.7 J/g). In the case of sulfur/organic copolymers, peaks characteristics for the ring-opening polymerization of the residual sulfur are very small and their enthalpy is negligible. This may tentatively confirm the possibility of unreacted sulfur molecules trapping in the solid solution.
The TGA curves of sulfur/organic copolymers reveal non-uniform and non-stable kinetics during thermal decomposition, compared to pure elemental sulfur (S
8
). The onset temperature is also significantly lower, which is a general affliction of polysulfide polymers [
47
] and starts at c.a. 245 °C, whereas elemental sulfur at 320 °C. The kinetics of thermal decomposition is influenced significantly by the presence of unreacted sulfur and the presence of organic fractions originating from used comonomers. What is more, the distribution of polymeric phase and crystalline sulfur in the structure of the copolymers are unknown on the micromorphological level and the structure of sulfur/organic copolymers is not well characterized in this term. According to the TGA results, sulfur/organic copolymers may be utilized in the selected temperature applications such as bitumen modification (190 °C) or rubber crosslinking (160 °C) [
32
] without intrusive degradation.
3.2. Properties of Bitumen Binders Modified with Sulfur/Organic Copolymers (BBMSOC)
3.2.1. Physical Properties of BBMSOC
Performance of the modified bitumen binders containing variable content of different sulfur/organic copolymers as modifiers were investigated and compared to the values of unmodified bitumen binder sample (BND 60/90) and standardized oil-oxidized polymer-modified bitumen (BMPA 60/90-53). The results obtained are shown in Table 3 and are presented in Figure 2 a–c. The results of short-term RTFOT aging of the unmodified bitumen and modified bitumen binders containing 2.5% wt sulfur/organic copolymers are presented in the form of a comparative Table 4 .
The incorporation of sulfur/organic copolymers either in 1.0% wt or 2.5% wt into BND 60/90 bitumen resulted in homogeneous polymer–bitumen blends. As can be noticed based on
Table 3
and
Figure 2
a–c, the performance parameters of the prepared BBMSOC differ significantly in comparison to the raw BND 60/90 bitumen binder. Regardless of sulfur/copolymer type, their addition increases the softening temperature and decreases penetration without significant impact on the behavior of binders in low temperatures (Fraas breaking point). A similar general trend of softening point and penetration changes has been obtained by Elkholy et al. [
30
], who used the thermally modified sulfur (90% wt) with a mixture of residual olefinic hydrocarbons (distillate fractions of C
5
) and bituminous residue (10% wt) as a modifier of bitumen binder (60/70). In turn, modification of BND 60/90 with elemental sulfur carried out by Syroezhko et al. [
25
] with small sulfur addition (below 10% wt) led to a decrease of softening point and increase of penetration (plasticization effect), while above 10% wt (up to 40 wt %) surprisingly reversed the trend.
The highest increase of softening point (+7 °C) has been observed in the case of S/DCPD and S/DCPD/LIM copolymers within 2.5% wt addition, which fulfills the softening point of standardized BMPA 60/90-53 bitumen. On the other hand, a decrease in penetration is significant, particularly with the addition of higher amounts of sulfur/organic copolymers. In the case of 2.5% wt addition of S/DCPD/LIM and S/DCPD/LIM/ST, penetration values were strongly reduced and went below the standardized values (61–90) of BMPA 60/90-53. Only the sample S/DCPD (2.5% wt) shows an acceptable value. The rigid character of samples with additive above 1.0% wt of the corresponding modifier can be also confirmed by the values of ductility at 25 °C, which were notably reduced compared to 1.0% wt additive as well as to unmodified bitumen, even up to 28 cm in the case of bitumen binder modified with S/DCPD/LIM copolymer. Overall, the modification enables to retain of the properties of bitumen binders in low temperatures, which is an additive value. The simulation of the RTFOT aging demonstrates an acceptable process, according to the specification contained in the PN-EN 12591 European standard test [
36
]. During aging, the bitumen penetration decreases and its softening temperature increases. The best example for short-term aging using RTFOT exhibits bitumen BND 60/90 with 2.5% wt addition of S/DCPD, because it has a high value of residual penetration (77%) together with the lowest change to weight (0.03 wt %) and to softening point (3 °C). The increase of softening point after aging in the case of raw BND 60/90 is 6 °C while in the case of the modified systems is 3 °C (S/DCPD and S/DCPD/LIM) or 4 °C (S/DCPD/LIM/ST). The lower increase indicates a higher resistance to aging processes.
For selected modification systems such as S/DCPD (2.5% wt), that fall within all the required parameters of standardized BMPA 60/90-53 bitumen, the presented results may be attractive to produce paving materials of less sensitivity to higher temperatures and loading time exposure, also presenting increased resistance to permanent deformations without intrusive deterioration of parameters at lower temperatures. Selected tested modification systems significantly increase the performance of bitumen binder compared to raw BND 60/90 and fulfill the majority of the comparative requirements (including adhesion presented in point 3.3.3). Some modification systems, unfortunately, do not fall within one parameter for the BMPA 60/90-53, such as softening point (S/DCPD (1.0% wt), S/DCPD/LIM (1.0% wt), and S/DCPD/LIM/ST (1.0% wt)), or penetration (S/DCPD/LIM (2.5% wt)). These limitations should be taken into consideration.
3.2.2. Nanoindentation Results
The nanoindentation investigation of BBMSOC has been performed to determine the plastic part of the sample deformation. This is to compare the potential behavior of the bitumen binders studied to rutting. The results obtained are shown in Figure 3 .
Nanoindentation measurements make it possible to determine the mechanical character of the surface layer of the materials. The incorporation of S/DCPD copolymer neither in 1 wt % nor in 2.5 wt % does not significantly change the mechanical characteristic of the bitumen surface compared to the reference BND 60/90. A minor increase in plastic deformation of the surface layer can be the result of the plasticization effect. It may be ascribed to the structure of the copolymer, which contains only dicyclopentadiene units along the macromolecules and presumably is unable to form crosslinked structures. The more structurally rich materials, such as S/DCPD/LIM and S/DCPD/LIM/ST copolymers, which contain units of limonene or limonene and styrene, respectively, may form more extended polymer networks during the inverse vulcanization process and added to the bitumen composition interpenetrate the network formed by high-molecular bitumen components such as asphaltenes. This may result in a more elastic behavior of the surface layer. It can be noticed that this effect increases with an increase in the addition of the copolymer in the case of S/DCPD/LIM and S/DCPD/LIM/ST modifiers. The highest effect is observed for the S/DCPD/LIM/ST within the addition of 2.5 wt %, making the elastic surface deformation of BBMSOC increase over 2.5 times compared to the unmodified BND 60/90 bitumen. Observed relationships are consistent with the penetration results trend. The bitumen binders after modification with the use of S/DCPD/LIM and S/DCPD/LIM/ST copolymers are more rigid and simultaneously of more elastic character. The nanoindentation results indicate that the application of selected sulfur/organic copolymers to raw bitumen binder may be attractive as potential successful rutting preventing modifiers.
3.2.3. Adhesive Properties and Surface Energy of BBMSOC
Adhesion of bitumen binders to the so-called “acidic” aggregates (aggregates with high content of silica) such as quartzite or granite is imperfect [ 10 ]. On the basis of that, many scientific groups and industrial companies are developing new bitumen promoters to enhance the adhesion of bitumen to aggregates and consequently increase the water-resistance of pavements [ 48 ].
In our study, an investigation of the adhesive properties of sulfur/organic copolymers-modified bitumen binders to granite aggregates and glass was performed. Their surface free energy calculated on the basis of the sessile drop technique measurements was also determined. The results are shown in Table 3 and Figure 4 a–c.
As can be observed, regardless of sulfur/organic copolymer type, its incorporation to bitumen binder significantly improves the adhesive properties to either glass or gravel surface (
Table 4
). The index of adhesion to the surface of glass increased 3.5 times comparing the unmodified BND 60/90 binder (adhesion 25%) and binder modified with the addition of 2.5% wt of S/DCPD copolymer (adhesion 87%). Generally, adhesion to glass increases with the higher addition of modifier. In turn, adhesion to granite gravel is more prominent with the addition of higher content of sulfur/organic copolymers (2.5% wt) and increase from mark 3 (unmodified bitumen binder and BBMSOC with 1.0% wt) to mark 5 (2.5% wt of copolymers addition). The high improvement of adhesion to both glass and granite gravel surfaces with a small contribution of sulfur/organic copolymers constitutes a very promising technological value for considering it as a potential adhesive promotor in pavement technology.
The presented results of adhesion are also consistent with the results of the surface free energy. Incorporation of sulfur/organic copolymer, regardless of its type, decreases the SFE of modified bitumen binders. It can be observed that the increase of sulfur/organic copolymer content in every example studied results in their lower total SFE, mostly due to the decrease of the polar part of surface energy. Theoretically, the lower the surface free energy of bitumen binders, the higher their adhesion to glass or granite gravel due to better wetting of their surface, as confirmed by the results presented.
3.2.4. FTIR Spectroscopy Analysis of BBMSOC
The FTIR spectra of sulfur/organic copolymers-modified bitumen binders as well as unmodified BND 60/90 bitumen in the overall scope (4000–400 cm −1 ) and the range of measurement characteristics for substantial changes are shown in Figure 5 a,b.
Although the chemical composition of bitumen materials is very complicated including components with variable molecular weight and structure, the FTIR spectra of bitumen are quite legible. The literature values of wavenumbers corresponding to specific bitumen bands were summarized and tabularized in Table 5 .
According to the data shown in Figure 5 a,b, the composition of bitumen with sulfur/organic copolymers contains all structural fragments of molecules that are characteristic of petroleum bitumen, namely: vibrations of C–H bonds in the groups CH 3 , –CH 2 –, (CH 2 ) n , as well as vibrations of C=C bond in the aromatic ring.
However, when a sufficiently large amount of sulfur/organic copolymers is introduced into bitumen, bands at 1275 cm
−1
and 1255 cm
−1
can be observed. Moreover, the absorption bands associated with the vibrations of the C–S and S–S groups (which are present when using a sulfur-based modifier) are of low intensity. Thus, it may be concluded that the bands at 1275 and 1255 cm
−1
correspond to wagging deformational vibrations of RCH
2
S– and R–CH
2
S–S– groups. In the case of pure bitumen, these bands are absent. The bands at 1010–1030 cm
−1
are vibrations associated with the S=O group, which is present in both the original bitumen (because bitumen contains sulfur) and in the modified products. The band at 755 cm
−1
corresponds to the trisubstituted aromatic compounds, which indicates the further interaction of bitumen molecules with the modifier.
3.2.5. Thermal Behavior of BBMSOC (TGA-DSC)
The differential scanning calorimetry (DSC) investigation was carried out to examine the general phase structure of bitumen binders as well as to assess their interaction with incorporated sulfur/organic copolymers. In turn, the thermogravimetric (TGA) studies were performed to investigate the thermal stability of unmodified bitumen binder BND 60/90 and to consider the impact of sulfur/organic copolymers addition on their thermal stability. The onset decomposition temperature was established as a temperature required for 5% mass loss during decomposition (T
5%
). Unfortunately, increased interactions between bitumen and the modifiers do not translate into an increase in the thermal stability of the former (T
5%
). The results are shown in
Figure 6
a,b and the values of temperature thermal effects are summarized in
Table 6
.
Taking into consideration the chemical structure of bitumen materials, it is well known that bitumen consists of chemically and molecularly diversified components, including high-molecular asphaltenes, exhibiting viscoelastic and viscous properties at elevated temperatures, similar to polymeric materials, and low-molecular (light-weight) fractions including resins, aromatic hydrocarbons and saturates (oils), which are aliphatic hydrocarbons [ 53 ].
The measured heat flow curves of the reference sample and bitumen binders modified with sulfur/organic copolymers reveal several thermal effects of bitumen fractions and confirm their complex nature. Typically, at low temperatures (below −20 °C), bitumen materials are in a glassy state, mainly because of the presence of amorphous asphaltenes in their structure [
53
,
54
]. In the case of the studied samples, the unmodified bitumen 60/90 possess a glass transition in the temperature interval from c.a. −40 °C with a midpoint of c.a. −30 °C. Analysis of the BBMSOC heat flow curves show similar, however, slightly shifted to lower values Tg.
Generally, incorporation of sulfur/organic copolymers subtly lowered the Tg values of analyzed bitumen, up to 4 °C in the case of the BND 60/90 + S/DCPD/LIM (2.5% wt) sample. This shift toward lower values may be ascribed to the presence in the bitumen of long sulfur/organic copolymer molecules. In bitumen materials, the glass transition is followed by a cold crystallization of low molecular weight saturated hydrocarbons that can order under slow heating [
53
]. In the samples studied, this transition peak may be spotted in a temperature interval from −20 °C to 10 °C with a midpoint around c.a. 0 °C. For better observation of the above transitions, temperature-modulated DSC (TMDSC) should be applied to analyze the reversing and non-reversing calorimetric signals [
53
]. Presumably, the cold crystallization of low-molecular weight fraction starts earlier and overlaps with the glass transition of high-molecular weight hydrocarbons. Further heating leads to the mild melting of the crystals and afterward recrystallization of high-molecular weight hydrocarbons is observed, due to increased mobility of the molecules, in the temperature range from c.a. 23 °C to 42 °C. The enthalpy of the latter varies from 0.95 J/g to 1.46 J/g, depending on the sample. The melting of this ordered phase can be found around 60 °C. Above this temperature, no more calorimetric signals are observed in conventional DSC curves such as a high-temperature glass transition of resin-asphaltene amorphous phase [
53
]. What is more, the endothermic signals in the temperature region c.a. 90–110 °C correspond to the melting of sulfur/organic copolymers that are not spotted on the DSC curves of BBMSOC. This may suggest that chemical interactions between elemental sulfur and sulfur/organic macromolecules with bitumen components might be formed.
The TGA analysis shows that the addition of sulfur/organic copolymers does not affect the thermal stability of the bitumen. The analyzed samples exhibit similar onset temperatures of thermal decomposition c.a. 360 °C. The thermal decomposition kinetics is smooth and very similar for all the samples studied.
4. Conclusions
The presented study showed that the sulfur/organic copolymers obtained by the facile method so-called “inverse vulcanization” can be potentially applied as modifiers for bitumen binders. Investigation of the modification impact onto the overall properties of bitumen binders shows that the bitumen binders modified with sulfur/organic copolymers are in general less sensitive to higher temperatures (higher softening point) and also more resistant to permanent deformations (lower penetration depth) without intrusive deterioration of parameters at lower temperatures. A consistent trend of softening point and penetration changing of bitumen binders has been presented by Elkholy et al. [
30
] with the use of elemental sulfur-olefin hydrocarbons/bituminous residue-derived polysulfides. What is more, the lower increase of softening point after short-term RTFOT aging in comparison to raw bitumen indicates a higher resistance to aging processes of the modified bitumen systems. Nanoindentation measurements revealed that the modified bitumen binders, particularly modified with S/DCPD/LIM and S/DCPD/LIM/ST copolymers, exhibit more elastic behavior (higher participation of elastic deformation), which, in combination with their lower penetration, constitutes promising materials from the point of view of their application as attractive rutting preventing additives. Modification of the bitumen binder BND 60/90 with the use of a small contribution of sulfur/organic copolymers results in significantly higher adhesive properties to both glass and granite gravel surfaces. In the best example, the adhesion to glass increased from 25% (raw BND 60/90) up to 87% (for 2.5 wt % addition of S/DCPD copolymer). Comparing all the studied samples, the most promising modification system seems to be S/DCPD (2.5% wt), which falls within all required parameters of standardized BMPA 60/90-53 and provides ultimate adhesion both to glass and gravel. Limitations of the tested modifiers ought to be taken into consideration, because some of the modifiers did not fall with all the standardized demands. The surprising lack of research works concerning the utilization of inverse vulcanization or other high-molecular sulfur-containing products in the field of bitumen/paving industry creates a research gap that should be fulfilled in the future by researchers bringing the progress in the both synthetic and application field of the presented work. This study proved that the improvement of the bitumen binders’ performance can be achieved by the addition of sulfur/organic copolymers. This opens the possibility to raise the level of standards applied in the bitumen/paving industry.
Author Contributions
Conceptualization, D.M.B. and M.B.; methodology, J.W., Y.D., V.G. and T.G.; investigation, J.W., Y.D., V.G., R.A. and T.G.; data curation, J.W. and Y.D.; writing—original draft preparation, J.W.; writing—review and editing, D.M.B., M.B., R.A. and Y.D.; supervision, D.M.B. and M.B.; project administration, J.W. and Y.D. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
The data presented in this manuscript are available on request from the corresponding authors.
Acknowledgments
Yuriy Demchuk is grateful to the ERASMUS program for the financial support during his internship in the group of Bieliński at the Lodz University of Technology.
Conflicts of Interest
The authors do not report any conflict of interest.
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Scheme 1. A schematic flow chart of the carried-out experimental work.
Scheme 1. A schematic flow chart of the carried-out experimental work.
Figure 1. Thermal analysis curves of sulfur/organic copolymers presented by: ( a ) differential scanning calorimetry (DSC); ( b ) thermogravimetry (TGA). The curves of elemental sulfur were added for comparison.
Figure 1. Thermal analysis curves of sulfur/organic copolymers presented by: ( a ) differential scanning calorimetry (DSC); ( b ) thermogravimetry (TGA). The curves of elemental sulfur were added for comparison.
Figure 2. Influence of sulfur/organic copolymers addition on the performance parameters of bitumen binders (BBMSOC) before and after RTFOT aging: ( a ) softening point; ( b ) penetration; ( c ) ductility.
Figure 2. Influence of sulfur/organic copolymers addition on the performance parameters of bitumen binders (BBMSOC) before and after RTFOT aging: ( a ) softening point; ( b ) penetration; ( c ) ductility.
Figure 3. Participation of plastic and elastic deformation in the total samples deformation of BBMSOC.
Figure 4. The results of ( a ) adhesion to the glass surface in graph form; ( b ) pictures of BND 60/90 (adhesion 25%) ( left ); BND 60/90 with and 2.5% wt addition of S/DCPD copolymer (adhesion 87%) ( right ); ( c ) participation of dispersive and polar part in the total surface free energy of BBMSOC.
Figure 4. The results of ( a ) adhesion to the glass surface in graph form; ( b ) pictures of BND 60/90 (adhesion 25%) ( left ); BND 60/90 with and 2.5% wt addition of S/DCPD copolymer (adhesion 87%) ( right ); ( c ) participation of dispersive and polar part in the total surface free energy of BBMSOC.
Figure 5. The FTIR spectra of unmodified and sulfur/organic copolymers-modified bitumen binders: ( a ) in the full wavenumber spectrum scope; ( b ) in the wavenumber region of significant changes.
Figure 5. The FTIR spectra of unmodified and sulfur/organic copolymers-modified bitumen binders: ( a ) in the full wavenumber spectrum scope; ( b ) in the wavenumber region of significant changes.
Figure 6. Thermal analysis of bitumen binders modified with sulfur/organic copolymers: ( a ) differential scanning calorimetry (DSC)—second heating scans; ( b ) thermogravimetry (TGA).
Figure 6. Thermal analysis of bitumen binders modified with sulfur/organic copolymers: ( a ) differential scanning calorimetry (DSC)—second heating scans; ( b ) thermogravimetry (TGA).
Table 1. Copolymerization conditions and composition of sulfur/organic copolymers as well as their organoleptic features.
Table 1. Copolymerization conditions and composition of sulfur/organic copolymers as well as their organoleptic features.
Sample Symbol Sulfur/Organic Comonomer(s) Ratio (wt %) Reaction Temperature (°C) Reaction Time 1 (h) Organoleptic Viscosity 2 S/DCPD 90.9/9.1 140 3 Low S/DCPD/LIM 87.0/8.7/4.3 140 3 Moderate S/DCPD/LIM/ST 83.3/8.3/4.2/4.2 140 3 Moderate to High
1 Reaction time measured after the total dripping of organic comonomer(s) into liquid sulfur at 140 °C; 2 Determined while pouring away the copolymerization mixture to molds; Abbreviations: DCPD—dicyclopentadiene, LIM—limonene, ST—styrene.
Table 2. Thermogravimetric and DSC characteristic parameters of the sulfur/organic copolymers. Elemental sulfur results were added for comparison.
Table 2. Thermogravimetric and DSC characteristic parameters of the sulfur/organic copolymers. Elemental sulfur results were added for comparison.
1 Temperature of characteristic phase transitions; 2 Enthalpy of characteristic phase transitions; 3 Decomposition temperature at 5% mass change; a Transition of orthorhombic sulfur to monoclinic sulfur; b Sulfur crystals melting; c Ring-opening polymerization of sulfur molecules; d Fused melting.
Table 3. Performance characteristic of the BBMSOC.
Table 3. Performance characteristic of the BBMSOC.
Property BND 60/90 BMPA 60/90-53 S/DCPD S/DCPD/LIM S/DCPD/LIM/ST 1% wt 2.5% wt 1% wt 2.5% wt 1% wt 2.5% wt Homogeneity (-) n.s. 1 2 + + + + + + Softening Point (°C) 46 ≥53 49 53 49 53 49 51 Ductility at 25 °C (cm) 63 ≥15 61 42 60 35 58 40 Penetration at 25 °C (0.1 mm) 70 61–90 68 62 62 50 64 46 Penetration index (-) −1.5 n.s. 1 −0.76 0.03 −0.96 −0.31 −1.5 −1.15 Fraas breaking point (°C) −18 ≤−20 −18 −19 −18 −18 −18 −19 Adhesion to gravel (mark) 3 ≥3 3 5 3 4 3 5 Adhesion to glass (%) 25 ≥20 43 87 50 65 54 80
1 not standardized; 2 clots and polymer particles should not be observed.
Table 4. Changes in performance characteristics of bitumen after RTFOT.
Table 4. Changes in performance characteristics of bitumen after RTFOT.
Property BND 60/90 S/DCPD (2.5% wt) S/DCPD/LIM (2.5% wt) S/DCPD/LIM/ST (2.5% wt) Unaged RTFOT Unaged RTFOT Unaged RTFOT Unaged RTFOT Softening Point (°C) 46 52 53 56 53 56 51 55 Change in Softening Point (°C) - 6 - 3 - 3 - 4 Penetration at 25 °C (0.1 mm) 70 55 62 48 50 30 46 24 Residual Penetration (%) - 79 - 77 - 60 - 52 Change in Weight (wt %) - 0.030 - 0.055 - 0.190 - 0.237
Table 5. Values of wavenumber attributed to the characteristic groups present in bitumen materials [ 49 , 50 , 51 , 52 ].
Table 5. Values of wavenumber attributed to the characteristic groups present in bitumen materials [ 49 , 50 , 51 , 52 ].
Wavenumber [cm −1 ] Characteristic of the Peak 2950 Asymmetric stretching vibrations ν (C–H) in CH 3 – group 2920 Asymmetric stretching vibrations ν (C–H) in CH 2 – group 2850 Symmetric stretching vibrations ν (C–H) in CH 2 – group 1600 Stretching vibrations ν (C=C) in aromatic rings 1455 Asymmetric bending vibrations δ (C–H) in CH 2 – group 1375 Symmetric bending vibrations δ (C–H) in CH 3 – group 1275 Wagging deformational vibrations ω (C–S and S–S) in RCH 2 S- and RCH 2 S-S-group 1255 1010–1030 Rocking vibrations (bending with torsion) ν (S=O) in sulfoxide group 870 Deformational vibrations of CH– group in 1,2,4-trisubstituted derivatives of benzene 810 Deformational vibrations of CH– group in tetrasubstituted derivatives of benzene 755 Deformational vibrations of CH– group in trisubstituted derivatives of benzene 745 Deformational vibrations of CH– group in 1,2,3-trisubstituted derivatives of benzene 720 Rocking vibrations of CH 2 – group in 1,3-disubstituted derivatives of benzene
Table 6. Thermogravimetric and DSC characteristic parameters of sulfur/organic copolymers-modified bitumen binders.
Table 6. Thermogravimetric and DSC characteristic parameters of sulfur/organic copolymers-modified bitumen binders.
Sample Symbol T g 1 [°C] T g 2 T 5% 3 [°C] BND 60/90 −39.6 −30.2 360 BND 60/90 + S/DCPD (1.0%) −34.9 −31.7 353 BND 60/90 + S/DCPD (2.5%) −32.4 −29.8 360 BND 60/90 + S/DCPD/LIM (1.0%) −39.2 −32.0 362 BND 60/90 + S/DCPD/LIM (2.5%) −43.9 −34.0 357 BND 60/90 + S/DCPD/LIM/ST (1.0%) −41.7 −31.8 360 BND 60/90 + S/DCPD/LIM/ST (2.5%) −39.8 −32.7 357
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The Vaping Crisis is Real, But the Response by States Misses the Point [FEATURE]
The Vaping Crisis is Real, But the Response by States Misses the Point [FEATURE]
While the culprit appears to be black market THC vapes, states are responding by banning flavored pot and nicotine vapes.
According to the
October 18 update
[14]
The update also provides this new syndrome with a name: E-cigarette or Vaping, product use Associated Lung Injury (EVALI).
In the update, the CDC notes that "all patients have reported a history of using e-cigarette, or vaping, products" and that "most patients report a history of using THC-containing products."
As EVALI cases began piling up this fall, the Food and Drug Administration (FDA)
warned consumers early this month
[15]
to "stop using THC-containing vaping products and any vaping products obtained off the street." The
CDC was on the same page
[16]
, recommending that people "should not use e-cigarette or vaping products that contain THC," buy black market vaping or e-cig products, especially those containing THC, or modify or add any substances to e-cig and vaping products.
Something new is going on. Marijuana and nicotine vaping products have been around for more than a decade by now -- who remembers the massive Volcano vape from early in this century? -- and the most popular nicotine vaping brand, Juul, has been on the market for more than four years. Yet this wave of vaping-related illness only broke out this summer.
The culprit increasingly appears to be
black market THC vaping cartridges
[17]
contaminated with new additives, particularly thinners including propylene glycol (PEG), Vitamin E acetate, and medium chain triglycerides (MCT oil). The FDA has begun investigating
Vitamin E acetate
[18]
, while public health officials in New York have found the substance in
a majority of seized vape cartridges
[19]
there. The FDA also announced in August that it is proposing adding PEG as a "respiratory toxicant" in its list of harmful tobacco product ingredients.
While federal health officials have been busy trying to find the actual cause of the EVALI outbreak, elected and public health officials at the state level have typically responded with much broader restrictions on vaping products overall, especially flavored vaping products for both nicotine and marijuana.
In Massachusetts [20] , Gov. Charlie Baker (R) last month declared a public health emergency and banned all vaping products and devices. "The use of e-cigarettes and marijuana vaping products is exploding, and we are seeing reports of serious lung illnesses, particularly in our young people," Baker said as he announced the ban. Medical marijuana patients can still vape, though.
In Michigan [21] , Gov. Gretchen Whitmer (D) used emergency administrative regulatory powers to make Michigan the first state to announce a ban on flavored nicotine products. "As governor, my No. 1 priority is keeping our kids safe," Whitmer said in a statement. "And right now, companies selling vaping products are using candy flavors to hook children on nicotine and misleading claims to promote the belief that these products are safe. That ends today."
In New York [22] , Gov. Andrew Cuomo (D) announced a ban on the sale of flavored e-cigarettes in September, citing both the outbreak of lung injury and concerns over teenage e-cig vaping. But that ban has been temporarily blocked in the courts in response to a challenge from the vaping industry.
In Oregon [23] , Gov. Kathleen Brown (D) ordered a six-month ban on all flavored vaping products early this month. In a joint statement, the Oregon Liquor Control Commission (which regulates marijuana) and the Oregon Health Authority said the emergency rules "are significant steps toward stemming the well-documented tide of e-cigarette use and vaping by youth, as well as keeping products that may expose people to unsafe chemicals and other contaminants off store shelves." But a state appeals court last week temporarily blocked the ban [24] on nicotine vaping product, but not marijuana ones.
In Rhode Island [25] , state health officials issued emergency health regulations at the end of September banning all flavored vaping products. Gov. Gina Raimondo (D) said she was concerned about the spread of e-cigarette use among teens and wanted to end the sale of flavored vaping products.
In Washington [26] , Gov. Jay Inslee (D) issued an executive order in late September banning flavored nicotine and marijuana vaping products for four months. "We need to act for the public health of our people," said Inslee. "I'm confident this executive order will save lives."
One state, though, has had a more reasoned and measured response. In
Colorado
[27]
, regulators this month proposed a ban not on flavored vape products or THC vape products, but one specifically targeting the additives that are in question: PEG, MCT Oil, and Vitamin E acetate. The move came after public hearings and consultations with industry stakeholders.
The plan also includes requiring labels that identify any additives to vaping products and vaping cartridge packaging for products that include additives will have to say "Not FDA Approved."
Drug reform advocates, while acknowledging the seriousness of the vaping illness, are critical of what they see as exaggerated and heavy-handed responses and suggest that the outbreak is all the more reason to legalize marijuana.
"All the vape bans really accomplish is to stoke more fear and stigma around yet another substance," Matt Sutton, director of media relations for the Drug Policy Alliance, said in an emailed statement. "What we are seeing play out right now is a real-life drama of how various substances are criminalized without justified reasoning and reliable research to do so. Taking this approach, we fail to consider the harm that may result from its removal from the marketplace, such as people turning to the black market or more harmful substances."
"Banning vapes will only stop legal vapes, with no known problems," said Dale Gieringer, long-time head of California NORML. "Illegal vapes won't be affected. There is a concerted campaign by public health officials, led by the FDA, the CDC, and the California Department of Public Health trying to demonize vaping in general, even though there's strong evidence that vaping in general is
much safer than smoking
[28]
, for all sorts of obvious reasons," said Gieringer. "In other countries, such as
Britain
[29]
, public health authorities are encouraging vaping to reduce smoking."
For concerns about vaping marijuana products, the policy prescription is obvious, said Sutton: "For THC, the issue is undoubtedly the lack of regulation, which cannot be put in place so long as it remains illegal at the federal level," he argued. "At this point, with these illnesses becoming a growing concern, it is incumbent on policymakers to legalize marijuana in the interest of public health."
For CANORML's Gieringer, the current vaping panic is just that -- a sort of moral panic that creates a demand for action, whether or not that action addresses the actual problem and whether or not that action leads to negative consequences.
over 50 percent
[30]
believe vaping is as dangerous as smoking. They've succeeded in panicking the public and misinforming it about the advantage of vaping over smoking," he argued.
"Another irony of this current hysteria is the resort to policies that ban flavored nicotine vapes when one of the attractions of vaping is flavor," said Gieringer. "Losing flavored vapes could drive people back to menthol cigarettes. If they're smart, they would at least keep menthol or some flavors on the market. The FDA could ban menthol cigarettes and smokers would go to vapes, which is a public health benefit."
Amidst all the concern about THC vaping, Gieringer had some simple advice for pot vapers: "Don't use underground products," he suggested. "There are also herbal vaporizers with no additives, just pot. And vape pens that operate on pure cannabis oil are also safe. That's the safest bet. There are a lot of reputable manufacturers who do nothing else."
[11] https://stopthedrugwar.org/taxonomy/term/192
[12] https://stopthedrugwar.org/taxonomy/term/68
[13] https://stopthedrugwar.org/taxonomy/term/156
[14] https://www.cdc.gov/mmwr/volumes/68/wr/mm6841e3.htm
[15] https://www.fda.gov/consumers/consumer-updates/vaping-illness-update-fda-warns-public-stop-using-tetrahydrocannabinol-thc-containing-vaping
[16] https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html#what-cdc-recommends
[17] https://www.leafly.com/news/health/vape-pen-lung-disease-advice-consumers
[18] https://www.fda.gov/consumers/consumer-updates/vaping-illnesses-consumers-can-help-protect-themselves-avoiding-tetrahydrocannabinol-thc-containing
[19] https://www.nytimes.com/2019/09/05/health/vaping-illness-lung-vitamin-e.html
[20] https://www.cbsnews.com/news/vaping-massachusetts-product-sales-banned-temporarily-today-2019-09-24/
[21] https://www.freep.com/story/news/local/michigan/2019/09/04/michigan-bans-flavored-vaping-products-what-know/2207323001/
[22] https://finance.yahoo.com/news/york-court-blocks-state-ban-054922585.html
[23] https://www.oregonlive.com/news/2019/10/oregon-will-ban-flavored-vaping-products-oct-15.html
[24] https://www.oregonlive.com/business/2019/10/oregon-appeals-court-halts-governors-flavored-vaping-ban.html
[25] https://www.sfgate.com/news/article/Rhode-Island-issues-emergency-rules-to-ban-vaping-14494931.php
[26] https://www.dailymail.co.uk/health/article-7526277/Washington-fourth-state-ban-flavored-e-cigarettes.html
[27] https://www.denverpost.com/2019/10/14/vaping-illness-regulation-marijuana-additives-colorado/
[28] https://www.nature.com/articles/s41598-017-14043-2
[29] https://www.cnbc.com/video/2019/07/11/uk-government-promotes-vaping-as-smoking-cessation-tool.html
[30] https://www.reuters.com/article/us-health-vaping-poll/more-americans-say-vaping-is-as-dangerous-as-smoking-cigarettes-reuters-poll-idUSKBN1W9136
[31] https://stopthedrugwar.org/chronicle/2019/oct/24/vaping_crisis_real_response#comments
[32] https://stopthedrugwar.org/license
[33] https://stopthedrugwar.org/subscribe
| https://stopthedrugwar.org/print/33548 |
SCOTT v. EXTRACORPOREAL, | 376 Pa.Super. 90 (1988) | super901461 | Leagle.com
HESTER Judge Ansy L. Scott appeals from the order of summary judgment entered in the Court of Common Pleas of Montgomery County...super901461
SCOTT v. EXTRACORPOREAL, INC.
View Case
Cited Cases
376 Pa.Super. 90 (1988)
545 A.2d 334
Ansy L. SCOTT, Appellant,
v.
EXTRACORPOREAL, INC.
Supreme Court of Pennsylvania. https://leagle.com/images/logo.png
Argued February 11, 1988.
Filed July 11, 1988.
Attorney(s) appearing for the Case
Richard W. Rogers, Norristown, for appellant.
James E. Farrell, Jr., New Hope, for appellee.
Before TAMILIA, HOFFMAN and HESTER, JJ.
Supreme Court of Pennsylvania.
[376 Pa. Superior Ct. 93]
HESTER, Judge:
Ansy L. Scott appeals from the order of summary judgment entered in the Court of Common Pleas of Montgomery County on July 6, 1987. This action arose out of appellant's discharge from her employment with appellee-Extracorporeal, Inc. In this appeal, appellant alleges that the entry of summary judgment was improper since she was under a contract precluding her dismissal without just cause and due to the fact that the discharge contravened public policy. We affirm.
Appellant was hired by Extracorporeal in 1980 to work on its assembly line at its manufacturing facility in Valley Forge, Pennsylvania. Extracorporeal's business is the development, manufacture, and distribution of medical devices. Upon hiring appellant, a company manager told her the job would be "permanent" and that there would be "a lot of overtime." Appellant executed a document acknowledging that she would be a permanent employee following the successful completion of a ninety-day probationary period. A handbook was distributed setting forth numerous details about company policies.
On August 25, 1983, a disturbance involving appellant occurred on the floor of the plant. One of appellant's co-worker's on the assembly line, Frances Adaey, "talked very loud . . . [about how] she was going to kick somebody's ass." Notes of Testimony, (N.T.), 10/17/86, at 18. Appellant attempted to ignore her. Ms. Adaey proceeded to insult appellant, stating that she knew a "state patient" when she saw one. Appellant's supervisor was informed of the disturbance, and he called all of the workers in the department into his office. The supervisor inquired about the disturbance and Ms. Adaey accused appellant of telling lies about her. The supervisor told those assembled he wanted the "nonsense" to stop. Ms. Adaey told him that she did not care what he said, that she and her husband were going to "kick some asses."
Id.
at 23. She told appellant that the remarks were directed at her. "I just ignored her and laughed," testified appellant, "and I told
[376 Pa. Superior Ct. 94]
her I wasn't afraid of her. . . . I said you hit me, I said I will hit you back." Id. The supervisor repeated his admonition that the disturbance must stop and dismissed the meeting. As appellant walked out the door, Ms. Adaey struck her on the head from behind, knocking her unconscious. When she awoke, she discovered Ms. Adaey's hand on her head. Ms. Adaey pulled hair from appellant's head. It required eight women to pull Ms. Adey from appellant. Id. 24-27. Both appellant and Ms. Adaey were sent home. Appellant was subsequently fired for fighting, and she filed suit against Extracorporeal. Summary judgment was entered in favor of the latter.
Our standard of review for orders of summary judgment is as follows:
Summary judgment may be granted if the pleadings, depositions, answers to interrogatories, and admissions on file, show that there is no genuine issue of material fact and that the moving party is entitled to judgment as a matter of law. . . . It is basic that summary judgment may be entered only in a case that is clear and free from doubt.
Rossi v. Pennsylvania State University,340 Pa.Super. 39, 44-45,489 A.2d 828, 831 (1988).
The employment at-will presumption holds that absent a contract to the contrary, an employee may be discharged for any or no reason. Darlington v. General Electric,350 Pa.Super. 183,504 A.2d 306(1986).
Taking a nationwide view of the law in this area, it is apparent that what once was the corpus juris of employment relations has lately become an amorphous mass of confusion replete with holdings that defy reconciliation from one jurisdiction to the next. The at-will presumption, the citadel that once governed the field with such predictability, has been eroded of late by piecemeal attacks on both the contract and tort fronts and the entire field seems precariously perched on the brink of change.
Martin v. Capital Cities Media, Inc.,354 Pa.Super. 199, 208,511 A.2d 830, 834 (1986).
[376 Pa. Superior Ct. 95]
"Pennsylvania has thus far escaped the widescale turbulence so common to the field and still clings to the at-will presumption." Id. The sine qua non of the presumption is that except in rare instances, discharges will not be reviewed in a judicial forum. The presumption may be overcome by express contract, implied in-fact contract (that is, the surrounding circumstances of the hiring may indicate that the parties did not intend it to be at-will), and additional consideration passing from the employee to the employer (that is, if the employee bestows a legally sufficient benefit or incurs a sufficient detriment for the benefit of the employer beyond the services for which he was hired, a court may infer that the parties intended to overcome the at-will presumption). An employer has no right to discharge even an at-will employee if the firing would contravene a clear public policy or if it is effected with the specific intent to harm the employee. A dismissal which is improper for either reason may be remedied by a tort action in wrongful discharge. Veno v. Meredith, 357 Pa.Super. 85 , 515 A.2d 571 (1986). Several recent decisions have noted that any further erosion of the at-will presumption in Pennsylvania should be effected by the legislature, not the courts. Darlington v. General Electric, supra; Martin v. Capital Cities Media, Inc., supra; and Veno v. Meredith, supra.
Appellant argues that the trial court erred in granting summary judgment as there was evidence raising a material question of fact that she had entered into a lifetime or permanent employment relationship. In support of this, she points to her deposition where she testified that upon being hired, her manager told her that she "could have a permanent job and there was a lot of overtime." N.T., 10/17/86, at 15. She also points to the fact that an employee handbook was delivered to her advising that she would achieve permanent employment status after the successful completion of a ninety day probationary period
1
and
[376 Pa. Superior Ct. 96]
also listing various offenses which could be cause for termination. She further cites an agreement she executed when she was hired which states, among other things, that the employer would have all rights to any inventions or improvements she might make or conceive and that she would not divulge the employer's confidential information.
We find no merit to this contention. We shall examine each of the factors asserted by appellant. The promise of "permanent" employment alone is too broad to be enforced. Pennsylvania appellate decisions have invariably evinced a marked reluctance to enforce employment contracts "for life" or of similar breadth. Recent cases holding that such promises do not overcome the at-will presumption include: Ross v. Montour Railroad Co.,357 Pa.Super. 376,516 A.2d 29(1986) (expectation of "life long" employment alone not sufficient to overcome the at-will rule); Murphy v. Publicker Industries, Inc.,357 Pa.Super. 409,516 A.2d 47(1986) (promise of life-time employment is not in itself definite enough to overcome the at-will presumption); Veno v. Meredith,357 Pa.Super. 85,515 A.2d 571(1986) (employer's statements to employee, including "I want to retire together," held too broad and vague to overcome the at-will presumption); Darlington v. General Electric,350 Pa.Super. 183,504 A.2d 306(1986) (employer's statement that employee was hired to work on a "long range project" held too vague and unspecified to overcome the at-will presumption); and Betts v. Stroehmann Bros.,355 Pa.Super. 195,512 A.2d 1280(1986) (employee's understanding that employment was to be "long term" insufficient to overcome the at-will presumption). See also Rogers v. International Business Machines Corp.,500 F.Supp. 867(W.D.Pa. 1980); Moorhouse v. Boeing Company,501 F.Supp. 390(E.D.Pa. 1980); Green v. Medford Knitwear Mills, Inc.,408 F.Supp. 577(E.D.Pa. 1976).
[376 Pa. Superior Ct. 97]
Appellant also points to a portion of the employee handbook given to her when she commenced her employment, which she contends contained a "just cause" provision precluding the employer from discharging her at-will. The handbook contains a provision in the "Standards of Behavior and Conduct" section which states that violation of certain enumerated offenses "can result in immediate suspension or termination." (Emphasis in original.) Included in the list are the following: "Fighting, horseplay, intoxication, gambling, and disorderly, immoral or unlawful conduct on Company property."
We find no merit to the contention that the handbook contains either expressly or by clear implication a just cause provision. The status of the contractual enforceability of employee handbooks has recently been clarified in several appellate decisions. A handbook is enforceable against an employer if a reasonable person in the employee's position would interpret its provisions as evidencing the employer's intent to supplant the at-will rule. See Martin v. Capital Cities Media, Inc.,354 Pa.Super. 199,511 A.2d 830(1986); Reilly v. Stroehmann Bros. Co.,367 Pa.Super. 411,532 A.2d 1212(1987); DiBonaventura v. Consolidated Rail Corporation,372 Pa.Super. 420,539 A.2d 865(1988). But See Richardson v. Charles Cole Memorial Hospital,320 Pa.Super. 106,466 A.2d 1084(1983) and Muscarella v. Milton Shoe Manufacturing Company, Inc.,352 Pa.Super. 158,507 A.2d 430(1986), which found handbooks and personnel policies unenforceable due to the fact that they are not bargained for by the employee but are unilaterally distributed by the employer. The absence of a bargained-for exchange was deemed to preclude their enforceability. The more recent decisions, see Martin v. Capital Cities Media Inc., supra, et al.,do not find the lack of a bargained-for exchange a bar to enforcing handbooks against employers. Since these decisions represent the most recent trend of our court in this evolving area, we will analyze the instant handbook by reference to the standard enunciated in them.
[376 Pa. Superior Ct. 98]
The instant handbook contains numerous provisions covering all manner of work-related information. The company's history is detailed along with numerous statements of company policy. Compensation is discussed as are benefits, holidays, vacations, and health and safety rules. The handbook states that engaging in certain offenses "can" result in termination, suggesting that discretion is left to the employer as to whether the ultimate sanction of discharge should be applied in a given instance. This discretion is completely at odds with any notion that the provision in question should be read to mean that an employee could not be discharged except for objective just cause. We stated in Martin v. Capital Cities Media, Inc., supra 354 Pa.Super. at 214, 511 A.2d at 838:
The handbook in the instant case does not evidence an intent to convert the employees who received it into employees who could only be discharged for an objective just cause. The list of actions that call for disciplinary action set forth in the handbook, supra, are nothing more than common sense enumerations of actions that any reasonable at-will employee would understand to generally call for disciplinary action. The handbook is an aspirational statement by the employer listing actions that generally will not be tolerated; it serves an information function. . . .
Appellant had been hired as an at-will employee. To now hold that the handbook allowed her discharge only for just cause would, in effect, convert her into an employee with a contract for an indefinite term who could be fired only for objective just cause. This would be a modification of immense proportions. For such an extreme modification of a preexisting contract, we would require a clear statement of an intent to so modify. We do not believe a reasonable person in the appellant's position would have read this handbook provision as converting her from an at-will employee to an employee with an indefinite contract who could never be discharged without objective just cause. . . . The handbook provision [citing actions which represent cause for disciplinary action] uses very general language such as dishonesty, insubordination, conduct which will reflect unfavorably on the Times Leader. The reasonable employee would understand these terms to include the phrase `. . . in the judgment of the employer.' The intent to overcome the at-will presumption must be stated with clarity.
This rationale is applicable instantly. The handbook does not contain a clear indication that the employer intended to overcome the at-will presumption. As in Martin,the actions which the handbook states "can" result in termination appear to be nothing more than common-sense enumerations of actions that any at-will employee would understand to call for disciplinary action. A reasonable employee would understand the provision in question to mean that the employer, in his subjective judgment, is free to decide whether a discharge would be appropriate. Appellant is entitled to no relief on the basis of this handbook provision. Appellant asserts, however, that the employer truly intended that those who satisfactorily completed the probationary period, as appellant did, would have "permanent" employment status which could not be terminated absent just cause.
This assertion is without merit. The employee handbook provision discussing the satisfactory completion of the probationary term (set forth in footnote one,
supra
), in no way suggests that once an employee achieves "permanent" status, she could never be fired except for objective just cause. To so hold would contravene the settled principle that great clarity is necessary to contract away the at-will presumption.
Clay v. Advanced Computer Applications,
370 Pa.Super. 497
,
536 A.2d 1375
(1988) (
en banc
);
Martin v. Capital Cities Media, Inc., supra.
We fail to see the requisite clarity in the probationary provision of the instant handbook. Appellant also argues that the written agreement whereby she gave the employer the rights to any inventions or improvements she might make or conceive and agreed not to divulge any of the employer's secrets
[376 Pa. Superior Ct. 100]
constitutes additional consideration sufficient to overcome the at-will presumption.
We disagree. Additional consideration has been described as follows:
Since at least 1946, Pennsylvania courts have recognized that even contracts for an indefinite duration can be brought out of the at-will presumption by a showing that the employee gave his employer additional consideration other than the services for which he was hired. See Lucacher v. Kerson, [158 Pa.Super. 437, 45 A.2d 245 (1946)]. The term consideration is not used here as it is in the usual contractual context to signify a validation device. The term is used, rather, more as an interpretation device. When sufficient additional consideration is present, courts infer that the parties intended that the contract will not be terminable at-will. This inference may be nothing more than a legal fiction because it is possible that in a given case, the parties never truly contemplated how long the employment would last even though additional consideration is present. Even so, the at-will presumption would be overcome. On the other hand, if the parties specifically agreed that the employment would be at-will, even though additional consideration were present, we would expect a court to construe the contract according to the parties' stated intention and hold it to be at-will.
. . . .
Thus, a court will find `additional consideration' when an employee affords his employer a substantial benefit other than the services which the employee is hired to perform, or when the employee undergoes a substantial hardship other than the services which he is hired to perform. `If the circumstances are such that a termination of the relation by one party will result in great hardship or loss to the other, as they must have known it would when they made the contract, this is a factor of great weight in inducing a holding that the parties agreed upon a specific period.' 3 A. Corbin, Corbin on Contracts § 684 (1960).
Darlington v. General Electric, supra350 Pa.Super. at 201 and 202, 504 A.2d at 314 and 315.
When sufficient additional consideration is present, an employee should not be subject to discharge without just cause for a reasonable time. . . . The length of time during which it would be unreasonable to terminate, without just cause, an employee who has given additional consideration should be commensurate with the hardship the employee has endured or the benefit he has bestowed.
Veno v. Meredith, supra357 Pa.Super. at 102, 515 A.2d at 580.
Instantly, there is no indication that appellant brought any abilities to the job, aside from the services for which she was compensated, which were beneficial to her employer or that she sacrificed anything tangible pursuant to the agreement beyond that for which she was paid. The at-will presumption is not overcome every time a worker sacrifices theoretical rights and privileges. The present agreement was based on a mere possibility that appellant would conceive something of value. We have no indication that she did conceive anything of value during her employment, or that at the time she was hired it was reasonably likely she would. The privileges and rights which appellant sacrificed were so minimal that in no sense can we say the agreement rose to the level of "additional consideration" as our courts have defined it.
None of the factors cited by appellant, either individually or in combination, is sufficient to overcome the at-will presumption. Appellant cites
Greene v. Oliver Realty, Inc.,
363 Pa.Super. 534
,
526 A.2d 1192
(1987), in support of her argument that the promise of permanent employment in combination with the handbook provisions, the successful completion of the probationary period, and the alleged additional consideration indicate that she and the employer truly
[376 Pa. Superior Ct. 102]
intended that she have "permanent" employment. Greene does not compel this holding. In Greene, the plaintiff was hired as a plasterer in a Pittsburgh office building in 1959. At that time, he agreed to work for less than union scale in exchange for a contract of employment for life. In 1983, without warning, he was discharged. The plaintiff sued, alleging that his contract of life-time employment precluded his discharge. The trial court granted the employer's motion for summary judgment. On appeal, we reversed, concluding that although a promise of life-time employment should not be enforced merely on the basis of the promise itself, such a promise should be enforced if the surrounding circumstances indicate that the parties truly intended to overcome the presumption of at-will employment or if there were additional consideration present. We left this determination for a jury.
By recognizing that the surrounding circumstances of the hiring should be examined to discern the terms of the employment relation, Greenemerely reaffirmed Pennsylvania's long-standing acceptance of the principle that the at-will presumption may be overcome by evidence of an implied in-fact contract. This theory of recovery was given a thorough exposition in Darlington v. General Electric, supra.There need not be additional consideration present to enforce a valid implied in-fact contract. Id. See also Veno v. Meredith, supra.Like additional consideration, the implied in-fact theory of recovery is an intention-discerning mechanism. A court will examine numerous factors surrounding the hiring to determine whether a reasonable person in the employee's situation would understand that his employment status is at-will. We properly stated in Greene,which was not a decision of the court en banc,that we did not view our holding as changing the law, but noted that it was an attempt to summarize and synthesize existing principles of employment contract jurisprudence.
The instant case is clearly distinguishable. Appellant cites no evidence that in agreeing to work for Extracorporeal,
[376 Pa. Superior Ct. 103]
she sacrificed anything nearly of the magnitude that the plaintiff in Greene bestowed on his employer. Unlike the plaintiff in Greene, appellant posits nothing beyond the naked assertion that she was promised "permanent" employment. As we have discussed, she fails to cite sufficient additional consideration or other surrounding circumstances which might lend validity to her claim. Likewise, the employee handbook given to her is insufficient to alter her at-will status.
We do not read Greeneto stand for the proposition that any time a discharged employee talismanically recites that he was promised "permanent" employment, the case must automatically proceed to trial. It is elementary that the employee must first present averments which would raise a legally sufficient factual dispute. Recent decisions have held it proper in similar instances for the courtto examine the factual averments and decide that the surrounding circumstances and additional consideration do not sufficiently manifest an intent to overcome the at-will presumption. See Darlington v. General Electric, supra; Ross v. Montour Railroad Co., supra; Betts v. Stroehmann Bros., supra; Veno v. Meredith, supra.
Whether a particular employment contract is terminable-at-will is a question of interpretation.
`The question of interpretation of language and conduct — the question of what is the meaning that should be given by a court to the words of a contract, is a question of fact, not a question of law.'
. . . .
`We must bear in mind, however that this question of fact is like other questions of fact in this: it may be a question that should be answered by the judge rather than by the jury.
`[If] the evidence is so clear no reasonable man would determine the issue before the court in any way but one, the court will itself determine the issue.'
3 A. Corbin, Corbin on Contracts (1960). (Emphasis added.) If the evidence is `so clear . . . a jury's verdict to the contrary would be set aside.' Id.
Darlington v. General Electric, supra350 Pa.Super. at 195, 504 A.2d at 312. Interpreting the facts of the instant case in appellant's favor, we find an insufficient factual basis upon which to remand this case for trial. 2
Scott next contends that her discharge violated a public policy which protects employees who exercise self-defense. She asserts that even if she struck Ms. Adaey during the disturbance, she acted in self-defense. The policy forbidding discharges of those acting in self-defense,
[376 Pa. Superior Ct. 105]
she argues, is articulated in 18 Pa.C.S. § 505, which states in pertinent part:
The use of force upon or toward another person is justifiable when the actor believes that such force is immediately necessary for the purpose of protecting himself against the use of unlawful force by such other person on the present occasion.
We find no merit to this assertion. The "wrongful discharge" cause of action had its Pennsylvania genesis in Geary v. United States Steel Corp.,456 Pa. 171, 319 A.2d 174 (1974). George Geary, a tubular products salesman for U.S. Steel, voiced misgivings to his superiors about the safety of a particular new product. Although the product was subsequently reevaluated and withdrawn due to his efforts, Geary was summarily discharged. He filed suit alleging wrongful discharge, and U.S. Steel's demurrer was sustained. On appeal, our supreme court affirmed, concluding that "Geary had made a nuisance of himself," and "[t]he praiseworthiness of Geary's motives does not detract from the company's legitimate interest in preserving its normal operational procedures from disruption." Id.456 Pa. at 180 and 183, 319 A.2d at 178 and 180. The court wrote: "It may be granted that there may be areas of an employee's life in which his employer has no legitimate interest. An intrusion into one of these areas by virtue of the employer's power of discharge might plausibly give rise to a cause of action, particularly where some recognized facet of public policy is threatened." But, "when the complaint itself discloses a plausible and legitimate reason for terminating an at-will employment relationship and no clear mandate of public policy is violated thereby, an employee at will has no right of action against his employer for wrongful discharge." Id.456 Pa. at 184 and 185, 319 A.2d at 180.
Subsequent to
Geary's
suggestion that certain discharged employees may successfully assert a "public policy" cause of action, our courts have consistently held that
[376 Pa. Superior Ct. 106]
The Gearycourt expressly declined to "define in comprehensive fashion the parameters" of the employer's privilege to discharge at will. Since then, acting on a case-by-case basis, our courts have carved very narrow exceptions to the at-will rule. It is generally accepted that to be actionable, the asserted public policy must be one which is already articulated in law or a constitutional provision. See Darlington v. General Electric, supra.It is clear that discharges which are merely arbitrary do not contravene public policy. See Marsh v. Boyle,366 Pa.Super. 1,530 A.2d 491(1987); Betts v. Stroehmann Bros.,355 Pa.Super. 195,512 A.2d 1280(1986).
Our state appellate courts have found a plausible wrongful discharge cause of action in only limited instances. In
Reuther v. Fowler & Williams,
255 Pa.Super. 28
,
386 A.2d 119
(1978), we held that a discharge motivated by an employee's service of jury duty is improper. We noted that jury service is of "the highest importance to our judicial process," but opined that even this public policy could be overcome by a separate, plausible and legitimate reason supporting it. In
Hunter v. Port Authority of Allegheny
[376 Pa. Superior Ct. 107]
County, 277 Pa.Super. 4 , 419 A.2d 631 (1980), a public bus company refused to hire appellant (a situation we deemed similar to a discharge) due to his prior convictions for aggravated assault and battery, despite the fact that the Governor had granted him an unconditional pardon for the offenses. We reversed a demurrer in the bus company's favor, holding that there was an important public policy in preventing the unwarranted stigmatization of, and unreasonable restrictions upon, former offenders. We found it significant that the employer was a government entity. Another example of a violation of a clear public policy is where a discharge is motivated by an employee's refusal to take a polygraph test. Leibowitz v. H.A. Winston, 342 Pa.Super. 456 , 493 A.2d 111 (1985).
In the instant case, appellant was discharged due to Extracorporeal's belief that she was involved in a fight on company premises. This discharge lies beyond our power to remedy. Our courts generally hold that the discharge of an employee who is believed by the employer, broadly speaking, to be disruptive, is beyond the pale of judicial review.
See Geary v. United States Steel, supra
(no cause of action for employee discharged after bypassing usual channels to complain about a new product's safety; the court found he had "made a nuisance of himself");
Rinehimer v. Luzerne Com. College,
372 Pa.Super. 420
,
539 A.2d 1298
(1988) (college's board of directors was free to fire president whose policies caused a "major upheaval" and "a great deal of internal unrest");
Martin v. Capital Cities Media, Inc., supra,
(no cause of action for newspaper employee discharged after she placed an advertisement in a competing newspaper as employer had the right to fire one it deemed insubordinate and disruptive);
Yaindl v. Ingersoll-Rand Co.,
422 A.2d 611
(1980) (no cause of action for fired employee who, among other things, displayed difficult and disruptive behavior);
Turner v. Letterkenny Federal Credit Union,
351 Pa.Super. 51
,
505 A.2d 259
(1985) (no cause of action for employee fired after
[376 Pa. Superior Ct. 108]
he had experienced deteriorating relations with those under his supervision); and Rossi v. Pennsylvania State University, 340 Pa.Super. 39 , 489 A.2d 828 (1985) (no cause of action for employee fired after continuously complaining to his supervisors about the financially wasteful manner in which his department was run; "troublesome" employee may be discharged at will).
Turning to the instant case, we find no public policy implicated by the discharge. Given the procedural posture of this case, we must believe that during the disturbance with Ms. Adaey, appellant either acted in self-defense or never landed a blow. Nevertheless, it is clear that the employer held her at least partially accountable for the disturbance. We may not deny the employer the right to dismiss due to its subjective evaluation that the employee behaved disruptively. Martin v. Capital Cities Media, Inc.,354 Pa.Super. 199,511 A.2d 830(1986); The moral fairness of the firing is simply beyond our power to review. See e.g., Gillespie v. St. Joseph University,355 Pa.Super. 362,513 A.2d 471(1986); Darlington v. General Electric, supra.We surely do not condone discharges which are by any objective measure unfair; however, in the context of the facts of this case, the public policy asserted by appellant — the right to exercise self-defense — strikes entirely too near the employer's legitimate interest in discharging employees it perceives to be disruptive. To reverse on this basis "would have the unwise effect of transferring to the judicial forum the duty of evaluating the propriety of management decisions." Rossi v. Pennsylvania State University, supra340 Pa.Super. at 54, 489 A.2d at 836. This we decline to allow.
Judgment affirmed.
FootNotes
1. The handbook states: "Prompt regular attendance, knowledge and performance of your job and working in a safe and efficient manner, while keeping your work area clean, are examples of the factors your supervisor will evaluate before approving you to become a permanent employee." Handbook at II-3.
2.
Marsh v. Boyle,
366 Pa.Super. 1
, 3-7,
530 A.2d 491
, 493-94 (1987), is also distinguishable. There, we wrote:
Appellant left his employment as circulation manager of the Lewistown Sentinel to begin working at an increased salary for Appellees as publisher of the Clarion News. It was Appellant's understanding that he would be working for a period of time along with the current publisher, who was about to retire. The date of the current publisher's retirement was never established. Appellant was informed at the time of hiring that he would work in Clarion as publisher for `at least two years' and thereafter would become general manager in Oil City, a position Appellant desired because it would result in a pay increase and because Oil City was Appellant's childhood home. Appellant placed his house in Lewistown for sale and relocated to Clarion to commence his employment on October 28, 1985. Appellant's family remained in Lewistown and his home there was not sold prior to his dismissal at the Clarion News on January 29, 1986.
. . . .
In the case before us, the employer's assurances that Appellant would be working as publisher for at least two years was not sufficiently definite to take the agreement out of the at-will employment presumption. Appellant, nevertheless, relies on the surrounding circumstances, particularly his resignation from his position with the Lewistown paper, his move to Clarion and his act of placing his house on the market as establishing sufficient consideration to rebut the at-will presumption. Appellant seeks to prove that the parties' discussion as to the terms of his employment, when examined in light of these circumstances, created a contract which could not be terminated at-will but, rather, would continue for a reasonable length of time, or at least two years.
We concluded that the issue was not one appropriately resolved by summary judgment. Again, the plaintiff in Marshpresented far more substantial evidence to rebut the at-will presumption than appellant presents instantly. Marshnoted that a promise of "permanent" employment standing alone will not overcome the at-will presumption.
| https://www.leagle.com/decision/1988466376pasuper901461 |
Phase 2a Study of PRV-6527 in Subjects With Moderately to Severely Active Crohn's Disease - Full Text View - ClinicalTrials.gov
Phase 2a Study of PRV-6527 in Subjects With Moderately to Severely Active Crohn's Disease (PRINCE)
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03854305 Recruitment Status :
Completed First Posted : February 26, 2019 Last Update Posted : September 16, 2021
Sponsor:
Provention Bio, Inc.
Information provided by (Responsible Party):
Provention Bio, Inc.
Study Details
Study Description
Brief Summary:
This study will evaluate the efficacy and safety of oral PRV-6527 in the treatment of moderately to severely active Crohn's disease
Condition or disease Intervention/treatment Phase Crohn's Disease Drug: PRV-6527 Drug: Placebo Phase 2
Detailed Description:
This is a Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in adult subjects with moderately to severely active Crohn's disease.
Eligible subjects include males and females aged 18-75 years with moderately to severely active CD for at least 3 months. Each subject will receive the assigned treatment over 12 weeks, followed by a 4-week safety follow-up period.
Study Design
Layout table for study information Study Type : Interventional
(Clinical Trial) Actual Enrollment : 93 participants Allocation: Randomized Intervention Model: Parallel Assignment Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Primary Purpose: Treatment Official Title: Phase 2a Multicenter Randomized Double-Blind Placebo-Controlled Parallel Study to Evaluate the Efficacy and Safety of Oral PRV-6527 (JNJ-40346527), an Inhibitor of CSF-1 Receptor, in Subjects With Moderately to Severely Active Crohn's Actual Study Start Date : March 20, 2018 Actual Primary Completion Date : August 13, 2019 Actual Study Completion Date : August 13, 2019
MedlinePlus Genetics related topics: Crohn disease
MedlinePlus related topics: Crohn's Disease
U.S. FDA Resources
Arms and Interventions
Arm Intervention/treatment Experimental: PRV-6527 Oral administration, 2X daily for 12 weeks Drug: PRV-6527 Treatment Placebo Comparator: Placebo Oral administration, 2X daily for 12 weeks Drug: Placebo Comparator
Outcome Measures
Primary Outcome Measures
:
Change from baseline to Week 12 in Crohn's Disease Activity Index score [ Time Frame: 12 weeks ]
Crohn's Disease Activity Scale will be assessed by collecting information on 8 different Crohn's Disease-related variables : extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stood, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being. The last 4 variable are based on dairy of patient for 7 days Scale range is 0 to 600 with 0 being the best oputcome and a score of 600, the worst outcome.
Eligibility Criteria
Information from the National Library of Medicine
Layout table for eligibility information Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Subject must be a man or woman between 18 years and 75 (inclusive) years of age.
Has moderate to severe CD and a histologic diagnosis of CD for at least 3 months before screening.
Exclusion Criteria:
Has other gastrointestinal inflammatory diseases.
Has any malignancy or lymphoproliferative disorder other than nonmelanoma cutaneous malignancies or cervical carcinoma in situ that has been treated with no evidence of recurrence.
Has colon cancer or severe dysplasia. Subjects with CD for ≥8 years involving the colon are not excluded if they had a colonoscopy to assess for the presence of dysplasia within 1 year before baseline or if they had a colonoscopy at the screening visit that excludes any evidence of malignancy.
Has current signs or symptoms of an acute infection or infected skin wounds or ulcers, with the exception of nonserious infections in the opinion of the Investigator (e.g. sepsis, pneumonia, or pyelonephritis), including any infection requiring hospitalization or IV antibiotics, within 8 weeks before baseline.
Has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof.
Has any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
| https://clinicaltrials.gov/show/NCT03854305 |
Les approches non-pharmacologiques des symptômes comportementaux et psychologiques de la démence dans la prise en charge des personnes ayant un trouble neurocognitif majeur de type Alzheimer ou une maladie apparentée par les infirmières en Groupe de Médecine Familiale
Les approches non-pharmacologiques des symptômes comportementaux et psychologiques de la démence dans la prise en charge des personnes ayant un trouble neurocognitif majeur de type Alzheimer ou une maladie apparentée par les infirmières en Groupe de Médecine Familiale
Document principal (2.748Mb)
Publication date
2019
Author(s)
Dame, Nathalie
Subject
Approches non-pharmacologiques
Alzheimer
Groupes de médecine familiale
Démence
Soins de première ligne
Troubles neuro-cognitifs majeurs
Symptômes comportementaux et psychologiques de la démence
Abstract
Dans un contexte de vieillissement de la population québécoise, qui prévoit que 25% des habitants seront âgés de 65 ans et plus en 2030 (Institut de la Statistique du Québec, 2015) et sachant que les risques de développer un trouble neurocognitif majeur (TNCM) augmentent avec l’âge, le nombre de personnes aux prises avec un TNCM au Québec pourrait passer de 120 000 en 2015 à plus de 200 000 en 2030 (Bergman et al., 2009). Or, 90% des personnes souffrant de TNCM présentent des manifestations comportementales en plus de déficits cognitifs à un moment de leur parcours (Engasser et al., 2015). Deux catégories d’interventions existent pour la gestion des symptômes comportementaux et psychologiques de la démence (SCPD) : les interventions pharmacologiques et les interventions non pharmacologiques (Benoit et al, 2005). Comme les écrits tendent à montrer que les interventions pharmacologiques génèrent des effets iatrogènes (Engasser et al, 2015, Cohen –Mansfield, 2103, Martini de Oliveira et al., 2015) et démontrent une efficacité limitée (Engasser et al, 2015), il importe donc d’intégrer des interventions non-pharmacologiques à la prise en charge de la clientèle aux prises avec un TNCM. Au
Québec, dans le cadre du Plan Alzheimer, le Ministère de la Santé et des Services Sociaux (MSSS) a émis toute une série de publications préconisant l’intégration et le suivi systématique d’approches non-pharmacologiques. La présente étude s’intéresse donc à l’intégration et au suivi d’approches non-pharmacologiques par la première ligne et vise quatre objectifs principaux: 1) Brosser le portrait actuel de la situation québécoise quant à l’utilisation, par les Groupes de Médecine Familiale (GMF) dans le cadre du Plan Alzheimer, des approches non-pharmacologiques lors de la prise en charge globale par les infirmières des personnes présentant un TNCM; 2) Évaluer la mise en oeuvre des processus de prise en charge émis par le MSSS relatives à l’intégration et au suivi des approches non-pharmacologiques dans le cadre du Plan Alzheimer; 3) Identifier les facteurs facilitants et les obstacles à l’intégration, à la mise en oeuvre et au suivi des approches non-pharmacologiques en GMF; 4) Dégager les potentiels supplémentaires d’intégration des approches non-pharmacologiques à l’intervention globale pour ces clientèles dans le contexte de la première ligne en GMF. Le type de devis utilisé pour la réalisation de cette étude est un devis mixte comprenant un volet quantitatif supporté par un questionnaire à choix multiples et réponses courtes rempli par 20 infirmières de GMF formées au Plan Alzheimer dans 6 régions du Québec et un volet qualitatif descriptif basé sur des entretiens semi-dirigés avec 4 infirmières ayant participé au volet quantitatif. L’analyse des données a montré qu’au moment de l’étude, les approches non-pharmacologiques étaient peu intégrées au traitement et encore moins suivies par les infirmières en GMF lors de la prise en charge de personnes présentant des TNCM associés à des SCPD et vivant à domicile. Il existe un écart significatif entre le processus clinique suggéré par le MSSS et la pratique des infirmières en GMF des régions participantes. Enfin la formation, les méthodes de
travail, les bonnes pratiques, la collaboration des professionnels, l’organisation du travail, la connaissance des effets des approches non-pharmacologiques, la disponibilité et de l’accessibilité de celles-ci dans la communauté et le volet des aidants sont des éléments à considérer pour améliorer l’intégration et le suivi des approches non-pharmacologiques pour la clientèle présentant un TNCM en contexte domiciliaire.
URI
http://hdl.handle.net/11143/15567
Collection
Moissonnage BAC [4262]
Gérontologie – Mémoires [47]
| https://savoirs.usherbrooke.ca/handle/11143/15567?locale-attribute=en |
(PDF) Theoretical Analysis on the Effect of Surface Horizontal Traction on Top-Down Cracking of Flexible Pavement
PDF | Fatigue cracking of flexible pavement is one of the most important elements that should be considered due to the damage occurs in asphalt layer... | Find, read and cite all the research you need on ResearchGate
Theoretical Analysis on the Effect of Surface Horizontal Traction on Top-Down Cracking of Flexible Pavement
March 2019
Association of Arab Universities Journal of Engineering Sciences 26(1)
DOI: 10.33261/jaaru.2019.26.1.022
License
CC BY-NC 4.0
Authors:
Abstract and Figures
Fatigue cracking of flexible pavement is one of the most important elements that should be
considered due to the damage occurs in asphalt layer under the effect of wheel load repetitions. This research
demonstrated theoretical study on top-down fatigue crackingusing the finite element method. A threedimensional
finite elastic structural element is used to modal pavement using (ABAQUS ver. 6.12.1)
program. The results obtained from this studydemonstrated that maximum value of tensile strain developed
at the surface of asphalt layer for flexible pavement due to the horizontal traction generated from wheel load
application at contact area. Also, the horizontal tensile strain () at surface of asphalt layer is increasing
rapidly with load repetitions with values greater than that generated at bottom by (94%) at failure. This
prescribed the basic or inherent features of top crack initiation and down propagates within asphalt layer in
flexible pavement. The top horizontal tensile strains obtained from the finite element model is higher than
the empirical relations by (20%); since the finite element analysis of flexible pavement considered the
surface horizontal tensile strains due to contact traction force at tire pavement interface. Finally, according
to the results of this study the horizontal tensile strains at the top of asphalt surface significantly increase
the damage intensity of fatigue failure for flexible pavement.
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https://doi.org/10.33261/jaaru.2019.26.1.022 Association of Arab Universities Journal of Engine ering Sciences (2019) 26(1): 170–174
Theoretical Analysis on the Effect of Surface Hori zontal Traction on
Top-Down Cracking of Flexible Pave ment
Zainab Ahmed Alkaissi 1 , Yasir M. Al-Badran 2 , and Najwa Wasif 3,*
1 Department of Highway and Transportation Eng ineering, Mustansiriyah University, Baghd ad, Iraq, zainabalkaisi77@googlemail.com,
3 Department of Highway and Transportation Eng ineering, Mustansiriyah University, Baghd ad, Iraq, najwawasif77@uomustansiriyah.edu.i q
*Corresponding author: NajwaWasif, najwaw asif77@uomustansiriyah.edu.iq
Published online: 31 March 2019
Abstract — Fatigue cracking of fl exible pavement is one of the most important elements that should be
considered due to the damage occurs in a sphalt lay er under the effect of wheel lo ad repe titions. Th is research
demonstrated theoretical study on top-down fatigue crackingusing the fini te element method. A three-
dimensional finite elastic structural element is used to modal pavement using (ABAQUS ver. 6.12.1)
program. The results obtain ed from this studydem onstrated that maximum value of tensile strain developed
at the su rface of asphalt layer for flexib le pavement due to the horizonta l traction generated f rom wheel load
application at contact area. Also, the horizontal tensile strain ( ) at surface of asphalt layer is increasing
rapidly with load repetitions with values greater than that generated at bottom by (94% ) at failure. This
prescribed the basic or inherent features of top crack initiation and down propagates within asphalt layer in
flexible pavement. The top horizontal tensile strains obtained from the finite element model is higher than
the empirical relations by (20%); since the finite el ement analysis of flexible pav ement considered th e
surface horizontal tensile strains due to contact traction force at tire pavement interface. Finally, according
to the results of this study the horizontal tensile strains at the top of asphalt surface significantly increase
the damage intensity of fatigue failure for flexible pav ement.
Keywords — Fatigue Damage, Finite Element. Flexible Pavement, T ensile Strain, Top -Down Cracking.
1. Introduction
The cracking of flexible pavement occurs when the
horizontal tensile strain exceed the allowable limits.
Fatigue cracking is associated with critical tensile s train
developed in asphalt layer under the application of moving
wheel load. The aim of this research is to simulate the
fatigue damage through estimating the critical tensile
strains produced at the bottom and top of asphalt layer
within flexible pavement using the finite element methods
which considered as one of the powerful techniques used
in several engineering problems. In the finite element
model of pavement structure, the horizo ntal, vertical,
normal and shear stresses can be computed.
Behiry (2012) studied the effect of increasing axle load and
variation of pavement modulus on the overall paveme nt
life. The results showed that tensile and com pressive strain
increased with increas ing axel loa ds anddecreased w ith
increasing asphalt layer modulus [2]. Jill et al, (2003)
performs a three-dimensional finite element using
ABAQUS program to estimate the stresses in flexible
pavement systems with present transverse crack [3]. It was
demonstrated that the existing of transverse crack increase
significantly the vertical stress in the base la yer and also
it’s has significant effect on the horizontal stresses in t he
asphalt layer.
Zhengetal. (2 017) provides an experimental investigatio n
on the fatigue performance of flexible pavement with high
modulus asphalt concretes including the cycles of stress -
strain test and direct tensile fatigue test. The modified
Neuber equation and local stress- strain method is used to
predict the initiation of fatigue crack lif e of hot mix asphalt
concrete pavement [8].
171
Zainab Ahmed Alkaissi et al. / Association of Arab Un iversities Journal of Engineering Sci ences (2019) 26(1): 170–174
2. Finite Element Modeling for Pavement
For modeling of fatigue damage o f flexible pavement to
emphasize the objectives of this research, three-
dimensional finite elastic solid continuum element of
pavement using element (C3 D8R). The finite element
mesh for pavement layers is shown in Figure (1) w ith fines
at the top and contact interface where large horizontal,
vertical stress a nd strains are developed under the applied
tire pressure. The finite element model including aspha lt
layer (100 mm thickness) and subgrade soil (3000 mm
thickness). To eliminate the effect of boundary d ue to the
fixed boundary that used to simulate the bo undaries of the
model, suitable dimensions of the model in lo ngitudinal
and transverse direction to the ap plied loa d is considered
as (3600x 6000) mm.
The tire pre ssure simulated by ABAQUS finite element
model using the rectangle shape shown in Figure (2) which
assumed that the standard axel load of one tire of (40 kN)
is transferred to pavement surface through uniform contact
pressure of ( 690 kPa ) with neglecti ng the stiffness effect
of tire wall, the contact pressure will equal to tire pressure
[3].
Figure 1: Finite Element Mesh of Pavement Mod el
Figure 2: Contact Area of Tire Pressure [4 ]
To determine the fatigue damag e of wheel load on the
flexible pavement, m oving load that varies in space and
time ha s been simulated in this research using ABAQUS
computer program through the application of Load
Module.
The step loading is divided i nto 8 steps (to complete one
cycle)as sho wn in Figure (3) to simulate the moving
repeated loading on the surface of flexible pavement using
the application of Step Mo dule.Also Figure (3) presents
the boundary conditions for pavement geometry m odel
which is f ixed at the botto m of subgrade soil layer ( no
vertical and horizontal movements) and the edges p arts of
pavement model fixed in all d irections except for vertical
directions.
The Interaction Module is app lied to simulate t he contact
surfaces and integration b etween asphalt layer and
foundation layer (ABAQUS Theory Manual, 2009) [1]a s
shown in Figure (4).
Figure 3: Moving Load for 3D Pave ment Model using
Step Module
Figure 4: Interaction of Pavement Model using
Interaction Module
The characteriza tion for lay er materials are presented in
Table (1) which have used as input for the finite element
program for flexible pavement model.
Zainab Ahmed Alkaissi et al. / Association of Arab Un iversities Journal of Engineering Sci ences (2019) 26(1): 170–174
172
Table 1: Pavement Layer Properties [5] and [ 6]
Pavement
Layers
Elastic
Modulus
(MPa)
Poisson’s
ratio ( )
Density
(Kg/m³)
Asphalt 508 0.35 2240
Local Subgrade
Layer
211.53 0.4 1870
3. Results and Discussions
3.1 Stresses and Strains Distributions in Flexible
Pavement
One of the most primary co nsidered element in the design
of flexible pavement are the stresses a nd strains generated
in pavement la yer and interfaces due to the application of
wheel loads repetitions. The obtained results of stres s and
strain distributions from the finite ele ment pavement
model u sed in this research by (ABAQUS) are displayed
and discussed in sections below.
For a specific interest of the fa tigue failure phenomena in
flexible pavement which considered as major problems in
pavement design that related to repetitions of loading; a
considerable interest f or the horizontal tensile stre ss and
strains at the asphalt layer are considered.
Figure 5: Horizontal Stress ( σ ) Distribution within
Pavement Layers
3.2 Effect of Load Application on Horizontal Stre ss
Distributions
As displayed in Figure (5) for the distribution of horizontal
stresses ( σ ) in p avement system as general and asphalt
layer as particular.
A maximum tensile horizontal stresses ( σ ) (645 kPa) is
concentrated on the top of asphalt layer under the tire print
interaction area which is about (93.5%) of applied tire
pressure (690 kPa) but reduced to about (48 kPa) which is
about 7.3 % of applied pressure then cha nge rapidly and
becomes compressive stresses within subgrade la yer were
a value of (110 kPa) is obtained which is about (16%) of
applied tire pressure. Increasing depth below pavement
show rapid decrease of generated stresses. The tensile
response of stresses immediately underneath the loaded
wheel load may b e consider ed as a critical response for
fatigue cracking (top-down cracking) in flexible pavement
surfaces.
Figure 6: Horizontal Strains ( ε ) Distribution within
Pavement Layers
3.3 Effect of Load Application on Horizontal Stre ss
Distributions
Conventionally most pavement design models are based
on horizontal strain value at bottom of asphalt layer to
predict th e performance of flexible pavement.Fig ure (6)
illustrated the distribu tion of horizo ntal strain ε within
pavement layers. Maximum value of te nsile strain
developed at the surface of asphalt layer for flexible
pavement due to the horizontal traction generated from
wheel load applicatio n at contact area. As observed from
the obtained results the horizontal tensile strains at surface
173
Zainab Ahmed Alkaissi et al. / Association of Arab Un iversities Journal of Engineering Sci ences (2019) 26(1): 170–174
of asphalt layer under the wheel load application is higher
than at bottom of asphalt layer. This demonstrated the
influence of higher tensile strains at surface on fatigue top-
down cracking. These tensile strains extend through t he
pavement depth until the bottom of asphalt layer then
change to compressive strain at the top of subgrad e layer.
3.4 Effect of Load Repetitions
Generally the fatigue cracking is related to tensile strain
developed within asphalt la yer surface and bottom. In this
research the top (surface) tensile s train is estimated and
compared to that at b ottom as shown in Figure (7) below
taking into consideration the effect of load repetitions of
applied wheel load.
It can be observed from the obtained results; the horizontal
tensile strain ( ε ) at surface of asphalt layer is increas ing
rapidly with load repetitions with values greater than that
generated at bottom b y (94%) at fail ure. This prescribed
the basic or inherent features of top crack initiation and
down propagates within asphalt layer in flexible pavement.
Figure 7: Effect of Load Repetitions on Horizo ntal
Tensile Strains ( ε )
4. Fatigue Cracking of flexible Pavement
Flexible pave ments exhibit fatigue cracking when the
horizontal tensile strain exceed cer tain limits. Thefatigue
failure criteria suggested by Asphalt In stitute (MS-1,
1982) have been used which relate the tensile strain on the
bottom of asphalt layer with design life of paveme nt:
N = 0.0796
ϵ .
. (1)
: Num ber of load repetitions to cause fatigue cr acking.
ϵ : Tensile strain at the bottom of asphalt layer.
: Elastic modulus of asphalt layer (psi).
Figure (8) illustrated the results for number of load
repetitions to cause fatigue cracking of N flexible
pavement based o n finite element program and empirical
relation. It can be depicted that the finite element results
underestimate for N as compared with empirical relatio n.
This is due to that the finite element model takes i nto
consideration the te nsile strain for the top ten sile strain o f
asphalt layer within flexible pavement which result s in
minimum design pavement life.
Where empirical relation based on bottom tensile strain of
asphalt layer only. This confirm the objectives of this
research that illustrated the significant effect of tensile
strain on the top of asphalt surface under the applied wheel
load on fatigue cracking failure of flexible pave ment.
Figure 8: Number of Load Repetitions to Cause Fa tigue
Failure of Flexible Pavement
Due to the application of repeated load on a fatigue damage
D of flexible pavement w ill pro duced; which estimated
from Eq.2 below (Huang, 2004):
D =
(2)
Figure (9) presents the fatigue damage of flexible
pavement due to the repetitions of wheel load based on the
results of finite element model and empirical equation.
The damage d ue to top surface cr acking using t he finite
element model is higher than the empirical relations by
(20%) as a p ercentage value; since the finite element
model of flexible pavement considered the surface
horizontal tensile strains due to contact traction force at tire
pavement inte rface and this demonstrated that the
additional of horizontal tensile strains at top of asphalt
surface significantly increase the damage intensity of
fatigue failure for flexible pavement.
Figure 9: Cracking Damage of Flexible Pave ment
5. Conclusions
This research illustrated a theoretical study on the fatig ue
damage of flexible pavement under re peated wheel load.
The following concluding remarks can be dra wn:
Zainab Ahmed Alkaissi et al. / Association of Arab Un iversities Journal of Engineering Sci ences (2019) 26(1): 170–174
174
1. A maximum tensile horizo ntal stresses ( σ ) is
concentrated on the top of asphalt layer under the tire print
interaction area which is about (93.5%) of applied tire
pressure but reduced to about (7.3 %) of app lied pressure
then change rapidly and becomes compressive stresses
within subgrade layer were a value of (16%) is ob tained.
2. The tensile response of stresses immediately underneath
the loaded wheel load may be considered as a critical
response for fatigue cracking (top -down cracking) in
flexible pavement surfaces.
3. Maximum value of tensile strain d eveloped at the
surface of asphalt layer for flexible pavement due to the
horizontal traction generated from wheel load application
at contact area.
4. T he horizontal tensile strain ( ε ) at surface of asphalt
layer is increasing rapidly w ith load repetitions with values
greater than that generated at bo ttom by (94%) at failure.
This prescribed the basic or inherent features of top crack
initiation and down propagates within asphalt layer in
flexible pavement.
5. The damage due to top surface cracking of flexible
pavement using the finite element m odel is higher than the
empirical relatio ns by (20%) as a percentage value; since
the finite element model of flexible p avement consider ed
the surface horizontal tensile strains due to contact traction
force at tire pavement interface.
6. The horizontal tensile strains at the top of asphalt surface
significantly increase the d amage intensity of fatigue
failure for flexible pavement.
Refrences
[1] Abaqus Theory Manual , Version, (2009), Hibbitt,
Karlsson and Sorenson, Inc., INC.
[2] Behiry, A (2012):" Fatigue and rutting lives in flexible
pavement ". Ain Shams Eng ineering Jo urnal, Ain
Shams University, Vol.3, pp. 376-347 .
[3] Huang, Y. H. (2004): “Pavement Analysis and
Design ” , 2nd edition, P rentice Hall, Englewood
Cliffs, New Jersey.
[4] Jill, et.al. (2003):" Investigation of Fa ctors to Surface
Initiated Cracks in Flexible Pavemen ts ". Department
of Civil Engineering, Universit y of Minnesota,
Minnesota Local Road Research Board, Report No.
MN/RC - 2003-07.
[5] Masood, G. (2013 ):" Experimental and Numerical
Investigation of Stab ilized Unbounded Granular
Pavement Materials ". Msc. Thesis, High way and
Transportation Department, Al-Mustansiriyah
University.
[6] Khalil, S. (2010): " Mechanistic Empirical Design of
Flexible Pavement". Msc. Thesis, Civil E ngineering
Department, University of Baghdad.
[7] Zheng, et.al. (2017):" Fatigue Life Prediction o f High
Modulus Asphalt Concrete Based on theLocal S tress-
Strain Method". Applied Science journal, Vol. 7, 305,
2017.
Numerical investigation of fatigue crack in asphalt concrete pavements using cohesive zone model
Conference Paper
Full-text available
Nov 2022
Hind A. Akram
Miami Hilal
Mohammed Yousif Fattah
One of the major and important distresses that functionally affect the performance of the flexible pavements which occurs in most of Iraqi roads is the fatigue crack. This paper presents the investigation of fracture behavior that happen in asphalt concrete pavements by the cohesive zone model (CZM). Finite element method is applied the CZM in ABAQUS 6.14 software that made simulation for a laboratory beam test data. Some result of the experimental program were used for developing an FE model of fatigue test by employing the finite element techniques for modeling an asphalt beam by using three dimensional model by a proper material characterizations. The inhomogeneity in the materials of asphalt could lead to the variation between examinations the simulation. Then the model used for investigating crack propagation in the flexural fatigue test and predicting simulations for experimental results. It was concluded that coupled model XFEM-CZM successfully simulated the flexural fatigue test process and propagation of the crack. This model was effective in predicting the 25 mm notch in depth of the testing for a specific limit. Analysis of Crack propagation shows that beam failure mechanism is principally to the tensile stress.
Previously published studies have proposed fatigue life prediction models for dense graded asphalt pavement based on flexural fatigue test. This study focused on the fatigue life prediction of High Modulus Asphalt Concrete (HMAC) pavement using the local strain-stress method and direct tension fatigue test. First, the direct tension fatigue test at various strain levels was conducted on HMAC prism samples cut from plate specimens. Afterwards, their true stress-strain loop curves were obtained and modified to develop the strain-fatigue life equation. Then the nominal strain of HMAC course determined using finite element method was converted into local strain using the Neuber method. Finally, based on the established fatigue equation and converted local strain, a method to predict the pavement fatigue crack initiation life was proposed and the fatigue life of a typical HMAC overlay pavement which runs a risk of bottom-up cracking was predicted and validated. Results show that the proposed method was able to produce satisfactory crack initiation life.
Fatigue and rutting lives in flexible pavement
Flexible pavement is designed based on axle load limits and climatic conditions. The Egyptian code has specified certain load limits that should not be exceeded. The overweight trucks cause severe deterioration to the pavement and thus reduce its life. The study aims at studying the effect of axle load increase, and the variation in pavement modulus, on the overall pavement life. The research uses the BISAR software and the Egyptian environmental and pavement materials conditions to estimate the tensile strains occurring under the asphalt concrete (AC) layer and the compressive strains above the subgrade surface. The results revealed that tensile and compressive strain increased with increasing axle loads and decreased with increasing asphalt layer modulus thus the violating trucks should be unloaded when their weights exceed certain limits. Base thickness and subgrade resilient modulus were the key elements which control the equilibrium between fatigue and rutting lives.
It is well known that pavement design and construction involve many uncertainties and variations from specified design parameters. To address this issue, a reliability concept is often incorporated into the pavement design and analysis process. However, because of the complexity of modern mechanistic-empirical approaches, most of the existing reliability analyses deal only with some overall variability. A genuine reliability analysis considering the variability of specific input parameters is often computationally prohibitive. After a review of reliability approaches used in existing pavement design systems, Rosenblueth's 2n + 1 method is recommended as a good candidate for modern mechanistic-empirical pavement designs. Implementation of Rosenblueth's 2n + I method in the Texas Mechanistic-Empirical Flexible Pavement Design and Analysis System shows the simplicity and practicality of this approach. A pilot comparison demonstrates that this approach can make rational predictions considering the variability of different combinations of input parameters.
Finite element analysis on mechanical properties of castor-capsule
| https://www.researchgate.net/publication/332738948_Theoretical_Analysis_on_the_Effect_of_Surface_Horizontal_Traction_on_Top-Down_Cracking_of_Flexible_Pavement |
(PDF) Classification of anisotropic rocks
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Conference Paper
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Classification of anisotropic rocks
September 2007
Conference: Proc. 11th Int. Congress of Rock Mechanics
At: 191-196
Volume: 1
Authors:
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Harry Saroglou
National Technical University of Athens
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George Tsiambaos
National Technical University of Athens
Figures
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Classification of metamorphic rocks based on point load strength index , Ia 50. (L): data from literature. …
<here is a image f5b664698772b56f-a7091c1e0b91b49d>
Scaling of the proposed anisotropy index I Vp based on anisotropy index Ισ c according to the results of the present study. …
Figures - uploaded by
Classification of Anisotropic Rocks
H. Saroglou
PhD Candidate, Department of Ge otechnics, National Technical University of Athens, Greece
G. Tsiambaos
Assoc. Professor, Department of Geotechnics, National Technical University of Athens, Greece
ABSTRACT: . The scope of the present study is the characterization of the inherent anisotropy of metamorphic rocks, based
on the most widely used laboratory tests for rocks. The proposed cla ssification system is based on data from literature and
results from tests carried out in metamorphic rocks. It takes into account the degree of anisotropy as it is determined from: a .
the uniaxial compressive strength, σ ci , b. the point load strength, Is 50 and c. the longitudinal wave velocity, V p . A new
anisotropy index for point load strength, determined from diametral tests on oriented core specimens, is also presented.
1 INTRODUCTION
A number of indices have been proposed for the
classification of inherent anisotropy of the intact rock,
mainly that of the uniaxial compressive strength and the
point load strength. The degree of strength anisotropy is
determined as the ratio of the strength perpendicular to the
planes of anisotropy (maximum strength) to that in the
weakest direction (minimum strength), as described by
ISRM (1981). A classification of the anisotropy of foliated
rocks was proposed by Tsidzi (1997) based on the
ultrasonic velocity. Tsidzi (1986, 1987) also proposed a
descriptive petrographic index (foliation index) for the
characterization of the development of anisotropic texture of
intact rock and a modification of the classification of point
load strength anisotropy (Tsidzi, 1990). Other indices that
have been used for the charact erization of anisotropy are
that based on the deformation modulus and the Poisson ratio
(Ramamurthy, 1993 and Kwasniewski, 1993), as well as
that of the tensile strength of rock.
The indices that have been used for the characterization
of anisotropy, possess a different classification scale, as
they refer to different mechani cal properties of intact rock.
These properties are influenced to a varying extend by the
anisotropic texture of intact rock.
The aim of the present study is the proposal of a concise
classification scheme of anisotropic rocks, which will take
into account the fundamental anisotropy indicesof
mechanical properties and will characterize the degree of
anisotropy of intact rock, by considering also the uniaxial
compressive strength, σ ci , perpendicular to the planes of
anisotropy. Thus, the strength and velocity anisotropy
indices are correlated to the uniaxial compressive strength.
2 EXISTING CLASSIFICATION OF ANISOTROPY
2.1 Uniaxial compressive strength anisotropy
The strength anisotropy index has been widely used for the
classification of anisotropy. The maximum uniaxial
compressive strength occurs when loading is perpendicular
to the planes of anisotropy ( β =90 0 ). The strength anisotropy
index is given as (Ramamurthy, 1993):
(min)
)90( 0
ci
ci
C
I
σ
σ
σ
= (1)
The application of uniaxial load relevant to the planes of
anisotropy in the direction of maximum and minimum
strength is shown in Figure 1.
Figure 1. Orientations of minimumand maximum
compressive strength of anisotropic intact rock.
Based on the strength data of anisotropic sedimentary
and metamorphic rocks, Ramamurthy(1993) proposed the
classification given in Table 1.
Table 1.Anisotropyclassifi cation according to uniaxial
compressive strength (Ramamurthy, 1993).
Degree of compressive
strength anisotropy, Ισ c
Descriptive term
1.0 - 1.1Isotropic
1.1 – 2.0Fairly anisotropic
2.0 – 4.0Moderately anisotropic
4.0 – 6.0Highly anisotropic
> 6.0Very highly anisotropic
2.2 Point load strength anisotropy
The point load strength anisotropy index was initially
proposed by ISRM (1981). The index Ια (50) is given as:
//)50(
)50(
)50(
s
s
I
Ia ⊥
= I (2)
where, Ι s (50)
⊥
and Is (50)// is the point load strength, for
samples of diameter equal to 50mm, perpendicular and
parallel to the foliation planes at the axial and diametral test.
The minimum point load strength of anisotropic rock
occurs when loading is applied parallel to the foliation
planes due to splitting along them, while the minimum
uniaxial compressive strength occurs when the angle
between the loading orientation and the anisotropy planes is
equal to 30 0 .
Consequently, the directions of minimumstrength in the
two tests differ and thus the minimumuniaxial compressive
strength cannot be indirectly estimated by the minimum
point load srength. The correlation of these two intact rock
properties, as initially proposed by Broch & Franklin (1972)
is valid only when loading is perpendicular to the planes of
anisotropy.
Based on the point load strength index, Ια (50) , a
classification of anisotropic rocks was proposed by ISRM
(1981), as given in Table 2, while a similar classification
was proposed by Tsidzi (1990).
Table 2.Anisotropy classifica tion according to point load
strength (ISRM, 1985).
Degree of Point load
strength anisotropy I α (50)
Descriptive term
1 Isotropic
1 – 2Fairly – moderately
anisotropic
2 – 4Highly anisotropic
> 4Very highly anisotropic
2.3 Wave velocity anisotropy
The determination of wave velocity anisotropy of intact
rock, has been used in the pa st, since its measurement is
relatively simple.
Tsidzi (1997) proposed a velocity anisotropy index, VA,
based on tests carried out on metamorphic rocks, whichis
described by the following equation.
mean
V
VV
VA minmax
= −
(%) (3)
where, V (max) is the maximum ultrasonic wave velocity,
V (min) is the minimum velocity, and V (mean) is the mean
velocity. The classification of anisotropy based on this
index is given in Table 3.
The velocity anisotropy index which is proposed and
scaled in the present study is given by the ratio :
)90(P
)0(P
Vp
0
0
V
I =
where, V p(0
ο
) is the maximum velocityof longitudinal waves
(P-waves), which occurs when their propagation is parallel
to the planes of anisotropy and V p(90
ο
) is the minimum
velocity, occurring when the propagation is perpendicular to
them. The ratio was also used by Birch (1961) for the
description of seismic waves, but here it is used solely for
the classification of wave velocity anisotropy and its
correlation with the strength anisotropy.
Table 3.Anisotropyclassifi cation according to ultrasonic
wave velocity (Tsidzi, 1997).
Degree of velocity
anisotropy VA (%)
Descriptive term
< 2Isotropic
2 – 6Fairly anisotropic
6 – 20Moderately anisotropic
20 – 40Highly anisotropic
> 40Very highly anisotropic
3 PROPOSED CLASSIFICATION METHODOLOGY
3.1 General
The classification scheme of anisotropic rocks proposed in
the present study is based on the following anisotropy
indices:
1.the strength anisotropy index, Ισ c (equation 1)
2.the point load anisotropyindex in the diametral test, Ι d
(based on equation 2)
3.the wave velocity anisotropy index Ι Vp (equation 4).
In order to develop this classification, a substantial
number of data for metamorphic rocks (shales, schists,
gneisses, phyllites, marbles) was collected by literature.
Attempt was made to gather sufficient data of mechanical
properties of anisotropic intact rocks (e.g. uniaxial
compressive strength, point load strength, wave velocity), in
order to:
1.Compare of the anisotr opic indices of each rock,
2.Define the variation of the anisotropic index of each
mechanical property in relation to the property itself
(when not influenced by anisotropy),
V
(4)
3.Define the variation of the anisotropy indices in
relation to the uniaxial compressive strength of intact
rock.
Additionally, a large number of tests were performed on
specimens of metamorphic rocks, namelyAthens Schist,
gneisses and marble (Saroglou et al., 2004a and Saroglou et
al., 2004b). The schist is ch aracterized as chloritic,
muscovitic and has moderately developed foliation. The
gneiss is characterized as a) muscovitic gneiss with
medium-grained fabric with very well developed banding
and b) a mica gneiss with coarse -grained fabric. The marble
is calcitic with a small amount of dolomite (3%) and has a
layered texture due to the existence of parallel
discontinuous layers of dolom ite, resulting in a low degree
of anisotropy.
3.2 Strength versus strength anisotropy index
The uniaxial compressive strength of intact rock, σ ci ,
perpendicular to the anisotropy planes seems to correlate, in
some way, to its degree of strength anisotropy. It was found
that the rocks with lower compressive strength tend to have
a higher degree of anisotropy.
Based on the classification chart of strength anisotropy,
shown in Figure 2, it is po ssible to characterize the
anisotropy of different types of metamorphic rocksin
relation to the uniaxial compressive strength categoryas per
ISRM (1981).
More precisely, it can be concluded that:
1.Rocks with high compressive strength ( σ ci > 100 MPa)
generally exhibit low degree of anisotropy.
2.Rocks with moderate compressive strength (50 MPa <
σ ci < 100 MPa) don’t tend to be characterized by a certain
category of anisotropy.
3.Rocks with low compressive strength (25 MPa < σ ci <
50 MPa), although the data are limited, tendto have
moderate degree of anisotropy.
The data for rocks with very low compressive strength
( σ ci < 25 MPa) are very limited, thus they do not provide a
basis for evaluation.
The available data don’t allow for correspondence of the
strength anisotropy categories with the nature or lithology
of the intact rock. For instance, the same rock type may be
classified in more than one strength anisotropy categories
depending on its mineralogical composition,structure but
also the weathering degree in int act rock state. Nevertheless,
marbles tend to be classified in the first anisotropy category
(isotropic), while schists and phyllites in the third category
(medium degree of anisotropy).
No data were found in literatures, which belong in the
category of very high strength anisotropy ( Ισ c > 5.0). It
should be stated that the range of the medium and high
strength anisotropy categories, as proposed by Ramamurthy
(1993), were altered as defined in Figure 2. The upper limit
of the high degree of anisotropy was changed to 5.0 instead
of 6.0 considering that no data with values of Ισ c higher
than 6.0 occurred in literature. Additionally, the limit of
medium – high degree of strength anisotropy was
correspondingly changed from Ισ c = 4.0 to Ισ c = 3.0.
3.3 Point load strength versus point load strength index
3.3.1 General
The point load strength anisotropy index has greater scatter
than the compressive strength index and the velocity index,
for the rocks tested and the data available from literature
(Figure 3). Specifically, only the degree of anisotropy of
gneiss, as determined by the point load strength index, Ia 50 ,
and compressive strength index, Ισ c , coincide, while this is
not true for the schist and the marble tested, especially for
the marble samples.
Based on the results from the present study and data from
literature, it is obvious that there is no relating trend
between the anisotropy index, Ia 50 , and the point load
strength normal to the planes of weakness, Is 50( ⊥)
Figure 2. Classification of metamorphic rocks based on strengt h index and uniaxial compressive strength. (L): data from
literature.
Most importantly, the distribution of the point load
index of the rocks tested shows that it is concentrated in one
category of anisotropy (moderately to highly anisotropic),
while the same rocks can be cl assified to more than one
categories and more evenly if they are characterized by the
strength index, Ισ c , and velocity index, Ι Vp .
Consequently, the classification of anisotropy of intact
rocks based on the point load strength index can sometimes
be inefficient. Additionally, the point load strength parallel
to the planes of anisotropy, Is 50(//) , is not a representative
mechanical property. This is pronounced, when comparing
a schist of low strength with a gneiss, where the point load
strength of the two rocks parallel to the foliation planes,
I s50(//) , may have little difference, in contrast to their point
load strength degree of anisotropy, Ia 50 , which may differ
significantly due to the difference of the point load strength
perpendicular to them, Is 50( ⊥ ) .
Thus, the index Ia 50 should be used with caution for the
classification of anisotropic intact rock. Concerning the
effect of weathering on the point load strength anisotropy
index, it seems that it does not decrease with increasing
weathering grade, as it was found from the tests of the schist
(weathering grades ΙΙ to III).
3.3.2 Proposed point load strength anisotropy index from
the diametral test
In the diametral test the mini mum strength is recorded when
the load is applied parallel to the weakness plane and the
specimen fails along it (Broch, 1983). Aagaard (1976) has
also demonstrated this in gneisses and mica schists.
In the present study, the same loading pattern was used in
the diametral test in order to determine the minimum and
maximum strength of the metamorphic rocks tested. Based
on this testing methodology, a new anisotropyindex, I d , was
proposed which is defined as the ratio of the point load
strength perpendicular to that parallel to the planes of
weakness, in the diametral test (Saroglou & Tsiambaos,
2006). The comparison of this index (I d ) with that proposed
by ISRM, 1985 (Ia (50) ) led to significant results.
The variation of the point load strength with the angleis
shown in Figure 4. The decrease of strength with angle is
more profound for the gneiss samples rather than the schist
and that is due to the higher strength of gneiss normal to the
planes of weakness.
The point load strength recorded parallel and
perpendicular to the planes of weakness in the diametral test
for the rocks tested, is summarized in Table 4.
Table 4. Anisotropy Index I a50 and proposed index I d from
diametral point load tests.
Rock
Type
Ia 50 Diam.
Is (50) ⊥
(MPa)
Diam.
Is (50)//
(MPa)
I d Descriptive
term for I d
(based on
Table 2)
Schist2.9 1.30.81.6 Fairly–
moderately
anisotropic
Gneiss3.4 4.71.72.8 Highly
anisotropic
Marble2.5 4.12.41.7 Fairly–
moderately
anisotropic
Based on the results from the diametral tests, it is obvious
that there is a significant difference between the two
anisotropy indices, I d and Ia (50 ). Generally, the minimum
strength, which is encountered parallel to the planes of
weakness, is closer to the maximum strength for rocks with
low intact rock strength. This is true for the schist samples
that were tested.
Figure 3. Classification of metamorphic rocks based on point load strength index , Ia 50 . (L): data from literature.
The velocity index Ι
Figure 4. Diametral point load strength as a function ofthe
angle, a, for schist and gneiss samples tested in the present
study.
The proposed anisotropy index, I d , gives a better
correlation with the strength anisotropy index, I σ ci , for the
metamorphic rocks tested. Thus, it can be used for the
determination of the degree of anisotropy of intactrocks
exhibiting inherent anisotropy (using the same ranges
proposed for Ia 50 , as in Table 2).
3.4 Wave velocity versus wave velocity index
The classification of velocity anisotropy is obtained with the
proposed index of the longitudinal wave velocity, Ι Vp
(equation 4).
The proposed velocity anisotropy index, for both the
data of the present study as well as those from literature,
correlates very well with the velocity of the longitudinal
waves perpendicular to the planes of anisotropy (V p90
ο ).
This velocity is a characteristic property of the intact rock.
The velocity anisotropy index, Ι Vp , is higher for rocks
that possess lower velocities of the longitudinal waves
perpendicular to the planes of anisotropy, V p90
ο (Figure 5).
The correlation of these parameters for all the samples is
exponential and is given by the equation, V p = 5240 I Vp
-1.28
(r 2 =0.88), while for the rocks ex amined in the present study
it is V p = 4615 I Vp
-1.13 (r 2 =0.95).
Vp doesn’t exceed the value of 2.0,
with only exception the data of weathered intact gneiss
which give a value of 3.0 (Dobereiner et al, 1993).
According to the velocity anisotropy index, Ι Vp , the
marble examined is characteri zed as isotropic to fairly
anisotropic. The schist tested as well as the schists from
literature are classified as fairly to moderately anisotropic,
while the gneisses as moderately to highly anisotropic
(shown by the hatched areas in Figure 5).
Figure 5. Classification of metamorphic rocks based on longitudinal velocity anisotropy. (L): data from literature.
3.5 Scaling of index I Vp according to index Ισ c
In order to define the limits of the anisotropycategories
using the velocity anisotropy index, I Vp , in the proposed
classification scheme, this inde x is scaled according to the
compressive strength index, Ισ c , from uniaxial compression
and ultrasonic tests carried out on the same samples in the
present study. The data from literature were not taken into
account since they usually refer to the same rock but not to
the same samples.
The scaling of the velocity anisotropy index is shownin
Figure 6. The proposed classification scheme of anisotropy
based on compressive strength index, Ισ c , longitudinal
velocity index, I Vp , and the proposed point load strength
index, I d , is presented in Table 5.
Table5.Suggested classes for the classification of
anisotropic rocks.
Anisotropy
Category
Strength Index
Ισ c *
Proposed
index Ι Vp
Proposed
index I d
Isotropic I σ c ≤ 1.1-I d = 1.0
Fair1.1 < I σ c ≤ 2.0I Vp ≤ 1.5
Moderate2.0 < I σ c ≤ 3.01.5 < I Vp ≤
2.0
1.0 < I d ≤
2.0
High3.0 < I σ c ≤ 5.0I Vp > 2.02.0 < I d ≤
4.0
Very highI σ c > 5.0-I d > 4.0
* The ranges of the categories of strength anisotropy
given in Table 1 (Ramamurthy, 1993) have been
modified.
Furthermore, the classifica tion charts of compressive
strength (Figure 2), point load strength (Figure 3) and
longitudinal wave velocity (Figure 5), allow also for the
characterization of the anisot ropic rocks concerning these
mechanical properties in junction with the corresponding
indices.
4 CONCLUSIONS
The longitudinal wave velocity index of anisotropic intact
rocks, I Vp , can be used for the cla ssification of anisotropy.
The index is defined as the ratio of the wave velocity
perpendicular and parallel to the planes of anisotropy.
In the present study, the cl assification of anisotropy
through the velocity index was scaled based on the uniaxial
compressive strength index, Ισ c , and anisotropy categories
were proposed.
Additionally, the analysis of the anisotropy indices of
compressive strength and wave velocity, shows that the
degree of anisotropy tends to increase for rocks with lower
uniaxial compressive strength, σ ci , or with lower
longitudinal velocities, V p (perpendicular to the planes of
anisotropy).
The anisotropy of intact rock can also be classified with
the point load strength index, Ia (50) . The use of index Ia (50)
can lead to a misleading estima tion of anisotropy degree for
some rocks, as it occurred with the marble in the present
study. The metamorphic rocks, in the present study, were
characterized as highly anisotropic based on the point load
strength index, Ia 50 , which did not agree with their
compressive strength anisotropy index, I σ ci .
Figure 6. Scaling of the proposed anisotropy index I Vp based on anisotropy index Ισ c according to the resu lts of the present
study.
Consequently, a new anisotropy index, I d , was proposed
which is defined as the ratio of point load strength normal to
planes of anisotropy to that parallel to them in the diametral
test.
The characterization of the ro cks tested according to the
proposed index, correlates quite well with the strength
anisotropy index, I σ ci in uniaxial compression.
ACKNOWLEDGEMENTS
The present work is part of the research for the
Operational Programme for Educational and Vocational
Training, “Pythagoras II”. The project is co-funded by the
European Social Fund (75%)and National Resources
(25%).
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... where Is (50) refers to the point load indexes that are perpendicular and parallel to the foliation planes in the axial and diametrical point load tests. The studies revealed that, due to the splitting through these weakness planes, the lowest point load value is found when loading is parallel to the foliation planes
[41]
. A classification of anisotropic rocks was proposed by ISRM based on the point load strength index, Iα (50) , as given in Table 7, while a similar classification was proposed by Tsidzi [42,43]. ...
... Very highly anisotropic Saroglou and Tsiambaos proposed another classification of anisotropic rocks based on the uniaxial compressive strength index (Iσ c ), the longitudinal velocity index (I Vp ), and the diametrical point load index (I d )
[41]
. This classification is presented in Table 9. ...
... This classification is presented in Table 9. Table 9. Suggested classes for the classification of anisotropic rocks
[41]
. ...
A Review of Relationship between Texture Characteristic and Mechanical Properties of Rock
The textural characteristics of rocks influence their petrophysical and mechanical properties. Such parameters largely control rock mass stability. The ability to evaluate both immediate and long-term rock behaviors based on the interaction between various parameters of rock texture, petrophysical and mechanical properties is therefore crucial to many geoengineering facilities. However, due to the common lack of high-quality core samples for geomechanics and rock texture laboratory tests, single and multivariable regression analyses are conducted between mechanical properties and textural characteristics based on experimental test data. This study presents a review of how rock texture characteristics influence the geomechanical properties of a rock, and summarizes the regression equations between two aspects. More specifically, a review of the available literature on the effects of mineralogy, grain size, grain shape, packing density, foliation index, porosity, degree of weathering, and other rock physical characteristics on geomechanics is presented. Similarly, a review of the literature discussing the failure criteria of anisotropic rocks, both continuous and discontinuous, is also presented. These reviews are accompanied by a comparison of the fundamentals of these methods, describing their equations and discussing their advantages and disadvantages. This exercise has the objective of providing better guidelines on how to use these criteria, allowing for safer underground excavations via an improved understanding of how rock texture parameters affects the mechanical behavior of rocks.
... where Is (50) refers to the point load indexes that are perpendicular and parallel to the foliation planes in the axial and diametrical point load tests. The studies revealed that, due to the splitting through these weakness planes, the lowest point load value is found when loading is parallel to the foliation planes
[41]
. A classification of anisotropic rocks was proposed by ISRM based on the point load strength index, Iα (50) , as given in Table 7, while a similar classification was proposed by Tsidzi [42,43]. ...
... Very highly anisotropic Saroglou and Tsiambaos proposed another classification of anisotropic rocks based on the uniaxial compressive strength index (Iσ c ), the longitudinal velocity index (I Vp ), and the diametrical point load index (I d )
[41]
. This classification is presented in Table 9. ...
... This classification is presented in Table 9. Table 9. Suggested classes for the classification of anisotropic rocks
[41]
. ...
Rockburst in underground excavations: A review of mechanism, classification, and prediction methods
Technical challenges have always been part of underground mining activities, however, some of these challenges grow in complexity as mining occurs in deeper and deeper settings. One such challenge is rock mass stability and the risk of rockburst events. To overcome these challenges, and to limit the risks and impacts of events such as rockbursts, advanced solutions must be developed and best practices implemented. Rockbursts are common in underground mines and substantially threaten the safety of personnel and equipment, and can cause major disruptions in mine development and operations. Rockbursts consist of violent wall rock failures associated with high energy rock projections in response to the instantaneous stress release in rock mass under high strain conditions. Therefore, it is necessary to develop a good understanding of the conditions and mechanisms leading to a rockburst, and to improve risk assessment methods. The capacity to properly estimate the risks of rockburst occurrence is essential in underground operations. However, a limited number of studies have examined and compared yet different empirical methods of rockburst. The current understanding of this important hazard in the mining industry is summarized in this paper to provide the necessary perspective or tools to best assess the risks of rockburst occurrence in deep mines. The various classifications of rockbursts and their mechanisms are discussed. The paper also reviews the current empirical methods of rockburst prediction, which are mostly dependent on geomechanical parameters of the rock such as uniaxial compressive strength of the rock, as well as its tensile strength and elasticity modulus. At the end of this paper, some current achievements and limitations of empirical methods are discussed.
... Rather, previous research notes that hardness reflects a rock's intrinsic anisotropy (e.g., Verwaal and Mulder, 1993;Aydin, 2008;Murray, 2015). Research concerning rock strength, however, found anisotropy to be dependent on the presence of elongate minerals such as clays and micas
(Saroglou and Tsiambaos, 2007;
Vakili et al., 2014). Saroglou and Tsiambaos (2007) suggest that rock strength can be fairly to highly anisotropic due to elongate minerals and defined bedding planes. ...
... Research concerning rock strength, however, found anisotropy to be dependent on the presence of elongate minerals such as clays and micas (Saroglou and Tsiambaos, 2007;Vakili et al., 2014).
Saroglou and Tsiambaos (2007)
suggest that rock strength can be fairly to highly anisotropic due to elongate minerals and defined bedding planes. In this study shales, conglomerates, and mudrocks were more anisotropic with respect to hardness than other groups and the aggregate anisotropy ( Figure 14; Appendix 2). ...
... Specifically, conglomerates, mudrocks, and shales have median values that are anywhere from 4-7.5% higher than the aggregate median with other groups only differing by 1-2 % compared to the same aggregate median (Appendix 2). However, strength anisotropy as determined by others (e.g.,
Saroglou and Tsiambaos, 2007;
Vakili et al., 2018) must be inferred from the correlation between hardness and UCS ( Figure 19). There is evidence that hardness anisotropy relates to strength anisotropy because perpendicular hardness correlated more strongly to UCS than parallel hardness ( Figure 19). ...
DETERMINING LEEB HARDNESS AND ITS CONTROLLING FACTORS TO ASSESS THE STRENGTH OF SEDIMENTARY ROCKS
... Therefore, the anisotropic degree and quality of rock mass should be distinguished distinctly when being classified. The former one denotes the variation degree of properties in different directions, which is always classified by the ratio of highest parameters to lowest parameters for anisotropic intact rock, e.g., uniaxial strength [14], ultrasonic velocity [15], point load strength [16], deformation modulus and Poisson ratio [17,18], longitudinal wave velocity index
[19]
as well as the tensile strength [20]. ...
... Besides, it should be mentioned that some igneous rocks can also be highly anisotropic due to eruption sequences and flow structures, e.g. basaltic rocks and Figure 2 Anisotropic rock masses in multi scale: (a, b) Inherent anisotropy of rock matrix stemming from oriented arrangement of minerals in micro scale and bedding plane in laboratory scale respectively, in which (a) is referred from Ref.
[19]
; (c) Structure anisotropy in engineering scale rhyolites [23]. ...
... R cmax and R cmin should be estimated by Eqs. (1) and (2) I are I s(50) under loading perpendicular and parallel, respectively, to the foliation planes at the axial and diametral test
[19]
. R c is determined from a uniaxial compression test on saturated intact rock samples through different loading directions with anisotropic plane. ...
A-BQ, a classification system for anisotropic rock mass based on China National Standard
The rock mass in nature is in most cases anisotropic, while the existing classifications are mostly developed with the assumption of isotropic conditions that not always meet the engineering requirements. In this study, an anisotropic system based on China National Standard of BQ, named as A-BQ, is developed to address the classification of anisotropic rock mass incorporating the anisotropy degree as well as the quality of rock mass. Two series of basic rating factors are incorporated including inherent anisotropy and structure anisotropy. The anisotropy degree of rock mass is characterized by the ratio of maximum to minimum quality score and adjusted by the confining stress. The quality score of rock mass is determined by the key factors of anisotropic structure occurrence and the correction factors of stress state and groundwater condition. The quality of rock mass is characterized by a quality score and classified in five grades. The assessment of stability status and probable failure modes are also suggested for tunnel and slope engineering for different quality grades. Finally, two cases of tunnel and slope are presented to illustrate the application of the developed classification system into the rock masses under varied stress state. Cite this article as: GUO Song-feng, QI Sheng-wen, SAROGLOU Charalampos. A-BQ, a classification system for anisotropic rock mass based on China National Standard [J].
... At the same time, it was decided to classify the strength anisotropy based on the classification pointed out by Refs. [28,
30]
, see Table 3. ...
... According to the classification suggested by Refs. [28,
30]
, from the calculation of the strength anisotropy index, the stones can be classified as isotropic or low anisotropic. It is also seen that in average the compressive strength is higher in the samples loaded in parallel direction to bedding planes. ...
Physical-mechanical characterization of limestones from Yucatan churches, Mexico
Churches in Yucatan region in Mexico are considered a built heritage legacy of great cultural interest. Some of these churches exhibit some pathologies with deformation mainly located at the stone masonry vaults. The churches are mostly built with ruble stone masonry walls and vaults in which limestone and lime mortar predominate. The design of any intervention on this type of structure requires the knowledge on the masonry materials, but very scarce information exist on the properties of limestone and lime mortar used in the construction of the churches. Therefore, the characterization of the existing materials, namely the limestone is considered to be of great interest.
This research aims at the characterization of limestones found in masonry churches from sixteenth to eighteenth centuries located in Yucatan region in Mexico. To achieve the objectives, an experimental campaign was designed with the following steps: (1) identification of churches under ruins and in situ collection of stone specimens, (2) characterization of physical and mechanical properties on the collected specimens; (3) evaluation of the mineralogical composition of limestones and petrography description; (4) assessment of correlation between physical and mechanical properties.
It was found that the limestones studied were mainly composed of calcium carbonate (CaCO3) and based on the physical properties, it was possible to group them in three different groups. It was also found that different ranges for the compressive strength and modulus of elasticity were obtained for the limestone belonging to each group defined. The relation between physical and mechanical properties was analyzed by a set of statistic correlations, for which very reasonable coefficients of determination were found.
... Franklin (1985) defined the strength anisotropy index, I a(50) , based on the ratio of point load strength index in parallel with, I a(50)∥ , and perpendicular to, I a(50)⊥ , the bedding planes. Also, in 1997, an index of velocity anisotropy, VA, was proposed by Tsidzi based on ultrasonic wave velocity ratio in two perpendicular directions
(Saroglou and Tsiambaos 2007)
. Saroglou et al. (2003) and Saroglou and Tsiambaos (2007) investigated the inherent anisotropy of metamorphic rocks to determine the degree of anisotropy. ...
... Also, in 1997, an index of velocity anisotropy, VA, was proposed by Tsidzi based on ultrasonic wave velocity ratio in two perpendicular directions (Saroglou and Tsiambaos 2007). Saroglou et al. (2003) and
Saroglou and Tsiambaos (2007)
investigated the inherent anisotropy of metamorphic rocks to determine the degree of anisotropy. The current anisotropy criteria used in literatures are summarized and presented in Table 2. ...
Numerical appraisal of rock mass anisotropy effect on elastic deformations of a circular tunnel
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Vahid Maazallahi
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Abbas Majdi
The paper describes effects of anisotropic mechanical properties of rock masses on elastic behaviour of a circular tunnel under both hydrostatic and non-hydrostatic in situ stress states. This study is based on field data obtained from two actual case studies. In both cases, the rock masses have transversely isotropic structures. Hence, a 2D finite element modelling based on the equivalent continuum approach is used for the analysis. The tunnel deformation behaviour has been investigated for both isotropic and transversely isotropic conditions. To evaluate the degree of anisotropy of rock mass, an “anisotropy index” and a “normalized displacement ratio” have been defined. The effect of orientation of the isotropic planes is further investigated. The results show that in a hydrostatic stress state, the maximum displacement always occurs in a direction perpendicular to the isotropic planes. In this case, three empirical equations have been developed to compute the normalized displacement ratio, the deviation, and the direction of displacement vector at any arbitrary point on the tunnel periphery. The results further show that if the anisotropy index increases, the displacement difference (the difference between the maximum and the minimum displacements) on the tunnel walls increases too. For the non-hydrostatic stress state, simultaneous effects of stress ratio, anisotropy index, and orientation of isotropic planes on normalized displacements have been investigated. In this case, the location of maximum displacement inclines towards the direction of major principal stress. This effect is more noticeable when the isotropic planes are oriented at an angle of 90° relative to the direction of the major principal stress. The paper also provides an empirical equation to determine the location of maximum displacement on the tunnel walls. Finally, the practical application of the results is further illustrated by an actual case study.
... Complementarily, uniaxial compressive strength tests were carried out on cylindrical specimens extracted from prismatic blocks using a core-drilling machine, in two orthogonal directions, parallel and perpendicular to bedding. The results indicate that Borriol Limestone is an almost isotropic rock since both the wave velocity anisotropy index (Ι Vp ) and the strength anisotropy index (Ι σc ) are close to 1
(Saroglou and Tsiambaos 2007)
. ...
Predicting the Uniaxial Compressive Strength of a Limestone Exposed to High Temperatures by Point Load and Leeb Rebound Hardness Testing
ROCK MECH ROCK ENG
<here is a image 7f5c79d5fb07747d-efd7b0ecd3362e10> María Elvira Garrido de la Torre
<here is a image 2e7098a45f62afe2-7ad569e91d8217d0> Ferry Blondo Petnga
Víctor Martínez-Ibáñez
<here is a image 512eb2205b5cea5f-ec87f0446b642ef5> Roberto Tomás
The effect of exposure to high temperature on rock strength is a topic of interest in many engineering fields. In general, rock strength is known to decrease as temperature increases. The most common test used to evaluate the rock strength is the uniaxial compressive strength test (UCS). It can only be carried out in laboratory and presents some limitations in terms of the number, type and preparation of the samples. Such constrains are more evident in case of rocks from historical monuments affected by a fire, where the availability of samples is limited. There are alternatives for an indirect determination of UCS, such as the point load test (PLT), or non-destructive tests such as the Schmidt’s hammer, that can also be performed in situ. The aims of this research are: (i) measuring the effect of high temperatures and cooling methods on the strength and hardness of a limestone named Pedra de Borriol widely used in several historic buildings on the E of Spain, and (ii) studying the possibility of indirectly obtaining UCS by means of PLT and Leeb hardness tests (LHT), using Equotip type D. Limestone samples were heated to 105 (standard conditions), 200, 300, 400, 500, 600, 700, 800 and 900 ºC and cooled slowly (in air) and quickly (immersed in water). After that, UCS, PLT and LHT tests were performed to evaluate the changes as temperature increases. Results show decreases over 90% in UCS, of between 50 and 70% in PLT index and smaller than 60% in LHT index. Insignificant differences between cooling methods were observed, although slowly cooled samples provide slightly higher values than quickly cooled ones. The results indicate that LHT can be used to indirectly estimate UCS, providing an acceptable prediction. Research on correlating strength parameters in rocks after thermally treated is still scarce. This research novelty provides correlations to predict UCS in historic buildings if affected by a fire, from PLT and non-destructive methods such as LHT whose determination is quicker and easier.
... The anisotropy ratio results revealed that the continental shale could be distinguished by its spatial anisotropy: The ratio variation of strain at peak strength was the largest, whereas the fluctuation of the elastic modulus was relatively slight, and the anisotropic ratio of strength was in between. Overall, according to the anisotropic indices of rocks based on testing
(Saroglou & Tsiambaos, 2007)
, the Chang 7 shale in this study is fairly anisotropic as the strength anisotropy ratio (α σc ¼ 1:59) is between 1.1 and 2.0. However, it is worth noting that mechanical anisotropy is complex and may also be affected by other factors, such as preexisting fractures formed by dehydration, stress release, or other defects, and more experimental efforts are demanded. ...
Investigating the Meso‐Mechanical Anisotropy and Fracture Surface Roughness of Continental Shale
<here is a image 81d0e7f934b17543-dbe71ddba01ed5bb> Beixiu Huang
<here is a image 0c6f6f33b65e7b84-088ae355a9eb59d4> Lihui Li
<here is a image 2ffe25fb44ede5c6-a93801d7d78087e2> Yufang Tan
Xiao Li
Continental shale is abundant with unconventional oil and gas and has considerable prospect for exploitation. However, due to deposited environment differences, continental shale presents unique characteristics in terms of structure and mineralogy compared to marine shale. The mechanical property is elemental parameter for reservoir production, but relevant studies of continental shale are rarely reported. In this study, several groups of mesoscale (0.1–10 mm) uniaxial compression tests were conducted on continental shale with various bedding angles, sourced from the Yanchang Formation in the southern Ordos Basin, China. A new integrated real‐time loading‐observation‐acquisition system, specifically, a miniature tensile instrument‐light microscope (MTI‐LM) system, was utilized, which allowed us to visualize the failure process and simultaneously record the stress‐strain curves, providing snapshots for investigation of fracture initiation, propagation, and fracture surface features. The results demonstrate that as the bedding angle relative to the maximum compression direction increases, the uniaxial compressive strength (σc) and the percentage of bedding‐parallel fractures (Fp) fluctuate reversely, namely, higher σc corresponds to lower Fp. Additionally, a good consistency is revealed among the variations of σc, failure time and fracture surface roughness with bedding angles, suggesting stronger shale having rougher fracture surfaces and longer failure time at a certain loading rate. The meso‐mechanical anisotropy of shales is supposed to have an origin in heterogeneous component and microtexture, as indicated by different bridges connecting the opposite facies of fractures. The findings help reveal the mechanism underlying mechanical anisotropy and facilitate fracability evaluation of shallow shale gas reservoir.
Experimental study of the anisotropic behaviour of the Naparima Hill argillite
INT J ROCK MECH MIN
<here is a image fcbb78b21d0498d6-ca0b09bfd53b522a> Uwaila Iyare
<here is a image 5f263f1389b05fbb-e3d00eb091f1ef96> Oshaine Omar Blake
<here is a image 5555c2413444de0f-4cce65e3b74f82fb> Ryan Ramsook
Daniel R. Faulkner
Argillite rocks are often anisotropic due to the presence of microfractures, clay minerals, laminations, and bedding planes. Understanding the anisotropic behaviour of organic-rich argillite rocks is critical for their successful exploitation as unconventional reservoirs. In this study, the anisotropic rock properties of the argillite in the Naparima Hill Formation, Trinidad, an unconventional reservoir, was studied in laboratory experiments. A series of laboratory measurements including permeability, P- and S-wave velocities, and compressive strength were conducted at effective pressures of up to 130 MPa. The rock samples tested were collected from the Naparima Hill outcrop described by three lithofacies: siliceous calcareous mudstones, calcareous mudstone, and siliceous mudstones. The anisotropy of the argillite was determined by the ratio of the rock property measured perpendicular to the outcrop bedding to the rock property measured parallel to the outcrop bedding. For all the studied argillites, the permeability anisotropy ratios is about 2, while the P- and S-wave velocities anisotropy ratios, and compressive strength anisotropy ratios are close to 1, indicating that the rocks are fairly anisotropic. With increasing effective pressure, the permeability, velocities, and strength anisotropy ratios all decreased marginally. A comparison analysis reveals that the anisotropies of permeability and strength, anisotropies of P-velocity and permeability and anisotropies of S-velocity and permeability are all unrelated. However, anisotropies of P-wave velocity and strength, anisotropies of S-wave velocity and strength, and anisotropies of P-wave velocity and S-wave velocity anisotropy all have a 1:1 relationship. Overall, the results of the study suggest that the Naparima Hill argillite is weak to fairly anisotropic, which can be attributed to the low clay content, poor laminations, lack of foliation and few microfractures in the rocks.
Investigation on physical and mechanical properties of bedded sandstone after high-temperature exposure
<here is a image e0d1e8d43ff47e0c-4d978f8fcf0fec2f> Xinshuai Shi
Hongwen Jing
<here is a image 97274d0889e2710a-e75e50d8500bb6d0> Qian Yin
<here is a image 4ece73263d474c62-47e0b98a5834a6f3> Yuan Gao
Uniaxial compression tests were carried out on bedded sandstone to explore the effect of exposure to high temperatures on the physical and mechanical properties of the specimens. The influences of testing temperature and bedding orientation on the physical and mechanical properties and failure behaviors of the bedded sandstone were analyzed. The results show that for sandstone with a constant bedding orientation, as the temperature increases, the P wave velocity first increases and then decreases, while the mass and density decrease. The mechanical properties of bedded sandstone, including its compressive strength and elastic modulus, first increase and then decrease with increasing temperature, and a thermal temperature of 400 °C was identified as the transition temperature, above which considerable changes in the mechanical properties were observed. In addition, the P wave velocity, strength, and elastic modulus also varied with increasing bedding orientation, which indicated that the bedded sandstone exhibits anisotropy in its P wave velocity, strength, and elastic modulus. The P wave velocity gradually increases with increasing inclination angle, and the fluctuation in the anisotropic degree of the P wave velocity remains small as the temperature increases. The strength and elastic modulus of the bedded sandstone exhibit U-shaped variations with increasing bedding orientation, and the anisotropy degree first increases and then decreases with increasing temperature. Furthermore, the failure modes are closely related to the designed heat treatment temperature and bedding orientation and can be generally classified into four categories: shearing across the rock matrix and bedding planes, shearing combined with tensile splitting, shearing along the bedding planes, and shearing combined with tensile splitting along the bedding planes. Finally, the effect of high temperatures on the mechanical properties of bedded sandstone was further revealed by means of SEM analysis from a microstructure point of view.
Point load strength of anisotropic rocks
Jan 2006
<here is a image 1e3c5d4a7dbd6230-e1adda22e3e4c496> Harry Saroglou
<here is a image eb680133887428d4-f4158621cb5c3689> George Tsiambaos
The anisotropic nature of selected metamorphic rocks from Greece
Article
May 2004
J S AFR I MIN METALL
<here is a image 1e3c5d4a7dbd6230-e1adda22e3e4c496> Harry Saroglou
<here is a image f126723b5d11cade-bf4d4964633aba97> P. Marinos
<here is a image eb680133887428d4-f4158621cb5c3689> George Tsiambaos
Anisotropy is a characteristic of intact foliated metamorphic rocks (slates, gneisses, phyllites, schists). Testing was used to establish the anisotropic behaviour of selected gneissic rocks. The effect of anisotropy on various mechanical properties (strength, deformation) and dynamic properties (wave velocity) was examined. The rock samples were also tested at successively higher confining pressures in order to evaluate the effect of anisotropic behaviour at high overburden pressures.
The point-load strength test
Article
Nov 1972
Int J Rock Mech Min Sci Geomech Abstr
<here is a image 32cd5bf8894eb0bd-f55f0c03eaae4ac6> Einar Broch
J.A. Franklin
An index test for strength classification of rock materials is described. The test uses portable equipment. Specimens require no machining and can take the form of either rock core or irregular lumps. A single ‘point-load strength index’ can be obtained whatever the shape of specimen, provided that this shape is maintained within prescribed limits and that a size correction is made. Results were found to correlate closely with those from uniaxial (unconfined) compressive strength testing, with the diametral point-load test giving less scatter. The development of a portable testing machine is described. Aspects of testing procedure that were investigated include size and shape effects, the measurement of anisotropy and the influence of water content on strength results. A suggested standard testing procedure is given as an Appendix.
| https://www.researchgate.net/publication/271186381_Classification_of_anisotropic_rocks |
Biologic Therapy for Severe Asthma
Biologic Therapy for Severe Asthma
Overview | Additional Details
How does biologic therapy treat severe asthma?
Asthmais a complex disease. Many patients are able to control asthma with inhaler therapy. But some patients with severe asthma have episodes of frequent symptoms and episodes where the asthma gets much worse even when they use more than one inhaler. Now there are new options called biologic therapy to help patients with severe asthma. Biologic therapies offer new ways of treatment because they target different molecules in the body that contribute to asthma.
What are the types of biologic therapy drugs for treating asthma?
Xolair® ( omalizumab)
Xolair is a medication for patients with poorly controlled asthma and allergies to year-round allergens like dust mites, pet dander, or cockroach debris. Xolair blocks the antibody that causes an allergic asthma response.
Xolair is given as one or two subcutaneous injections (shots given under the skin), depending on the dose prescribed.
It is given every 2 or 4 weeks, depending on the dose prescribed.
After you receive a dose of medication, most infusion centers will monitor you for a period of time to make sure you do not have any reactions to the medication.
The most common side effects with Xolair are:
Muscle aches
Joint aches
Fatigue
Injection site reaction
Severe allergic reactions (rare)
Nucala® ( mepolizumab)
Nucala is a medication for patients with eosinophilic asthma. Eosinophils are a type of white blood cell that can cause inflammation in the lungs of some patients with asthma. Nucala works by reducing the number of eosinophils in your blood.
Nucala is administered as a shot under the skin once every 4 weeks.
After you receive a dose of medication, most infusion centers will monitor you for a period of time to make sure you do not have any reactions to the medication.
The most common side effects with Nucala are:
Headaches
Injection site reaction
Back pain
Weakness
Fatigue
Severe allergic reactions (rare)
Cinqair® ( reslizumab)
Cinqair is also a medication for patients with eosinophilic asthma. It also works by reducing the number of eosinophils in your blood.
Cinqair is administered as an intravenous (IV, or through the vein) infusion. It takes about 20 to 50 minutes to receive the infusion. It is given once every 4 weeks.
After you receive a dose of medication, most infusion centers will monitor you for a period of time to make sure you do not have any reactions to the medication.
The most common side effects with Cinqair are:
Sore throat
Muscle aches
Severe allergic reactions (rare)
Fasenra® ( benralizumab)
Fasenra is a medication for patients with eosinophilic asthma and works by reducing the number of eosinophils in your blood.
Fasenra is administered as a shot under the skin.
It is given once every 4 weeks for the first 3 doses, then once every 8 weeks.
After you receive a dose of medication, most infusion centers will monitor you for a period of time to make sure you do not have any reactions to the medication.
The most common side effects with Fasenra are:
Headache
Sore throat
Severe allergic reactions (rare)
Dupixent® ( dupilumab)
Dupixent is also a medication for patients with poorly controlled eosinophilic asthma and works by blocking a number of inflammatory cells that affect patients with asthma
Dupixent is administered as a shot under the skin.
It is given once every other week.
You will receive the first three doses of Dupixent in clinic so that we can teach you how to inject it. You will be monitored for one hour after the first dose to make sure you do not have a reaction to the medication. You will be monitored for 30 minutes after the next two doses. After that, Dupixent can be administered at home by yourself.
The most common side effects with Dupixent are:
Sore throat
Injection site reaction (temporary redness or pain)
Elevated eosinophil level
Severe allergic reactions (rare)
Additional Details
Where can I get biologic treatments for asthma?
Your doctor will decide if you would benefit from any of these therapies based on your symptoms, the medications you are already on, and your blood test results. These drugs are given in an infusion center.
Will my insurance cover biologic therapy for asthma ?
Your doctor’s office will work with your insurance company before starting treatment to make sure everything is approved. Many pharmaceutical companies also have programs to help patients afford these treatments.
Will I still need to take my inhalers?
Yes! It is very important that you continue to take all your other asthma medications andinhalers. Your doctor will tell you if you can decrease the dose of any of your other inhalers over time if your asthma is under good control.
References:
U.S. Food and Drug Administration. CINQAIR label. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761033lbl.pdf) Accessed 3/14/2019.
U.S. Food and Drug Administration. FASENRA label. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761070s000lbl.pdf) Accessed 3/14/2019.
U.S. Food and Drug Administration. NUCALA label. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125526Orig1s000Lbl.pdf) Accessed 3/14/2019.
U.S. Food and Drug Administration. XOLAIR label. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/103976s5102lbl.pdf) Accessed 3/14/2019.
US. Food and Drug Administration. DUPIXENT label. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761055lbl.pdf) Accessed 3/14/2019.
Hom S, Pisano M. Reslizumab (Cinqair): An Interleukin-5 Antagonist for Severe Asthma of the Eosinophilic Phenotype. P T. 2017;42(9):564-568.
Terms Linked In This Article:
Asthma ( https://my.clevelandclinic.org/health/diseases/6424-asthma-overview )
omalizumab ( https://my.clevelandclinic.org/health/drugs/19805-omalizumab-injection )
mepolizumab ( https://my.clevelandclinic.org/health/drugs/20442-mepolizumab-injection )
Headaches ( https://my.clevelandclinic.org/health/diseases/9639-headaches-in-adults-overview )
Back pain ( https://my.clevelandclinic.org/health/diseases/9516-back-pain-basics )
reslizumab ( https://my.clevelandclinic.org/health/drugs/18148-reslizumab-injection )
benralizumab ( https://my.clevelandclinic.org/health/drugs/19268-benralizumab-injection )
dupilumab ( https://my.clevelandclinic.org/health/drugs/20590-dupilumab-injection )
Elevated eosinophil level ( https://my.clevelandclinic.org/health/diagnostics/17704-high-white-blood-cell-count )
inhalers ( https://my.clevelandclinic.org/health/drugs/8694-inhalers )
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Aung San Suu Kyi of Myanmar: A Review of the Lady´ s Biographies
Download Citation | Aung San Suu Kyi of Myanmar: A Review of the Lady´ s Biographies | It is an undeniable fact that Aung San Suu Kyi has played a critical role in the political development of Myanmar since late 1988 and will remain... | Find, read and cite all the research you need on ResearchGate
Aung San Suu Kyi of Myanmar: A Review of the Lady´ s Biographies
August 2007
Contemporary Southeast Asia A Journal of International and Strategic Affairs 29(2):359-376
DOI: 10.1355/CS29-2G
Authors:
Kyaw Yin Hlaing
Kyaw Yin Hlaing
Abstract
It is an undeniable fact that Aung San Suu Kyi has played a critical role in the political development of Myanmar since late 1988 and will remain a very important political figure in the near-term future. Accordingly, those who want to understand Myanmar politics will have to understand her personality, her political philosophy and her role in the political life of the country. Biographies written by Barbara Victor and Justin Wintle detail Suu Kyi's life as the offspring of a national hero, a loving wife and a pro-democracy leader. However, the readers of these two books must understand that there are several myths associated with the political deadlock in Myanmar. While the two authors do mention them, they sometimes confuse rumours for facts. The purpose of this review essay is to provide some context absent from these two books, and identify missing links in some of the issues discussed.
... The expansion of religious communication, with its interplay among actors in global politics, has placed additional pressure on ruling elites and political contenders like Suu Kyi. Bidding audiences to consider them politically relevant requires more than historical legacy or political maneuvering (Hammer, 2011;
Hlaing, 2007)
. In postcolonial communication, Shome and Hegde (2002) demand both theorist and theorized to evince a "transformative stance" (p. ...
... For instance, having been Western educated and married to an Englishman, since 1989 she has continually had to address political adversaries' attempts to frame her as a Westerner. Being called Western, by implication, renders her as a postcolonial colonizer, someone who is only Burmese in name or Asian ethnic appearance
(Hlaing, 2007)
, but not in religious or cultural substance. ...
... Having left Myanmar/Burma when she was 15, living abroad in countries such as India and Nepal with her diplomat mother, and then later in Bhutan, England and Japan with her British husband (Guardian UK, 2010), Suu Kyi's ethos as a true citizen of Burma has been persistently questioned. She has felt compelled to address her citizenship directly and indirectly in speeches, interviews, and writings
(Hlaing, 2007)
. Having studied meditation and other esoteric Buddhist practices under Burmese master monks from Myanmar's Karen ethnic group, Suu Kyi has risen to the status of being an honorary spiritual leader beyond her political leader status (Hlaing, 2007;McCarthy, 2004). ...
Priest as teacher I: Understanding source credibility
Article
Apr 2013
Sean M. Horan
Peter C. J. Raposo
This study is the first in the Priest As Teacher series, which applies
instructional communication research to the church. To that end, this first study
examined Catholic parishioners’ perceptions of their priests’ credibility to see how
it related to perceived nonverbal immediacy and socio-communicative orientation
(e.g., assertiveness and responsiveness). Perceptions of priests’ credibility were
directly related to perceived immediacy, priests’ responsiveness and, to a lesser
extent, assertiveness. Parishioners’ perceptions of credibility were key in
understanding their own reports of nonverbal responsiveness during mass.
Implications, limitations, and future research are discussed.
The Role of Tatmadaw in Myanmar’s Transformation: A Burmese Version of Indonesia’s Dwifungsi
Chapter
Apr 2023
Michal Lubina
Prior to 2010 the Myanmar armed forces, or the Tatmadaw have established a Burmese version of dwifungsi, or dual role, a praetorian system of power, where the army ruled the country. Starting from late 2000s, the Tatmadaw however, initiated changes and established “the disciplined democracy”: a system where the army no longer ruled the country, but still had checks and balances. Looking from this point of view, the army has been steadily withdrawing from political life, just as the Indonesian ABRI (Army) did in 2000s. In Myanmar, too, just like previously in Indonesia, the army remains (and probably will remain) unaccounted for past crimes and keeps a privileged position in the society. However, differently to Indonesia, the Tatmadaw did not lose the power. It decided to share it and relinquish significant part of it, but it kept its own checks and balances over the system (the constitutional provisions). In this regard, the Burmese version of dwifungsi was not rejected: just limited and modified to suit the present conditions. With coup d’état of 1st February 2021, the Tatmadaw came back to a Burmese version of dwifungsi.KeywordsMyanmarTatmadawBurmese version of dwifungsiPolitical transformationPolitical transitionReformsChanges in Myanmar
Myanmar one year after the coup. Interview with Professor Michał Lubina
Article
Full-text available
Jun 2022
Przemysław Gasztold
Michal Lubina
The Role of Aung San Suu Kyi in Myanmar’s Transition (2011–2021)
Chapter
Jan 2022
Michal Lubina
Aung San Suu Kyi had played the critical role in Myanmar’s political transformation. Although it was not she who initiated the 2010–2011 changes, she adjusted to the “disciplined democracy” and had been changing the system from within. This allowed Myanmar to move forward, secure the reforms enacted by Thein Sein’s administration, re-engage with the global world and achieve a splendid decade of 2011–2021 (which unfortunately ended with the 2021 coup d’état). In short, Suu Kyi’s choice allowed Myanmar to break the two decades (1990s and 2000s) deadlock which cost Myanmar dearly. Suu Kyi made many concessions and compromises on the way, but eventually she emerged victorious both in 2015 and 2020. Unfortunately, she was unable to secure her last electoral victory which led to Tatmadaw’s ultimate coup.
A Disciplined Dissident—Aung San Suu Kyi as Opposition Backbencher (2012–2016)
Article
Jun 2021
PARLIAMENT AFF
Renaud Egreteau
This article investigates the legislative activity of Aung San Suu Kyi, Myanmar's iconic dissident, during her inaugural tenure as opposition MP in the country’s first post-junta parliament (2012–2016). How did such a totemic figure behave in a legislature dominated by an army-backed party and military-appointed MPs? What legislative tools did she use? The study draws evidence from Burmese-language proceedings of Myanmar’s Union legislature and field interviews. The findings point to a largely marginal, yet disciplined, involvement of Aung San Suu Kyi in legislative business. She neither acted as party whip nor openly criticised government record or took disruptive action in the context of Myanmar’s ‘discipline-flourishing democracy’. Yet, she joined policy debates through the occasional motion, used her position as a catalyst for engaging the government and the world, and successfully marshalled her party to win the next two general elections in 2015 and 2020. The findings have implications for understanding how the strategies of such near-mythical figure can explain subsequent electoral or political (mis)fortunes.
Book Review: The Daughter: A Political Biography of Aung San Suu Kyi
Article
Full-text available
Dec 2018
Andrew Selth
Approached to China: Myanmar’s China Policy (2016–2020)
Chapter
Jan 2021
Peng Nian
Since NLD assumed office in March 2016, Myanmar’s China policy has experienced with adjustments due to the changing external environments and domestic politics. Externally, the rising tensions in the SCS indicated high risks of getting involved in Sino-US power rivalry for Myanmar. Internally, the deepening cooperative relations between the democratic government and the military ensured the stability in Myanmar while the Rohingya refugee crisis deteriorated Myanmar’s relations with the West. Given this, the Burmese democratic leaders have pursued China’s help for economic development and diplomatic protection while continuing to counterbalance China by practising an active neighborhood diplomacy and multilateralism.
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Show abstract
Hedged Against China: Myanmar’s China Policy (2011–2015)
Chapter
Sep 2020
Peng Nian
In light of the increasing competition between China and the US in Southeast Asia, the reformist Burmese leaders seized opportunity to engage with the US and thus to hedge against the high risks of the over-dependence on China since the establishment of the civilian government in 2011. In the meantime, the Burmese generals were becoming increasingly discontented with Chinese interference in the ethnic conflicts and pressured China to cut off its connections with the ethnic groups.
Swung to China: Myanmar’s China Policy (1988–2004)
Chapter
Sep 2020
Peng Nian
The fierce political competition between China and the US during the period of 1988–2004 presented serious threats and opportunities to Myanmar, in which the junta had to engage with China in order to resist the U.S. threat and survive the military regime. Given this, the moderate Burmese leaders who were in charge of foreign affairs were committed to seeking Chinese help to reduce U.S. pressure while expanding Myanmar’s foreign partners with the aim to obtain more political support and economic assistance.
Myanmar: Religion, Identity, and Conflict in a Democratic Transition
Chapter
May 2017
Nicholas Farrelly
Farrelly provides an in-depth assessment of identity-based conflict dynamics within Myanmar’s gradual shift to a more democratic system of government. Civil conflicts, that long raged in the country’s ethnically distinct corners, encourage the fortification of political discourses about identity, unity, and non-disintegration. With its difficult history of bloodshed and trauma, social cohesion is a goal worth pursuing. Myanmar’s transition to an increasingly open, inclusive, prosperous, and peaceful society requires new capacity to be built at every level of government, and across the broad range of ethnic and religious identities. Farrelly argues that working cooperatively and effectively with different identity-based factions in Myanmar is a profound test of the concepts of peacebuilding and conflict resolution.
The Human Rights Report as Discursive Genre: Evolving Discourses in Human Rights Activism in Myanmar/Burma, 1988–2011
Jun 2017
ALTERNATIVES
Camilla Buzzi
This article is a case study of Myanmar, where activists adopted the international discourse of human rights in their struggle for democratic political and social change almost three decades ago, and examines the impact of this decision for the resistance against military rule. The article examines the use of human rights discourse in the struggle for democratic transformation between 1988 and 2011 rather than the ongoing political transition in Myanmar. During this period, international human rights discourse acquired dominant global status, and Myanmar became a global human rights issue. The discourse of human rights offers a framework of norms and related practices that is associated with a regime of conventions and institutions. This international regime evolved during the period under study, thereby offering different opportunities and constraints for action that affected how it would be used by Myanmar activists. The article analyzes how this discourse was used in about fifty reports published by different local organizations, in particular how different discursive techniques convey agency, how the reports provide alternative forms of truth telling and how human rights discourse produces claims for action, and hence how the human rights report has emerged as discursive genre. The study of the reports allows us to follow developments in political events in Myanmar but more importantly to assess the evolution in the reports in the context of the adoption of new tactics of struggle, new forms of organizing resistance and an evolving international context after 1988.
Las problemáticas de género: una introducción para su aplicación en estudios de contabilidad
Aug 2016
Martha Giovanna Acosta Sahamuel
Ruth Alejandra Patiño Jacinto
Gloria Milena Valero Zapata
Michael Andrés Díaz Jiménez
p>El presente trabajo constituye la revisión de publicaciones en distintos contextos relacionados con problemáticas y tendencias ideológicas relacionadas con las mujeres; se propone una caracterización en Europa, Estados Unidos, Canadá, Latinoamérica, Asia y África, con el propósito de identificar unas condiciones de la situación a nivel general y autores representativos en el tema de referencia, con el propósito de utilizar posteriormente los resultados, en otros escritos, vinculándolos con las investigadoras contables. La metodología utilizada fue cualitativa–documental, por cuanto se basó en la revisión de publicaciones con problemáticas relacionadas con las mujeres. El resultado más significativo es que en todos los contextos se presentan problemáticas, algunos con mayor impacto que otros, sin embargo, asimismo surgen autores muchas veces como respuesta a la necesidad de proponer soluciones o simplemente dar a conocer los problemas, muchos de los cuales han tenido gran transcendencia social a lo largo de la historia.</p
WHY THE MILITARY RULE CONTINUE IN MYANMAR?
Presentation
Sep 2016
Myo AUNG Myanmar
WHY THE MILITARY RULE CONTINUE IN MYANMAR? Myanmar’s post-colonial era is characterised by the domination of the military as the key actor in the state’s politics over the 62-year period since British rule ended. A comparatively brief ‘parliamentary period’ (1948 – 1962) aside – when the ruling coalition was riven by factionalism, and internecine conflict plagued the nascent state – military domination has persisted under various guises through to the present day, to the extent that the Tatmadaw (‘military’) is synonymous with the state and that Myanmar’s system of rule can be described as ‘praetorian’, in that “military officers are the major…political actors by virtue of their actual or threatened use of force”.Democratic elections have only once resulted in the installation of a civilian-led government in Myanmar. Indeed, the country offers a counter-argument to the “conventional wisdom among political scientists that ‘military rule is the shortest form of authoritarian regime in the developing world’”. Myanmar military rule not over yet: Observers. “As soldiers, we gave our lives for the country. In parliament, we are doing the same thing,” said the former RICH brigadier-general.THAT IS RADICULUS. Why its military dictatorship still survives----Burma is slowly transitioning from military dictatorship, but the old elite still pulls the strings. As the country moves towards more societal freedoms, they increasingly find themselves confronted with victims of the old regime.
Aung San Suu Kyi and U.S. Policy toward Burma/Myanmar
Sep 2010
David I. Steinberg
No living foreigner has shaped contemporary U.S. attitudes toward a single country more than Aung San Suu Kyi. As the seemingly vulnerable international avatar of democracy, she has effectively determined the parameters of possible U.S. policy choices. Although her Burma/Myanmar specific goals and those of the U.S. overlap, they are not contiguous. That country is a “boutique” issue in U.S. politics – important but not of the highest priority. The U.S. will face difficult policy decisions toward Burma/Myanmar following the formation of the new Burmese administration after the elections of November 7, 2010.
Modern Burma Studies: A Survey of the Field
Mar 2010
MOD ASIAN STUD
Andrew Selth
Burma has never been a popular subject for academic research but, since a massive pro-democracy uprising drew worldwide attention to the country in 1988, the number of scholars and students engaged in the field has grown considerably. However, they still face a number of major challenges. Along with other kinds of area studies, Burma studies have been accused by academics from the more 'scientific' disciplines of being too narrowly focused and lacking theoretical rigour. Also, it has been difficult to conduct research in Burma's closed society. While the latest military government has relaxed some controls, field work is still constrained and reliable sources are hard to find. Often, the knowledge gap has been filled by myths and misconceptions. Adding to these problems, since 1988 the Burma studies community has become highly polarised, with political and moral factors often featuring more prominently in the public debate than considered arguments based on objective analysis. All these factors have adversely affected modern Burma studies and restricted understanding of this deeply troubled country by both scholars and the wider community. Yes Yes
Burma, Hollywood and the Politics of Entertainment
Jun 2009
Andrew Selth
For almost a century, movies about or set in Burma, particularly those made by the major American studios, have had certain elements in common. While emphasizing its more colourful and exotic characteristics, they have either romanticized the country or depicted it as a remote and untamed wilderness. Also, Burma has served as a backdrop for dramatic Occidental adventures, in which the local inhabitants played little role. More recent movies pay the Burmese people greater attention, but they are still secondary to the main plot, even when the movies consciously draw attention to the current military regime's human rights abuses. In films like Beyond Rangoon and Rambo, however, complex issues are over-simplified or exaggerated to the point of unreality. These movies have proved effective at planting vivid images in the popular mind and helping to mobilize support for the country's opposition movement (including in Hollywood itself), but crude and misleading messages such as those sent by Rambo can actually hinder the resolution of Burma's many problems. Yes Yes
Recommended publications
Kyaw Yin Hlaing. - Aung San Suu Kyi of Myanmar:A Review of the Lady's Biographies - Contemporary Sou...
Kyaw Yin Hlaing
It is an undeniable fact that Aung San Suu Kyi has played a critical role in the political development of Myanmar since late 1988 and will remain a very important political figure in the near-term future. Accordingly, those who want to understand Myanmar politics will have to understand her personality, her political philosophy and her role in the political life of the country. Biographies ... [Show full abstract] written by Barbara Victor and Justin Wintle detail Suu Kyi's life as the offspring of a national hero, a loving wife and a pro-democracy leader. However, the readers of these two books must understand that there are several myths associated with the political deadlock in Myanmar. While the two authors do mention them, they sometimes confuse rumours for facts. The purpose of this review essay is to provide some context absent from these two books, and identify missing links in some of the issues discussed.
| https://www.researchgate.net/publication/249915693_Aung_San_Suu_Kyi_of_Myanmar_A_Review_of_the_Lady_s_Biographies |
Ontology-Based Regression Testing | Encyclopedia MDPI
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Ontology-Based Regression Testing
This entry is adapted from 10.3390/app11209709
0
Regression testing is a relevant research field focused on ensuring software works correctly after being modified or when new functionalities are added. The widespread use of information technology techniques has enabled the rapid development of applications.
Regression Testing semantic rules scalability surveillance systems security
Information
Table of Contents
1. Introduction
2. Research Method
3. Current Studies
4. Future Implications
1. Introduction
Modifications or the addition of new features in the applications require retesting the web applications, which adds the problem or concern for software testers to retest the applications. Retesting web services/web applications is a relatively hard job for testers, and it also incurs a high cost. ‘ Regression Testing’ (RT) with its subtypes ‘test case selection’, ‘test case reduction’, and ‘test case prioritization’ have been widely examined in research studies [ 1 ]. Test case selection approaches aim at increasing the effectiveness based on their measurement capabilities, including the cost, coverage, and fault detection [ 2 ] [ 3 ] [ 4 ]. Test case prioritization (TCP) approaches let researchers’ reorder test cases to reveal maximum faults based on specific criteria. Test cases with the top defects are tested before the test cases with fewer failures [ 5 ]. Proposed RT approaches rely on some criteria, and the ontology of systems is one of these criteria proposed to perform test case selection, reduction, and prioritization.
Ontology refers to basic concepts and their relationship in a research domain [ 6 ]. Due to ontology reasoning, the ideas which are harder for their explicit expression are derived. Ontology provides further analysis and assessment knowledge, including the accurate classification of faulty and non-faulty software engineering modules. The field of ontology covers the aspects of methodologies and metrics applied to solve issues in software engineering [ 7 ]. OntoClean is one of these methods that covers the use of some properties, including unity, rigidity, identity, and dependency [ 8 ]. The OntoClean method, along with meta-properties, is proposed to provide entities’ semantic and logical meaning. In [ 9 ], researchers made extensions to define ontology by expressing vocabulary concepts and their use. In this entire document, web applications and web services are interchangeably used.
The motivation behind this ‘systematic literature review’ (SLR) is to investigate the continuous lack of discussion on ontology-derived regression testing in several SLRs [ 10 ]. Ontology-derived testing can be considered under the domain of regression testing [ 11 ].
Table 1. Existing SLRs on regression testing.
Sr. No Research Focus Ontology-Based Regression Testing Number of Scholarly Studies Reference 1. Regression Testing x 159 [ 9 ] 2. Regression test case prioritization x 65 [ 10 ] 3. Test case prioritization x 120 [ 11 ] 4. Regression testing of web services √ 30 [ 12 ] 5. Regression test case selection x 47 [ 3 ] 6. Test case prioritization x 69 [ 13 ] 7. Test Case prioritization of systems x 90 [ 14 ] 8. Testing of semantic web services √ 43 [ 15 ] 9. Agent-based test generation x 115 [ 16 ]
Table 1is the illustration of SLRs in the area of regression testing. The first SLR by Qui et al. [ 12 ]includes two papers discussing web services’ semantic behavior. Studies [ 13 ] [ 14 ]did not include papers on ontology-based regression testing. A study by de Souza et al. [ 15 ]presented a description of web services ontologies. They include two ontology-driven models, ‘web services modeling ontology’ (WSMO) and ‘web services description language semantics’ (WSDL-S). Therefore, our SLR’s motivation is to help researchers and software practitioners working on the ontologies in regression testing by presenting the state-of-the-art ontology-based RT approaches.
2. Research Method
Below are the research questions studied for this SLR (seeTable 2).
Table 2. Proposed research questions.
RQ ID. Description RQ1 What is the roadmap of regression testing? RQ2 What are the state-of-the-art techniques of ontology-based regression testing? RQ3 What are the challenges and limitations of current approaches? RQ4 What are the possible future research directions? RQ5 What are the unique issues of ontology-based regression testing compared to other regression testing approaches?
A set of keywords was constructed using the words and phrases from research questions. Search strings relevant to the topic of interest and research questions were formulated [ 17 ]. Researchers used well-known research repositories, including IEEE Xplore, ACM digital library, ScienceDirect, Springer Link, Web of Science, and Wiley & Sons, to search the research articles published between 2007 and 2019. The search strings applied to the digital repositories mentioned above are shown in the followingTable 3.
Table 3. Search strings used for paper’s retrieval.
Data Repository Name Search String IEEE Xplore (((((“All Metadata”: Ontology) AND “All Metadata”: Regression Testing) OR “All Metadata”: Test Case Prioritization) AND “All Metadata”: Test Case Selection) AND “All Metadata”: Test Case Generation) ACM digital Library (+Ontology + Regression + Testing + Test + Case + Prioritization + Test + Case + Selection + Test + Case + Generation) ScienceDirect “Ontology, regression testing, test case prioritization, Test Case Selection, Test Case Generation.” SpringerLink ‘Ontology AND “Regression Testing” AND (Test OR Case OR Prioritization, OR Test OR Case OR Selection, OR Test OR Case OR Generation)’ Web of Science (Ontology) AND TOPIC: (Regression Testing) OR TOPIC: (test case prioritization) OR TOPIC: (Test Case Selection) OR TOPIC: (Test Case Generation) Wiley & Sons “Ontology” anywhere and “Regression Testing” anywhere and “Test Case Prioritization” anywhere and "Test Case Selection” anywhere and “Test Case Generation”.
It was found that when researchers applied “regression testing” OR “test case prioritization” strings, many irrelevant studies to the topic of this SLR were returned. Researchers refined the search strings using Boolean ‘AND’ and ‘OR’ operators between search keywords to find relevant publications.
The obtained research documents were examined by two independent reviewers (MH and IG). This phase mainly aimed at verifying the research articles, which were potentially eligible and could be used for further analysis. At the screening phase, research documents were screened via title, abstract, and keywords. However, two reviewers (MFP and SRJ) read and reviewed full-length documents resulting from the screening phase at the eligibility phase. Since ontology has been used in software testing, reviewers included papers related to the topic “ontology-based regression testing” with great caution in this systematic review. Therefore, 24 research documents were included in this study.
3. Current Studies
In the followingTable 4, researchers summarize the studies that focused on ontologies in proposing approaches in regression testing.
Table 4. Summary of ontology-based approaches.
Authors Problem Proposed Technique Advantage Limitation Askarunisa et al. [ 18 ] High cost on web services testing An automated testing framework Effective prioritization of web services No cost resources were used in the proposed approach Askarunisa et al. [ 19 ] An increase in cost due to source code unavailability Semantic-based protégé tool Faults detection is better than the traditional approaches Coverage criteria is not clearly mentioned Bai et al. [ 20 ] Web services testing in an open platform A risk-based approach using semantics Faults detection with a high impact The reliability of web services is not mentioned Kim et al. [ 21 ] Handling changes in the evolving system is a difficult task Regression test selection Reduces the overall time to rerun test cases This approach might have missed some necessary test cases Fan et al. [ 22 ] Validation of tests in an ad hoc fashion Domain-specific ontology-based approach Systematic generation of TCG from safety analysis report The cost to ensure the safety of a web system is not mentioned Tseng et al. [ 23 ] Uncertain test coverage from random testing Domain-specific ontology using requirements Ensures users’ safety, more effective than random testing Validation of web systems at large-scale systems is not done
Table 4shows ontology-based studies and authors’ information, problems, proposed techniques, advantages, and limitations of the proposed approaches. The proposed approaches mainly addressed cost, testing in an open platform, modification in evolving web systems, and validation of test cases in nuclear safety systems. This SLR shows the remarkable penetration of ontologies in the prioritization of test cases in web services. Ontology-based regression testing approaches were found effective in saving costs and time compared with random testing approaches. Semantics-based designing of approaches can be further used with the help of ‘artificial intelligence’ to monitor the continuous performance of web services.
A study [ 20 ]proposed a risk assessment approach for the ranking of test cases. Researchers in this study considered risk assessment in the context of users’ input/output and pre/post conditions, processes, and ontology constraints. The risk assessment covers the dissatisfaction of regulatory/legal requirements and relates mainly to a process, work, or project that does not achieve the expected functional behavior. The proposed TCP approach does not involve the reliability of web services. A product risk carefully refers to security and safety behaviors [ 24 ], as well as it also concerns the reliability behavior of the web services. Therefore, web services’ reliability factor can improve regression testing and prioritize test cases. In addition to the challenges mentioned earlier, the failure of critical systems is closely related to the proposed maintenance approach [ 25 ], which cannot detect earlier faults. It is still challenging for researchers to optimize the test case selection and TCP in regression testing.
Before SLR, de Souza et al. [ 15 ]identified the research gap that the model-based testing has not dealt with because abstract test cases are trivial to map them to executable and concrete test cases. Compared with the paper [ 26 ], scalability is a focused research problem regarding test brokers because they face re-execution of test cases of a suitable size. The scalability issue remains a commonly identified challenge for both ontology-based RT and collaborative testing of web services. Due to web services’ evolution, scalability is still an open issue in the software testing domain. Validation of proposed RT approaches is mentioned as a problem [ 27 ]because all proposed simulation-based approaches do not address the testing of web applications in real-world scenarios. Therefore, the validation problem is close to our identified problem. A study [ 28 ]stated that cloud testing faces the scalability challenge because distributed systems need enhancement in their performance over time. This performance enhancement can combat the increasing workload on web services. Finally, inadequate validation of test cases is a unique challenge for automated test case generation [ 29 ]. Validation of the test cases is crucial for real-time processing to reduce software testing costs and effort.
4. Future Implications
This SLR identified ontology-based RT approaches proposed between 2007 and 2019. Most of the studies focused on TCG and TCP research topics. Our SLR presented the roadmap by identifying the benchmark approaches along with their objectives. This study identified six challenges of ontology-based RT approaches. The cost and validation were difficulties widely examined in the selected studies. Scalability, risk assessment, failure of critical systems, and reliability are still open regression testing issues. Our SLR presented the effectiveness of ontology-based RT approaches for addressing the failure in systems other than bioinformatics. This SLR’s findings suggested developing more specific simulation tools regarding the security of the critical system in future works.
References
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Spieker, H.; Gotlieb, A.; Marijan, D.; Mossige, M. Reinforcement learning for automatic test case prioritization and selection in continuous integration. In Proceedings of the ISSTA 2017: 26th ACM SIGSOFT International Symposium on Software Testing and Analysis, Santa Barbara, CA, USA, 10–14 July 2017; pp. 12–22.
Kazmi, R.; Jawawi, D.N.; Mohamad, R.; Ghani, I. Effective Regression Test Case Selection: A Systematic Literature Review. ACM Comput. Surv. 2017, 50, 1–32.
de Oliveira Neto, F.G.; Torkar, R.; Machado, P.D. Full modification coverage through automatic similarity-based test case selection. Inf. Softw. Technol. 2016, 80, 124–137.
Krishnamoorthi, R.; Mary, S.S.A. Factor oriented requirement coverage based system test case prioritization of new and regression test cases. Inf. Softw. Technol. 2009, 51, 799–808.
Koutsomitropoulos, D.A.; Kalou, A.K. A standards-based ontology and support for Big Data Analytics in the insurance industry. ICT Express 2017, 3, 57–61.
García-Peñalvo, F.J.; Colomo-Palacios, R.; García, J.; Theron, R. Towards an ontology modeling tool. A validation in software engineering scenarios. Expert Syst. Appl. 2012, 39, 11468–11478.
García, J.; Jose’García-Penalvo, F.; Therón, R. A Survey on Ontology Metrics. In World Summit on Knowledge Society; Springer: Berlin/Heidelberg, Germany, 2010; pp. 22–27.
Yoo, S.; Harman, M. Regression testing minimization, selection and prioritization: A survey. Softw. Test. Verif. Reliab. 2010, 22, 67–120.
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Askarunisa, A.; Punitha, K.A.J.; Ramaraj, N. Test case generation and prioritization for composite web service based on owl-s. Neural Netw. World 2011, 21, 519–538.
Askarunisa, A.; Punitha, K.A.J.; Abirami, A.M. Black box test case prioritization techniques for semantic based composite web services using OWL-S. In Proceedings of the 2011 International Conference on Recent Trends in Information Technology (ICRTIT), Chennai, India, 3–5 June 2011; pp. 1215–1220.
Bai, X.; Kenett, R.S.; Yu, W. Risk assessment and adaptive group testing of semantic web services. Int. J. Softw. Eng. Knowl. Eng. 2012, 22, 595–620.
Kim, M.; Cobb, J.; Harrold, M.J.; Kurc, T.; Orso, A.; Saltz, J.; Post, A.; Malhotra, K.; Navathe, S.B. Efficient regression testing of ontology-driven systems. In Proceedings of the ISSTA 2012 International Symposium on Software Testing and Analysis, Minneapolis, MN, USA, 15–20 July 2012; pp. 320–330.
Fan, C.-F.; Wang, W.-S. Validation test case generation based on safety analysis ontology. Ann. Nucl. Energy 2012, 45, 46–58.
Tseng, W.-H.; Fan, C.-F. Systematic scenario test case generation for nuclear safety systems. Inf. Softw. Technol. 2013, 55, 344–356.
Ali, S.; Yue, T.; Hoffmann, A.; Wendland, M.-F.; Bagnato, A.; Brosse, E.; Schacher, M.; Dai, Z.R. How Does the UML Testing Profile Support Risk-Based Testing. In Proceedings of the 2014 IEEE International Symposium on Software Reliability Engineering Workshops, Naples, Italy, 3–6 November 2014; pp. 311–316.
Li, Y.; Tao, J.; Wotawa, F. Ontology-based test generation for automated and autonomous driving functions. Inf. Softw. Technol. 2020, 117, 106200.
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Mei, L.; Chan, W.K.; Tse, T.H.; Jiang, B.; Zhai, K. Preemptive regression testing of workflow-based web services. IEEE Trans. Serv. Comput. 2014, 8, 740–754.
Hillah, L.M.; Maesano, A.-P.; De Rosa, F.; Kordon, F.; Wuillemin, P.-H.; Fontanelli, R.; Di Bona, S.; Guerri, D.; Maesano, L. Automation and intelligent scheduling of distributed system functional testing. Int. J. Softw. Tools Technol. Transf. 2017, 19, 281–308.
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1. Introduction
2. Research Method
3. Current Studies
4. Future Implications
Hasnain, M. (2021, November 03). Ontology-Based Regression Testing. In Encyclopedia . https://encyclopedia.pub/entry/15666
| https://encyclopedia.pub/entry/15666 |
Teaching Resource for the Teaching of Geometry: Circular Trigonometric Geoplane - International Electronic Journal of Mathematics Education
The difficulty in the process of trigonometry teaching, served as a stimulus for the present research, in which the objective consisted of designing and proposing the use of a Trigonometric Cicular Geoplane for the construction of meaningful learning in the area of Mathematics at Israel Technological University. For Its development, a field research, descriptive type, and a special project modality was conducted. As key informants, the participation of twenty (20) students and three (3) teachers that work in distinct levels of the institution described above. In order to gather information, observations and interviews were used, and the instrument of an observation and interview guides were submitted to a valid process. For the purpose of reliability, it was implemented through a standardization of registers and categories, then the findings were analyzed based on a cultivated and descriptive analysis in order to elaborate the conclusions in search of the proposed objectives about the design and use of the teaching tool that contributes in a positive manner to the teaching and learning of Geometry, in the same manner, the motivation and receptivity to use of Geoplane were used, in response to permit the development of innovated methodologies that show a change of andragogy practice, as it is, to teach learning skills that last a lifetime.
Teaching Resource for the Teaching of Geometry: Circular Trigonometric Geoplane
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Derling José Mendoza Velazco 1 * , Yoandry Rivero Padrón 1
1 Universidad Tecnológica Israel, ECUADOR * Corresponding Author
Abstract
The difficulty in the process of trigonometry teaching, served as a stimulus for the present research, in which the objective consisted of designing and proposing the use of a Trigonometric Cicular Geoplane for the construction of meaningful learning in the area of Mathematics at Israel Technological University. For Its development, a field research, descriptive type, and a special project modality was conducted. As key informants, the participation of twenty (20) students and three (3) teachers that work in distinct levels of the institution described above. In order to gather information, observations and interviews were used, and the instrument of an observation and interview guides were submitted to a valid process. For the purpose of reliability, it was implemented through a standardization of registers and categories, then the findings were analyzed based on a cultivated and descriptive analysis in order to elaborate the conclusions in search of the proposed objectives about the design and use of the teaching tool that contributes in a positive manner to the teaching and learning of Geometry, in the same manner, the motivation and receptivity to use of Geoplane were used, in response to permit the development of innovated methodologies that show a change of andragogy practice, as it is, to teach learning skills that last a lifetime.
Keywords
mathematic education
meaningful learning
trigonometry
License
This is an open access article distributed under theCreative Commons Attribution Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article Type:Research Article
INT ELECT J MATH ED, 2019, Volume 14, Issue 1, 3-13
https://doi.org/10.12973/iejme/3936
Publication date:06 Nov 2018
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References
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APA
Mendoza Velazco, D. J., & Rivero Padrón, Y. (2019). Teaching Resource for the Teaching of Geometry: Circular Trigonometric Geoplane. International Electronic Journal of Mathematics Education, 14(1), 3-13.https://doi.org/10.12973/iejme/3936
Vancouver
Mendoza Velazco DJ, Rivero Padrón Y. Teaching Resource for the Teaching of Geometry: Circular Trigonometric Geoplane. INT ELECT J MATH ED. 2019;14(1):3-13.https://doi.org/10.12973/iejme/3936
AMA
Mendoza Velazco DJ, Rivero Padrón Y. Teaching Resource for the Teaching of Geometry: Circular Trigonometric Geoplane. INT ELECT J MATH ED. 2019;14(1), 3-13.https://doi.org/10.12973/iejme/3936
Chicago
Mendoza Velazco, Derling José, and Yoandry Rivero Padrón. "Teaching Resource for the Teaching of Geometry: Circular Trigonometric Geoplane". International Electronic Journal of Mathematics Education2019 14 no. 1 (2019): 3-13.https://doi.org/10.12973/iejme/3936
Mendoza Velazco, D. J., and Rivero Padrón, Y. (2019). Teaching Resource for the Teaching of Geometry: Circular Trigonometric Geoplane. International Electronic Journal of Mathematics Education, 14(1), pp. 3-13.https://doi.org/10.12973/iejme/3936
MLA
Mendoza Velazco, Derling José et al. "Teaching Resource for the Teaching of Geometry: Circular Trigonometric Geoplane". International Electronic Journal of Mathematics Education, vol. 14, no. 1, 2019, pp. 3-13.https://doi.org/10.12973/iejme/3936
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Plants | Free Full-Text | The Short-Term Effects of Mineral- and Plant-Derived Fulvic Acids on Some Selected Soil Properties: Improvement in the Growth, Yield, and Mineral Nutritional Status of Wheat (Triticum aestivum L.) under Soils of Contrasting Textures
Fulvic acids (FAs) improve the structure and fertility of soils with varying textures and also play a crucial role in increasing crop production. The pot experiment was carried out using wheat grown on three soils with a silty clay, sandy loam, and clay loam texture, respectively. The soils were treated with FAs derived from plant and mineral materials. Plant-derived solid (PSFA), mineral-derived liquid (NLFA), and plant-derived liquid (PLFA) were applied at a rate of 2.5, 5, and 5 g kg& minus;1 and control applied at 0 g kg& minus;1. The results showed that in treated soils, the heavy fraction C was higher by 10%& ndash;60%, and the light fraction C increased by 30%& ndash;60%. Similarly, the available N content significantly increased in treated soils by 30%& ndash;70% and the available K content increased by 20%& ndash;45%, while P content significantly increased by 80%& ndash;90% in Aridisols and Vertisols and decreased by 60%& ndash;70% in Mollisols. In contrast, for P, the organic& ndash;inorganic compounds were greater in Aridisols and Vertisols and lower in Mollisols. However, organic& ndash;inorganic composites decreased in Vertisols relative to the other two soils. Further results showed that PSFA and NLFA accelerated the plant growth parameters in Mollisols and Aridisols, respectively. Our study demonstrates that the application of PSFA and NLFA had a positive effect on the physical and chemical properties and plant growth characteristics of Mollisol and Vertisol soils. Moreover, the application of solid-state FA yields better results in Mollisols. However, liquid FA increases the nutrient availability and the effects on the chemical, biological, and physical properties of Aridisol and Vertisol soils.
The Short-Term Effects of Mineral- and Plant-Derived Fulvic Acids on Some Selected Soil Properties: Improvement in the Growth, Yield, and Mineral Nutritional Status of Wheat ( Triticum aestivum L.) under Soils of Contrasting Textures
by
Mahendar Kumar Sootahar 1,2 ,
Xibai Zeng 1,* ,
Yanan Wang 1 ,
Shiming Su 1 ,
Permanand Soothar 3 ,
Lingyu Bai 1 ,
Mukesh Kumar 2,4 ,
Yang Zhang 1 ,
Adnan Mustafa 5 and
Ning Ye 1
1
Institute of Environment and Sustainable Development in Agriculture, Chinese Academy of Agriculture Sciences, Beijing 100081, China
2
Department of Soil Science, Sindh Agriculture University, Tando Jam 70060, Pakistan
3
School of Electronic and Optical Engineering, Nanjing University of Science and Technology, Nanjing 210094, China
4
Key Laboratory of Crop Water Use and Regulation, Ministry of Agriculture, Farmland Irrigation Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Xinxiang 453003, China
5
National Engineering Laboratory for Improving Quality of Arable Land, Institute of Agricultural Resources and Regional Planning, Chinese Academy of Agricultural Sciences, Beijing 100081, China
*
Author to whom correspondence should be addressed.
Plants 2020 , 9 (2), 205; https://doi.org/10.3390/plants9020205
Received: 7 January 2020 / Revised: 30 January 2020 / Accepted: 3 February 2020 / Published: 6 February 2020
(This article belongs to the Special Issue Soil Nutrition and Plants Growth )
Abstract
Fulvic acids (FAs) improve the structure and fertility of soils with varying textures and also play a crucial role in increasing crop production. The pot experiment was carried out using wheat grown on three soils with a silty clay, sandy loam, and clay loam texture, respectively. The soils were treated with FAs derived from plant and mineral materials. Plant-derived solid (PSFA), mineral-derived liquid (NLFA), and plant-derived liquid (PLFA) were applied at a rate of 2.5, 5, and 5 g kg
−1
and control applied at 0 g kg
−1
. The results showed that in treated soils, the heavy fraction C was higher by 10%–60%, and the light fraction C increased by 30%–60%. Similarly, the available N content significantly increased in treated soils by 30%–70% and the available K content increased by 20%–45%, while P content significantly increased by 80%–90% in Aridisols and Vertisols and decreased by 60%–70% in Mollisols. In contrast, for P, the organic–inorganic compounds were greater in Aridisols and Vertisols and lower in Mollisols. However, organic–inorganic composites decreased in Vertisols relative to the other two soils. Further results showed that PSFA and NLFA accelerated the plant growth parameters in Mollisols and Aridisols, respectively. Our study demonstrates that the application of PSFA and NLFA had a positive effect on the physical and chemical properties and plant growth characteristics of Mollisol and Vertisol soils. Moreover, the application of solid-state FA yields better results in Mollisols. However, liquid FA increases the nutrient availability and the effects on the chemical, biological, and physical properties of Aridisol and Vertisol soils.
Keywords:
fulvic acids
;
soil fertility
;
soil organic carbon
;
organic–inorganic composite
;
plant growth
;
available nutrients
1. Introduction
The structures and inherent fertility of soils are important features that govern sustainable crop production, particularly under intensively managed agroecosystems [ 1 ]. It is well established that the texture of soil containing varying types of clay minerals affects crop production. Vertisols are characterized by high swelling and shrinkage capacity soils that stop crop production through alternate wetting and drying periods [ 2 ]. This poor soil structure restricts the application of Vertisols to sustainable agricultural practices and makes management difficult for engineering purposes as well [ 2 , 3 ]. By virtue of their parent material, Vertisols are rich in calcium carbonates, which causes a calcareousness of soils that prevents the uptake of essential nutrients by influencing the physico–chemical and biological properties of the soils [ 4 ]. Despite these limitations, these types of soils are broadly exploited all over the world for crop production. Locally, Vertisols soils are called Shahjiang black and cultivated around 4 × 10 −6 near the Huai River in the northeast part of China [ 2 ]. Mollisols accumulate illite and vermiculite minerals, organic–inorganic complexes, and demonstrate an increasing cation exchange capacity (CEC), leading to the replication of redox conditions in Mollisols [ 5 , 6 ] that would otherwise regulate key physical, chemical, and biological processes. Improper land management, soil acidification resulting from extensive fertilization, and low microbial biodiversity have contributed to a considerable reduction in the soil productivity of Mollisols [ 7 , 8 ]. Mollisols (called Albic soils) in China are distributed primarily in the northeast region, which is one of the three largest areas in the world in which Mollisols occur naturally [ 9 ]. Due to elevated soil aggregate destruction, wind and water erosion are associated with the loss of clay particles and subsequent deposition of silt/sand. These soils exhibit poor nutrition for supporting crop production [ 10 ]. Although such soils are known for their high inherent fertility [ 11 ], a significant decline in soil productivity has been observed due to inappropriate agricultural practices, such as irrigation and fertilization [ 12 ]. Therefore, it is necessary to find alternate strategies in order to improve the productive capacity of such soils to realize sustainable agricultural production.
Aridisols are typical cultivated soils of arid and semiarid regions and are distributed around the world. The Hexi Corridor and Yellow River basin are the most representative area of Aridisols in China and occupy half of their total area [ 13 ]. Although Aridisols are considered the most productive soils, they are also the most nutrient-demanding soils in China [ 13 ]. Water availability, salinization, and wind erosion threaten the productive capacity of Aridisols in agriculture [ 14 , 15 ]. They are also vulnerable to erosion, which depletes the top soil, thereby lowering the content of clay and organic matter and the availability of macro and micronutrients [ 16 , 17 ].
A significant number of studies have focused on the application of manure (mainly of animal origin), crop straw return, and mineral fertilization in the above-referenced soils to sustain soil and crop productivity. A hitherto unexploited area within this context is the application of humic substances, which have shown promise to improve the productivity of soils and the establishment of crops under soils of varying mineralogical compositions [ 5 , 18 , 19 ]. Humic substances (HSs) comprise ~60% of soil organic compounds; these compounds are considered to be a crucial constituent of the agro-ecosystem and are responsible for numerous composite and chemical reactions in the soil [ 20 ]. They are rarely decayed because of their interactions with inorganic segments [ 21 ]. In soil, one of the most prominent characteristics of HSs is their ability to interact with metallic ions, oxides, hydroxides, minerals, and carbon-based compounds [ 22 ]. Moreover, HSs can interact with xenobiotic organic molecules, such as pesticides, and affect micro and macronutrients [ 23 ]. Humic substances become more effective when they are separated into their constituent forms, e.g., fulvic (FA), humic, and humin acids. Humic substances can enhance various soil properties, such as the water holding capacity, through increased aggregation and enhanced soil aeration, leading to increased microbial activity that, in turn, increases the mineralization of organic matter and enhances the bioavailable fractions of both micro and macronutrients for plant uptake [ 5 , 24 ]. Various researchers have revealed that such humic substances enhance root, leaf, and shoot growth by stimulating the germination of various crop species [ 25 ]. The application of FA increases nutrient uptake [ 25 , 26 ] and cell permeability [ 27 ] and appears to regulate key plant metabolic mechanisms [ 28 ].
Importantly, the addition of organic additions to improve soil properties and enhance crop growth and productivity are governed by the quantity, type, and properties of added humic substances. Furthermore, mineralogical and soil textural differences may vary the effects on plant growth [
29
]. We hypothesized that application of various FAs (mineral- and plant-derived solids/liquids) would cause different improvements to plants’ growth and soil properties in soils with contrasting textures (i.e., Mollisols, Aridisols, and Vertisols). The objectives of our study were to measure the effects of mineral- and plant-derived FAs on the selected soil properties and to determine their effects on the development of the growth parameters, yield, and mineral content of wheat grown on Mollisols, Aridisols, and Vertisols. We examined the interaction of fulvic acids and soil types, as these plant and mineral types of fulvic acids have been the least studied to date.
2. Results
2.1. Effect of FA on Electrical Conductivity and Soil pH
The effects of the FAs on electrical conductivity and soil pH are presented in
Figure 1
. The electrical conductivity increased between the treatments and decreased with the NLFA in Mollisols compared to the control. The electrical conductivity increased by 10.5% and 0.18% and decreased by 14.1% in Mollisols but increased by 96.8%, 130.5%, and 195.2% in Aridisols and by 57.5%, 10.1%, and 104.7% in Vertisols between the applied treatments and the control (
Figure 1
A). However, soil pH decreased in Mollisols and Aridisols and increased with NLFA in Vertisols between the treatments and the control. The soil pH decreased by 5.5%, 12%, and 12.6% in Mollisols; 3.59%, 2.35%, and 3.03% in Aridisols; and 1.4% and 1.53% in Vertisols; and increased by 0.25% with NLFA in Vertisols compared to the control (
Figure 1
B).
Figure 1. The effect of plant-derived solid fulvic acid (PSFA), mineral-derived liquid fulvic acid (NLFA), and plant-derived liquid fulvic acid (PLFA) on ( A ) electrical conductivity and ( B ) soil pH of Mollisol, Aridisol, and Vertisol soils. The means ± standard errors are shown ( n = 4). Different letters (a, b, and c) indicate significant differences between the initial and final values of the soils based on a least significant difference test at a 5% significance level.
2.2. Effect of FAs on Heavy and Light Fractions of Organic Carbon
The light and heavy fractions of labile organic carbon after the application of FAs are presented in
Figure 2
. The heavy fraction carbon decreased in Mollisols and with PSFA in Vertisols and increased in Aridisols and Vertisols in the treatments compared to the control. The heavy fraction carbon decreased by 36.8%, 17.9%, and 19.6% in Mollisols, increased by 51.3%, 59.5%, and 53.4% in Aridisols and 5.14% and 10.6% in Vertisols, and decreased by 3.54% in Vertisols between the treatments and the control (
Figure 2
A). However, the light fraction carbon increased in Mollisols and Vertisols and decreased in Aridisols relative to the control. The light fraction carbon content increased by 69.6%, 94.7%, and 12.8% in Mollisols and by 36.4%, 76.8%, and 46.3% in Vertisols and decreased by 17.6%, 12.9%, and 12.3% in Aridisols between the treatments and the control (
Figure 2
B).
Figure 2. The effect of plant-derived solid fulvic acid (PSFA), mineral-derived liquid fulvic acid (NLFA), and plant-derived liquid fulvic acid (PLFA) on ( A ) heavy fraction C and ( B ) light fraction C content of Mollisols, Aridisols, and Vertisols soils. The means ± standard errors are shown ( n = 4). Different letters (a, b, and c) indicate significant differences between the initial and final values of the soils based on a least significant difference test at a 5% significance level.
2.3. Effect of FAs on Soil Chemical Properties
The influences of the FAs on the chemical properties of the soil are presented in Figure 3 . The soil organic carbon content increased in Mollisols and Vertisols and decreased in Aridisols with PSFA in the treatments compared to the control. The soil organic carbon content increased by 16%, 37.8%, and 5.7% in Mollisols; by 1.68% and 24.3% in Aridisols; and by 8.7%, 32.5%, and 10.4% in Vertisols; and decreased by 11.7% with PLFA in Aridisols between the treatments and the control ( Figure 3 A). However, the available nitrogen (AN) content increased in between the treatments and the control within the soil. The AN content increased by 32.2%, 25.4%, and 63.6% in Mollisols; 25.2%, 76%, and 76.1% in Aridisols; and 0.57%, 4.83%, and 10% in Vertisols between the treatments and the control ( Figure 3 B). Similarly, the available phosphorus (AP) content decreased in Mollisols and increased in Aridisols and Vertisols. AP content decreased by 31.1%, 70.3%, and 62.2% in Mollisols and increased by 206.1%, 207.2%, and 93.2% and 13.6%, 185.6%, and 25.3% in Aridisols and Vertisols, respectively, compared to the control ( Figure 3 C). The available potassium (AK) content increased in the treatments compared to the control in the soil. AK content increased by 44.9%, 32.9%, and 43.3%; 23.4%, 12%, and 30%; and 3.53%, 2%, and 9.5% in Mollisols, Aridisols, and Vertisols, respectively, in the treatments compared to the control ( Figure 3 D).
Figure 3. The effect of plant-derived solid fulvic acid (PSFA), mineral-derived liquid fulvic acid (NLFA), and plant-derived liquid fulvic acid (PLFA) on ( A ) soil organic carbon, ( B ) available nitrogen, ( C ) available phosphorus and ( D ) available potassium content of Mollisols, Aridisols, and Vertisols soils. The means ± standard errors are shown ( n = 4). Different letters (a, b, and c) indicate significant differences between the initial and final values of the soils based on a least significant difference test at a 5% significance level.
2.4. Effect of FAs on the Organic–Inorganic Compounds and Their Complexes
The effects of the FAs on organic–inorganic degree compounds and organic–inorganic composites are presented in
Table 1
. The organic–inorganic degree compounds increased in Aridisols and Vertisols; however, they decreased in Mollisols in the treatments compared to the control. The organic–inorganic degree compounds increased by 30.7%, 31.5%, and 46.6% in Aridisols and 23%, 40.7%, and 29% in Vertisols and decreased by 37.7%, 31%, and 13.7% in Mollisols in the treatments compared to the control. However, the organic–inorganic compound content increased in Aridisols and in Mollisols with PLFA. The organic–inorganic compound content increased by 13.3% with PLFA in Mollisols and by 57.1%, 57%, and 50% in Aridisols and decreased by 26.6% and 6.66% in Mollisols and by 13%, 15%, and 9% in Vertisols in the treatments compared to the control (
Table 1
).
Table 1. Effect of FAs on organic–inorganic degree compounds and organic–inorganic composites (g/kg).
2.5. Effect of FA on Wheat Grain and Spike Grain weight (g pot −1 )
The effects of FAs on the grain weight and spike grain weight of wheat are given in
Table 2
. The wheat grain weight decreased in Aridisols and Vertisols and increased with PSFA in Mollisols in the treatments compared to the control. The wheat grain weight increased by 1.60% with PSFA and decreased by 6.43% and 5.03% with NLFA and PLFA in Mollisols; however, the weight decreased by 15.6%, 8.25%, and 15.2% in Aridisols and by 11.4%, 13.4%, and 6.17% in Vertisols between the treatments and the control. The spike grain weight increased with PSFA and PLFA in Mollisols and with NLFA in Aridisols and decreased in Vertisols in the treatments compared to the control. The spike grain weight increased by 23.6% and 10.8% in Mollisols and by 13.5% in Aridisols and decreased by 2.40% in Mollisols, 60.4% and 10.6% in Vertisols, and 6.19%, 4.22%, and 42% in Vertisols in the treatments compared to the control (
Table 2
).
Table 2. Effect of FA on wheat grain weight and the spike grain weight of wheat (g pot −1 ).
2.6. Effect of FAs on Plant Growth and Biomass Accumulation
The plant height and plant biomass content of wheat after the application of FA are given in
Table 3
. The plant height increased in Mollisols and Aridisols with PSFA and NLFA and decreased in Vertisols in the treatments compared to the control. The plant height increased by 11.2%, 7.67%, and 4.34% in Mollisols and increased by 3.33%, 28.7%, and 7.83% in Aridisols and by 13.5%, 98.4%, and 7.82% in Vertisols in the treatments compared to the control. The plant biomass content increased in Mollisols, Aridisols, and Vertisols and decreased with PSFA in Aridisols and Vertisols compared with the control. The plant biomass content increased by 21%, 11.8%, and 28.4% in Mollisols; by 8.48% and 5% in Aridisols; and by 22% and 1.44% in Vertisols and decreased by 46.1% and 14% with PSFA in Aridisols and Vertisols compared with the control (
Table 3
).
Table 3. Effect of FAs on the plant height and plant biomass content of wheat (g pot -1 ).
2.7. Effect of FAs on the Nutrient Content of Wheat
The uptake of wheat nutrients after the application of FA to Mollisols, Aridisols, and Vertisols is presented in
Figure 4
. The total nitrogen (TN) content increased with PSFA and NLFA in Mollisols and with PSFA in Aridisols but decreased in Vertisols in the treatments compared to the control. The TN content increased by 36.6% and 9.1% in Mollisols and by 5.93% in Aridisols and decreased by 36.4%, 47.3%, and 32.4% in Vertisols in the treatments compared to the control (
Figure 4
A). However, the total phosphorus (TP) content increased with NLFA and PLFA in Mollisols and with PSFA in Aridisols but decreased in Vertisols in the treatments. The TP content increased by 5.84% and 10.7% in Mollisols and by 8.23% with PSFA in Aridisols and decreased by 2.3% and 6.17%, 6.79% and 21.7%, and 63.77% and 11.7% in Mollisols, Aridisols, and Vertisols, respectively, in the treatments compared to the control (
Figure 4
B). The total potassium (TK) content significantly increased in the treatments of Mollisols and Vertisols and non-significantly decreased in Vertisols. The TK increased by 8.98% and 7.86% in Mollisols, by 36.1% and 3.07% in Aridisols, and by 30% and 0.73% in Vertisols. The TK similarly decreased by 9.36% with PSFA in Mollisols and by 8.05% and 1.46% in Vertisols between the treatments and the control (
Figure 4
C).
Figure 4. The effect of plant-derived solid fulvic acid (PSFA), mineral-derived liquid fulvic acid (NLFA), and plant-derived liquid fulvic acid (PLFA) on ( A ) nitrogen, ( B ) phosphorus and ( C ) potassium uptake of wheat grown in Mollisols, Aridisols, and Vertisols soils. The means ± standard errors are shown ( n = 4). Different letters (a, b, and c) indicate significant differences between the initial and final values of the soils based on a least significant difference test at a 5% significance level.
3. Discussion
3.1. Influences of FAs on the Physiochemical Properties of Mollisol, Ardisol, and Vertisol Soils
Soil electrical conductivity and pH are important soil quality parameters. Soil pH and electrical conductivity directly affect the buffering capacity of soils, regulate soil acidification, and release carbon dioxide [ 30 ]. Because acidic FAs remain in the soil solution, FAs are soluble in water irrespective of the pH conditions [ 31 ]. Our study demonstrated that FAs increased the physiochemical properties of all soil types studied in the current experiment. It was observed that the electrical conductivity significantly increased in Mollisols, Aridisols, and Vertisols irrespective of the applied treatments, except for the NLFA in Mollislos ( Figure 1 A). Similarly, FAs significantly decreased the pH of Mollisol and Ardisol soils and increased the pH of Vertisols with NLFA ( Figure 1 B). The increases in electrical conductivity between the treatments among the soils are related to the dominance of ion dissolution over biological assimilation or ion pair formation [ 32 ]. However, the variability in pH values can be attributed to the transformation of the substrate from a reduced to an oxidized material during mineralization and to the intense liberation of CO 2 [ 33 ]. The predominance of alkaline (compared to mineral) pH suggests that HS established a buffer system, which is a characteristic of FA molecules [ 34 ]. Inverse results were obtained by Santio et al. [ 35 ], who reported that a decrease in electrical conductivity and an increase in soil pH values were observed during the mineralization of humic substances (HA/FA) during incubation. FAs are organically produced substances that release soil nutrients and make them available for plant use [ 36 ]. Similarly, Horie et al. [ 37 ] reported that the treatments of organic alterations enhanced the soil’s physical structure and also improved its nutrient content. Our results indicate that FA application can significantly improve the soil organic carbon content of Mollisols, Aridisols, and Vertisols ( Figure 3 A). The increases in soil organic carbon content among various soils with different textures caused by the application of FAs may be due to the fact that FAs are organic compounds that directly enhance the soil organic matter content in Mollisols and Vertisols and, therefore, increased organic matter mineralization [ 24 ]. Similarly, FAs significantly increased the N content of Mollisols, Aridisols, and Vertisols. Nitrogen was highly observed in the PLFA of the soils ( Figure 3 B). These results are similar to the results of Boguta et al. [ 38 ], who reported that the soil application of humus had a significant effect on N content. Similarly, Defline et al. [ 39 ] investigated the influence of humic acid on the form of a foliar spray along with N content increases and a greater uptake of N in corn. Likewise, available P significantly increased in Aridisols and Vertisols and decreased in Mollisols between the treatments and the control ( Figure 3 C). The solubility of the phosphorus concentration in the soil can be increased by the FAs. For instance, if an aluminum molecule is bound on phosphorus, FAs break the bond between these molecules, making the phosphorus available for the plants [ 34 ]. However, a decrease in Mollisols could occur because organic products in these types of soils reduce P absorption in competition with phosphorus adhering to the surface of humic acid, which behaves as a chelating agent, such as ethylenediamine, o-Hydroxyphenylecetic (EDDHA) [ 38 , 40 ]. These results agree with those of Wang et al. [ 41 ], who reported that the accumulation of HA in soil with P fertilizer significantly increases the amount of water-soluble phosphate, steadily retarding the foundation of occluded phosphate and improving P uptake and yield. However, Cimrin and Yilmaz [ 42 ] observed that the application of humic acid did not increase the P content a lettuce plant. On the other hand, the available K content was significantly increased in the soil in the treatment compared to the control conditions. A higher K content was detected with PLFA ( Figure 3 D). The increase of the K content among the soils could be because FAs release the fixed K and make it available for plants. Moreover, FAs may expand the clayey soil and release K [ 41 ]. These results are in line with those of Imbufe et al. [ 43 ], who observed that the application of humic acid and K fertilizer significantly increased the K content with 100 ppm of humic acid and 300 kg/ha K fertilizer.
3.2. The Influence of FAs on Heavy and Light Fraction C and Organic Complexes
The soil organic carbon dynamic is generally defined by separating soil organic matter (SOM) into two or more fractions. The SOM’s physical fractionation features distinctive specific C pools responsive to managing and classifying the physical control of SOM [ 44 ]. Previously, it was observed that labile pools of soil organic matter are more complex than total soil organic C pools due to the cropping practices in temperate soils [ 45 ]. The light fraction is generally considered plant-like, with a minimal quantity exhibiting a high C concentration [ 46 ], a light fraction sensitive to change, and strong management practices [ 46 ]. Nevertheless, the light fraction also correlates well with the rate of N mineralization [ 47 ]. However, heavy fraction C has low C concentrations and is more stable at a high density [ 48 , 49 ]. Heavy fraction C can be a major problem for soil fertility because it contains mineralizable C [ 50 ]. In our study, heavy fraction C increased by 50% to 60% in Aridisols, 5% to 10% in Vertisols, and decreased by 20% to 36% in Mollisols in the treatments compared to the control. A higher amount of the heavy fraction was observed in the PLFA compared to the control ( Figure 2 A). Similarly, the light fraction C content significantly increased by 60% to 90% and 40% to 70% in Mollisols and Vertisols, respectively, and decreased by 12% to 15% in Aridisols ( Figure 2 B). The increases and decreases of heavy and light fraction C among the treatments could be because FA enhanced the soil organic matter content. Organic matter also improved the organic matter mineralization within the soil. We observed that SOM was solubilized by soil organic materials when the sample was processed through NaI during the sonication and densitometric analyses, which could be the reason for the decreases and increases in light and heavy fraction C between the soils [ 51 ]. These conclusions are similar to those of Crow et al. [ 52 ], who reported that the recombined density fraction C was observed to be 40% in bulk soil compared with light fraction C during a one-year incubation experiment. Crow et al. [ 52 ] also found that heavy fraction C decomposed more than light fraction C during the experimental periods. Similarly, vo Lutzow et al. [ 53 ] observed that precipitation treatments stimulated the light fraction C, the ratio of the light/heavy fraction, and artificial warming, which reduced soil labile C during the soil labile and recalcitrant C experiments.
The organic–inorganic composite is the structural basis of soil fertility, and the organic–inorganic degree complexes are an important indicator for evaluating soil fertility [
54
]. In our study, the organic–inorganic degree compound content significantly increased under the treatments of Aridisols and Vertisols and decreased in Mollisols. Similarly, the organic–inorganic composite presented significantly lower amounts among the soils in the treatments compared to those of the control (
Table 1
). The increases and decreases in organic–inorganic complexes and organic–inorganic composites may have been caused by the different sources of FAs and the different FA concentrations applied [
55
].
It has been reported by many scientists that FA increases nutrient content, enhances plant growth, reduces the uptake of perilous elements, and improves plant metabolism [
56
]. However, to date, the effect of FA in different forms on soil organic fractions, available nutrients, plant growth, and nutrient uptake has not been studied for Mollisol, Aridisol, and Vertisol soils. The application of lignite-derived HA increased plant growth, grain weight (19% to 58%), and NPK uptake in plants [
57
]. The present study indicates that the application of NLFA and PLFA FA increases plant growth and nutrient content in soils. These results support the findings of Arjumend et al. [
57
], which show that lignite-derived HA significantly increases the plant growth and nutrient content of wheat in loam and silty loam soils.
3.3. Influence of FAs on the Plant Growth Characteristics of Wheat
The increase in plant growth, plant biomass, thousand-grain weight, and spike grain weight under NLFA and PLFA FA treatments between the soils confirms that FA directly influences plant growth characteristics ( Table 2 and Table 3 ). The application of PSFA significantly increases the plant growth, plant biomass, and thousand-grain weight content in Mollisols compared to the other two soils. However, NLFA and PLFA performed better in Aridisols and Vertisols. The increase in growth parameters due to PSFA, NLFA, and PLFA may be caused by the application of these FAs, which are completely dissolved in soils and directly absorbed by the roots. Another reason could be that the application of liquid FA directly affects the metabolic sites and plant cells. These liquid FAs polarize the soil and release the nutrients of plants because of soil microbes [ 58 ]. These results are in good agreement with those of Defline et al. [ 39 ], who observed that HA significantly increases the growth and yield of corn. However, other researchers have observed that the foliar- or soil-based application of FA/HA temporarily increased plant production and plant dry mass compared to the control [ 59 ]. Our results revealed that PSFA, NLFA, and PLFA significantly increased the NPK uptake of wheat in Mollisols and Aridisols. However, Vertisols were decreased compared to the control ( Figure 4 ). The decreases of the nutrient uptake in Vertisols could be due to the compaction of soils, which prevents the nutrients in soils from penetrating into the roots. Similar results were obtained by Arjumend et al. [ 57 ], who reported that the application of HA to soil significantly increased aspects of plant growth, such as the shoot length, shoot dry weight, and plant height, compared to the foliar-applied HA. Similarly, Eshwar et al. [ 60 ] observed that the foliar application of FA along with FeSO 4 increased the nutrient uptake and dry matter yield of aerobic rice. The results of this study show that the application of liquid forms of FA increase the plant growth and soil properties of Aridisols and Vertisols. However, PSFA had a strong impact on Mollisols. This result supports the conclusions of Khaled et al. [ 61 ], who observed that HA significantly increased cell permeability, showing that the plant membrane can improve root development in sandy soils. Similarly, Celik et al. [ 62 ] concluded that HA can inhibit plant growth and the uptake of nutrient elements; HA also ameliorated damaged soil properties and, when combined with fertilizers, increased agricultural yield and plant growth.
4. Materials and Methods
4.1. Collection and Preparation of Soil and Plant Samples
The soils used in the present experiment were collected from three different fields/locations situated in the Anhui, Gansu, and Heilongjiang provinces in China. These soils were characterized as having typical silty clay, sandy loam, and clay loam textures. The soils were previously cultivated with summer maize and winter wheat crops with an area of approximately 580 farms. The soils were taken at a depth of 0–20 cm in the topsoil of agricultural lands. To determine their chemical and physical properties, the soils were air-dried, ground, and sieved with a 5-mm sieve to eliminate plant debris and rocks. Their physical and chemical properties were then analyzed. The soil texture was determined by the hydrometer method [ 63 ]. Electrical conductivity (EC) and pH were analyzed in the soil water extract (1:2.5 w / v ) [ 63 ]. Organic matter content was analyzed by a modified Walkley–Black method [ 64 ]. Available N was determined by the Kjheldal method using a Buchi K-437/K-350 digestion/distillation unit [ 63 ]. Available P was determined using a Shimadzu UV 1208 model spectrophotometer according to the Olsen method [ 63 ]. Exchangeable cations (Ca, K, and Mg) were extracted using ammonium acetate at pH 7.0 [ 32 ] and were determined using an Eppendorf Elex 636 model flame photometer. Five to 10 flag leaves of wheat were selected for their N, P, and K content. The leaf tissues were ground and passed through a 0.2-mm sieve, digested with the mixture of acids (H 2 SO 4 + HCLO 4 ) [ 65 ], and diluted with DI water. The samples for P and K were run through an ICP Mass spectrophotometer (ICP-OES) (Thermo Fisher Scientific, 7000 Series, Waltham, MA, USA). The chemical and physical properties of the soil are presented in Table 4 . All the chemicals used were of analytical grade and provided by Master Liao Company, Beijing, China. The soil samples were collected from the Heilongjiang, Gansu, and Anhui provinces of the country ( Figure 5 ).
Figure 5. The map showing the purple (Mollisols), yellow (Vertisols), and green (Aridisols) soils of the Heilongjiang, Gansu and Anhui Provinces.
Table 4. Properties of the soils used in the experiment.
4.2. Organic–Inorganic Compound and Organic–Inorganic Composite Analysis
The soil labile and recalcitrant fractions of soil organic matter were separated by density fractionation, which is one of the physical fractionation methods widely used across the world. The light fraction C of low density (<1.7 g cm
−3
) was partly decayed plant and animal products, and the heavy fraction of a high density (>1.7 g cm
−3
) consisted of mineral-associated humic substances [
34
]. Approximately 5 g of the sample was placed in a centrifuged tube with 25 mL of NaI solution at a density of around 1.7 g cm
−3
. Samples were shaken in a mechanical shaker for 30 min. Then, the tubes were transferred to a centrifuge at 3000×
g
rpm for 10 min. A fiber glass filter in a Buchner funnel was used to separate the light fraction that is typically present on the surfaces of soils. This process was repeated 2–3 times to separate the light and heavy fractions. Residual material was washed with distilled water 3–4 times on a centrifuge machine. After rinsing with water, the light fractions were washed with 0.01 M CaCl
2
and then 25 mL of deionized water. The light and heavy fractions were dried at 60 °C for 48 h, weighed, and ground to determine their C content, after which, the fractions of both organic and inorganic complexes were calculated by the following equations:
Organic–inorganic compound% = HC × HW/SW × SC × 100,
(1)
Organic–inorganic composite g/kg = HC × HW/SW,
(2)
where HC (g/kg) is the carbon content in the heavy fraction, HW (g/kg) is the tube weight subtracting the final weight of soil after the removal of the light and heavy fraction, SW (g) is the weight of the air-dried soil, and soil organic carbon (g/kg) is the content of soil organic carbon.
4.3. Experimental Design and Crop Maintenance
A pot experiment was carried out on the Experimental Farm of the Institute of Environment and Sustainable Development in Agriculture (IDEA, CAAS), located in Shunyi, Beijing, China (40°09′ N, 116°92′ E). Pots of 30 × 50 cm in size were filled with air-dried soil, and 15 seeds of wheat were sown separately in the homogenized soil (15 kg). The pots were arranged in light humid conditions under a randomized complete block design (RCBD) for the entire growing season (from November 2017 to June 2018). To maintain the field capacity of the soils, the pots were watered weekly from November to January 2018 and simultaneously from February to June. The compound fertilizer (high tower) was applied at a rate of 15 g pot −1 with a composition of 30% N, 9% P 2 O 5 , and 9% K 2 O.
4.4. Collection of Plant- and Mineral-Derived FA
The experiment consisted of fulvic acids (FAs) extracted from both plant (vegetables, flowers, and fruits) and mineral sources, which are the by-products of aluminum sulfite produced by (Shandong Quan Linjia fertilizer Co. Ltd., Linyi, China) with a purity of 300 g/L in which N + P 2 O 5 + K 2 O ≥ 80 g/L. The present study included four concentrations of FA 0 for the control and 2.5, 5, and 5 kg/ha of plant-derived solid (PSFA), mineral-derived liquid (NLFA), and plant-derived liquid (PLFA) FA, respectively, with three replications. The initial material of the FAs was derived by the International Humic Acid Society (IHSS) method [ 19 ]. More details on fulvic acid application can be found from [ 18 ].
4.5. Elemental Analysis of FAs
The elemental makeup of FAs like nitrogen (N), carbon (C), hydrogen (H), and sulfur (S) (CHNS) was determined by combustion in oxygen gas using a Parkin-Elmer 240-C elemental analyzer. The elemental ratio was determined among different elements, where N, C, H, and S are the atomic ratios, as reported by Kumada (1987), using Equation (3): The elemental composition of plant and mineral-derived fulvic acids are presented in (
Table 5
).
O% = 100 − (N% + C% + S%).
(3)
Table 5. Elemental composition of plant- and mineral-derived fulvic acid.
4.6. Calculation and Statistical Analyses
Statistical tests were performed using SPSS (SPSS Version 21.0, Chicago, IL, USA). A one-way analysis of variance (ANOVA) was performed on the soil and plant parameters (SOC, N, P, and K, spike length, plant height, and biomass). Data are expressed as the means ± SE (standard error). The means ( n = 4) were subjected to a one-way analysis of variance (ANOVA) and compared using Bonferroni multiple comparison tests at a significance level of p < 0.05. The location of the experimental site is shown by a map drawn in Corel Draw m version X7.
5. Conclusions
The present study demonstrated that the application of FAs improved the physico-chemical properties of soils with varying texture. In addition, the application of FAs increased the nutrient uptake and production of wheat grown on these soils. Along with the soil organic carbon fractions, FAs also had a great impact on the growth characteristics of wheat. Overall, we determined that PSFA exerted a large effect on the properties of Mollisols. On the other hand, NLFA and PLFA increased the properties of Aridisol and Vertisol soils. It is therefore recommended that the application of mineral- and plant-derived FAs should be studied at the field level, and the underlying mechanisms that exert variable effects on the soil properties should be explored in detail.
Author Contributions
Data curation, S.S.; Formal analysis, L.B.; Funding acquisition, X.Z.; Project administration, Investigation, Y.Z.; Software, Y.W.; Visualization, M.K.; Writing—original draft, N.Y. and M.K.S.; Writing—review and editing, P.S. and A.M. All authors have read and agreed to the published version of the manuscript.
Funding
National Natural Science Foundation of China: 41671308.
Acknowledgments
The Authors would like to express appreciation to the Natural Science Foundation of China (41671308), Science Innovation Project of the Chinese Academy of Agricultural Sciences (CAAS-ASTIP-2016-IEDA) and Chinese Scholarship Council.
Conflicts of Interest
The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
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Figure 1. The effect of plant-derived solid fulvic acid (PSFA), mineral-derived liquid fulvic acid (NLFA), and plant-derived liquid fulvic acid (PLFA) on ( A ) electrical conductivity and ( B ) soil pH of Mollisol, Aridisol, and Vertisol soils. The means ± standard errors are shown ( n = 4). Different letters (a, b, and c) indicate significant differences between the initial and final values of the soils based on a least significant difference test at a 5% significance level.
Figure 2. The effect of plant-derived solid fulvic acid (PSFA), mineral-derived liquid fulvic acid (NLFA), and plant-derived liquid fulvic acid (PLFA) on ( A ) heavy fraction C and ( B ) light fraction C content of Mollisols, Aridisols, and Vertisols soils. The means ± standard errors are shown ( n = 4). Different letters (a, b, and c) indicate significant differences between the initial and final values of the soils based on a least significant difference test at a 5% significance level.
Figure 3. The effect of plant-derived solid fulvic acid (PSFA), mineral-derived liquid fulvic acid (NLFA), and plant-derived liquid fulvic acid (PLFA) on ( A ) soil organic carbon, ( B ) available nitrogen, ( C ) available phosphorus and ( D ) available potassium content of Mollisols, Aridisols, and Vertisols soils. The means ± standard errors are shown ( n = 4). Different letters (a, b, and c) indicate significant differences between the initial and final values of the soils based on a least significant difference test at a 5% significance level.
Figure 4. The effect of plant-derived solid fulvic acid (PSFA), mineral-derived liquid fulvic acid (NLFA), and plant-derived liquid fulvic acid (PLFA) on ( A ) nitrogen, ( B ) phosphorus and ( C ) potassium uptake of wheat grown in Mollisols, Aridisols, and Vertisols soils. The means ± standard errors are shown ( n = 4). Different letters (a, b, and c) indicate significant differences between the initial and final values of the soils based on a least significant difference test at a 5% significance level.
Figure 5. The map showing the purple (Mollisols), yellow (Vertisols), and green (Aridisols) soils of the Heilongjiang, Gansu and Anhui Provinces.
Table 1. Effect of FAs on organic–inorganic degree compounds and organic–inorganic composites (g/kg).
FA Oganic–Inorganic Degree Compound (g/kg) Orgnanic–Inorganic Composite (g/kg) Mollisols Aridisols Vertisols Mollisols Aridisols Vertisols CK 71.85 ± 5.41 a 46.9 ± 1.36 c 53.0 ± 1.39 c 0.30 ± 0.03 a 0.14 ± 0.006 b 0.497 ± 0.03 a PSFA 44.7 ± 2.42 b 61.3 ± 1.04 b 65.2 ± 1.24 b 0.22 ± 0.008 b 0.22 ± 0.009 a 0.432 ± 0.04 ab NLFA 49.7 ± 0.65 a 61.7 ± 2.3 b 74.6 ± 1.42 a 0.28 ± 0.01 ab 0.22 ± 0.006 a 0.422 ± 0.02 b PLFA 61.9 ± 5.3 a 68.8 ± 0.86 a 68.4 ± 1.78 b 0.34 ± 0.02 a 0.21 ± 0.009 a 0.452 ± 0.01 ab
Values are the means ± standard error ( n = 4) for PSFA (plant-derived solid fulvic acid), NLFA (mineral-derived liquid fulvic acid), and PLFA (plant-derived liquid fulvic acid). Different letters (a, b, and c) indicate significant differences between the soils ( p < 0.05).
Table 2. Effect of FA on wheat grain weight and the spike grain weight of wheat (g pot −1 ).
FA Thousand Grain Weight (g) Spike Grain Weight (g) Mollisols Aridisols Vertisols Mollisols Aridisols Vertisols CK 49.7 ± 1.9 a 55.79 ± 2.55 a 53.4 ± 0.12 a 99 ± 6.55 b 76.7 ± 5.57 ab 138.4 ± 8.23 a PSFA 50.5 ± 2.0 a 47.0 ± 1.89 b 47.3 ± 1.12 b 123.2 ± 6.63 a 30.3 ± 5.5 b 124.2 ± 8.85 ab NLFA 46.5 ± 0.57 a 51.1 ± 1.27 ab 46.2 ± 188 b 97.2 ± 4.63 b 87.1 ± 5.73 a 126.8 ± 5.23 ab PLFA 47.2 ± 1.21 a 47.2 ± 1.49 b 50.1 ± 1.15 a 110.4 ± 8.20 ab 68.5 ± 9.21 ab 76.7 ± 8.45 b
Values are the means ± standard error ( n = 4) for PSFA (plant-derived solid fulvic acid), NLFA (mineral-derived liquid fulvic acid), and PLFA (plant-derived liquid fulvic acid). Different letters (a, b, and c) indicate significant differences between the soils ( p < 0.05).
Table 3. Effect of FAs on the plant height and plant biomass content of wheat (g pot -1 ).
FA Plant Height (cm) Plant Biomass (g) Mollisols Aridisols Vertisols Mollisols Aridisols Vertisols CK 78.2.0 ± 0.91 b 68.9.5 ± 1.26 b 76.7 ± 1.78 b 160.6 ± 1.75 d 153.3 ± 4.37 a 207.4 ± 1.73 b PSFA 87.0 ± 2.65 a 71.2 ± 1.65 b 84 ± 1.35 a 194.2 ± 4.08 b 82.6 ± 1.42 b 178.3 ± 6.40 c NLFA 84.2 ± 0.75 ab 88.7 ± 1.11 a 88.2 ± 1.18 a 179.6 ± 3.89 c 166.3 ± 7.29 a 253.0 ± 3.76 a PLFA 81.6 ± 1.17 b 74.3 ± 1.49 b 82.7 ± 3.03 a 206.3 ± 1.84 a 161.1 ± 9.16 a 210.4 ± 1.8 2 b
Values are the means ± standard error ( n = 4) for PSFA (plant-derived solid fulvic acid), NLFA (mineral-derived liquid fulvic acid), and PLFA (plant-derived liquid fulvic acid). Different letters (a, b, c, and d) indicate significant differences between the soils ( p < 0.05).
Table 4. Properties of the soils used in the experiment.
Soil EC us/cm pH OM g/kg CEC cmol/kg AN mg/kg AP mg/kg AK mg/kg TN g/kg TP g/kg TK g/kg Textural Class Mollisols 30.1 5.2 8.4 21.6 66.0 0.44 78.0 0.70 0.39 20.4 Silty clay Aridisols 2063 8.4 2.2 4.6 19.0 2.4 525.3 0.20 0.39 20.1 Sandy Loam Vertisols 132 7.9 11.7 25.2 52.0 1.19 186.6 0.83 0.39 17.3 Clay loam
Table 5. Elemental composition of plant- and mineral-derived fulvic acid.
FA Type N C H S % PSFA 5.39 25.31 5.75 8.47 NLFA 10.29 52.476 9.74 14.84 PLFA 10.78 50.61 11.56 16.96
PS = plant-derived solid, NL = mineral-derived, and PL = plant-derived fulvic acids.
Chicago/Turabian Style
Kumar Sootahar, M.; Zeng, X.; Wang, Y.; Su, S.; Soothar, P.; Bai, L.; Kumar, M.; Zhang, Y.; Mustafa, A.; Ye, N. The Short-Term Effects of Mineral- and Plant-Derived Fulvic Acids on Some Selected Soil Properties: Improvement in the Growth, Yield, and Mineral Nutritional Status of Wheat ( Triticum aestivumL.) under Soils of Contrasting Textures. Plants 2020, 9, 205.
https://doi.org/10.3390/plants9020205
AMA Style
Kumar Sootahar M, Zeng X, Wang Y, Su S, Soothar P, Bai L, Kumar M, Zhang Y, Mustafa A, Ye N. The Short-Term Effects of Mineral- and Plant-Derived Fulvic Acids on Some Selected Soil Properties: Improvement in the Growth, Yield, and Mineral Nutritional Status of Wheat ( Triticum aestivumL.) under Soils of Contrasting Textures. Plants. 2020; 9(2):205.
https://doi.org/10.3390/plants9020205
Chicago/Turabian Style
| https://www.mdpi.com/2223-7747/9/2/205 |
Changing the Law on Medical Use and Research
Major Studies of Drugs and Drug Policy House of Lords Report on Marijuana, 1998
CHAPTER 7 CHANGING THE LAW ON MEDICAL USE AND
RESEARCH: REVIEW OF THE EVIDENCE7.1 In law, it would be possible to make cannabis
and/or additional cannabinoids prescribable by moving them from Schedule 1 to
Schedule 2 to the Misuse of Drugs Regulations, in advance of any cannabis-based
medicine being licensed and reaching the market. However, the Government are not willing
to reschedule cannabis in advance of licensing. Licensing depends on research and clinical
trials: the Government are satisfied with the arrangements for allowing research and
trials, but some of our witnesses are not. In the mean time, medical use remains illegal. Prosecution for use of cannabis for medical purposes7.2 It is not known what proportion of prosecutions
for possession of cannabis arise from medical use. The ACT drew our attention to 15
reported cases of people charged with cultivation, possession and/or supply in medical
situations since 1996: of the 12 cases where the outcome was known, one resulted in a
sentence of 50 hours' community service; in the other 11, either the prosecution was
abandoned, the defendant was acquitted, or the sentence was no greater than a conditional
discharge. IDMU offer further figures (p 258); they comment that, although outcomes in
such cases are highly variable, juries seem more likely to acquit "where there is
convincing medical evidence, given similar circumstances concerning paraphernalia".7.3 People who use cannabis for medical purposes
face prosecution if caught cultivating or possessing cannabis; but, according to Austin
Mitchell MP, "It is bringing the law into a certain amount of difficulty and
disrepute because either the police are cautioning or the courts are giving very lenient
sentences" (Q 132). Dr Pertwee considers it unsatisfactory that such people
are sometimes prosecuted, unsatisfactory that law-breaking is sometimes tolerated, and
unsatisfactory that the position is inconsistent around the country (Q 313).7.4 The BMA report recommends, "While research
is under way, police, the courts and other prosecuting authorities should be aware of the
medicinal reasons for the unlawful use of cannabis by those suffering from certain medical
conditions for whom other drugs have proved ineffective" (cp Q 55). Similarly
the Multiple Sclerosis Society want the law to treat people caught using cannabis for
medical reasons in an "appropriately compassionate fashion" (p 90). They
report that most people convicted in such circumstances receive a suspended sentence; but
they are concerned about the way the system treats people as much as about the verdict
(Q 341; cp IDMU p 261).7.5 Mr Howarth, the Under-Secretary of State,
declined to comment on how the Crown Prosecution Service and the courts treat such cases
(QQ 668-673), beyond observing that in some cases the plea-in-mitigation of medical
use might be trumped-up (Q 674). The Home Office added that official statistics do
not distinguish between cases with a medical aspect and cases without; but that, on the
anecdotal evidence, outcomes in medical cases were not obviously out of line with outcomes
in purely recreational cases (Q 675). (The proportion of persons in the United Kingdom
dealt with for possession of cannabis who are cautioned rather than prosecuted rose from
35 per cent in 1986 to 62 per cent in 1995— Home Office Statistical Bulletin10/98.) Possible transfer from Schedule 1 to Schedule 27.6 According to the Home Office (p 150),
cannabis could be transferred from Schedule 1 to Schedule 2 by statutory instrument,
subject to negative resolution in Parliament. The ACMD would have to be consulted first.
According to the Minister (Q 676), under the 1961 UN Convention, rescheduling
cannabis itself and cannabis resin would not require international agreement; but, under
the 1971 Convention, rescheduling cannabinol and its derivatives other than dronabinol
would require prior amendment of the Schedules to the Convention through the WHO and the
UN Commission on Narcotic Drugs, as happened in the case of dronabinol in 1995.7.7 Rescheduling would allow doctors to prescribe;
but the Home Office say, "Our understanding is that the ability of doctors to
prescribe cannabis would be hampered in practice if a cannabis-based medicine had not been
granted a marketing authorisation by the MCA". The Minister said that there were
"compelling policy reasons" for requiring an MCA licence first (Q 676).
When asked to explain the practical difficulties, he referred to the extra burden of
responsibility which a doctor takes on by prescribing an unlicensed medicine (Q 679);
he queried the wisdom of permitting prescription without proof of safety and quality
(Q 680); and he noted that the ACMD had not called for change (Q 688).7.8 Rescheduling would also allow doctors and
pharmacists to manufacture and supply (Q 680); anyone else, including a pharmaceutical
company, would require a Home Office licence. It would not in itself disapply section 8 of
the Misuse of Drugs Act, which makes it an offence to allow cannabis to be smoked on
premises; but this could be done by secondary legislation (Q 684).7.9 So the Government couldreschedule
cannabis; the next question is, whether they should. Dr Lambert says, "Many
patients are already illegally using cannabis...Their needs must be addressed whilst
formal studies are undertaken"[25]. IDMU
finds the present position "inhumane", and "unjustifiable both on moral and
on public health grounds" (p 229). Dr Pertwee says (p 68), "A
strong case can be made on the grounds of common sense and compassion for allowing doctors
to prescribe...(oral) cannabis now for serious symptoms including muscle spasms"; but
he admits that it will take better evidence to persuade the Department of Health
(Q 263; see also paragraph 7.15 below).7.10 Dr Robson described the present position as an
"affront to humanity" (Q 460). He called for "compassionate
reefers" for AIDS and cancer patients (p 118), and possibly for patients with
non-terminal conditions who might feel that the increased risk of cancer was worth taking
(Q 469). He suggested that patients might be made to confirm in writing that the doctor
had explained the risks; and that, if it were felt necessary, the number of doctors
entitled to prescribe cannabis could be limited, as in the case of diamorphine (heroin) or
cocaine prescribed for addicts under the Misuse of Drugs (Supply to Addicts) Regulations
1997 (Q 471). He added that research into synthetic cannabinoids might soon make
herbal cannabis obsolete; but, in the mean time, "it just is not a dangerous enough
drug for me to want to ban it" (Q 472).7.11 The ACT want "medical preparations of
natural cannabis...to be made available on a doctor's prescription while research is going
ahead" (p 28), by moving cannabis from Schedule 1 to Schedule 2
(Q 133). They argue that "we know now that cannabis can be effective and is safe
enough to be prescribed by a doctor...and there are people who need treatment now".
Similarly, six of our witnesses, all users of cannabis for medical purposes themselves,
want cannabis to be prescribable or otherwise legalised for medical use. 195 out of 200
respondents to the Disability Nowsurvey, of whom 192 were disabled and 134 had
taken cannabis for medical purposes, wanted such use to be legalised.7.12 The London Medical Marijuana Support Group
(p 271) consider the issue to be one of patients' rights: "Please do not
continue to make sick people criminals". They call for either rescheduling, or a new
system involving registration of patients. They would solve the problem of supply by
allowing patients to grow their own, or by setting up co-operatives, or by permitting
commercial cultivation. They argue that different users get benefit from different
preparations; so they do not want a standardised preparation—though this would be
better than nothing.7.13 If the law cannot be changed, it could in
theory be applied with flexibility. IDMU suggest "directives to the CPS on criteria
to use when deciding whether a prosecution of a medical cannabis user is in the public
interest" (p 225). According to the Home Office, however, systematic
non-enforcement would be "quite unacceptable" (Q 671).7.14 Though some witnesses to this Committee favour
immediate transfer from Schedule 1 to Schedule 2, others are against it. Professor Radda
insisted that anecdotal evidence, however large in volume, was not sufficient reason for
rescheduling (Q 657). Sir William Asscher considers that immediate rescheduling would
actually threaten proper trials, such as those proposed by his working party (see Chapter
5), by encouraging patients to use cannabis in an uncontrolled way rather than enrolling
for the trial and risking receiving a placebo (Q 808).7.15 The Multiple Sclerosis Society want sufferers
to be able to make "informed choice about therapeutic agents"; therefore they
would not support prescription of cannabis for MS in advance of proper trials (p 90,
Q 368). The Royal Society say that, pending proper trials, "There is no
persuasive case for the non-experimental medical use of cannabis"; and they are
against smoking (p 295). The Royal Pharmaceutical Society take the same line
(p 289); so does Professor Strang, who would be worried if cannabis were given
"some easy track" (Q 249); so does Edward Jurith, on sabbatical in
Manchester from the post of General Counsel to the White House Office of National Drug
Control Policy (p 265). The Christian Institute agree: "The rules must remain
the same for all substances...Rescheduling cannabis would declare that cannabis is
suitable for medical use. The studies have not been done to demonstrate this"
(p 207). They add that permitting cannabis to be smoked "would profoundly damage
current health promotion attempts to dissuade smoking". They suggest that other steps
might be taken to help MS sufferers who are resorting to cannabis. Dr Pertwee considers
that permitting prescription of cannabis could not be justified until both nabilone and
dronabinol had been tried and failed (Q 314).7.16 The BMA report recommends, "The WHO
should advise the UN Commission on Narcotic Drugs to reschedule certain cannabinoids under
the UN Convention on Psychotropic Substances, as in the case of dronabinol [which was
rescheduled in 1995]. In response the Home Office should alter the Misuse of Drugs Act
accordingly." Alternatively, "The Government should consider changing the Misuse
of Drugs Act to allow the prescription of cannabinoids to patients with particular medical
conditions that are not adequately controlled by existing treatments". On the other
hand, David Nutt, Professor of Psychopharmacology at the University of Bristol[26], considers that the availability of nabilone,
which may be prescribed on an unlicensed basis for any of the conditions identified by the
BMA, makes it unnecessary to change the law (p 280).7.17 The Royal Pharmaceutical Society caution that,
if unlicensed use of cannabinoids becomes more common (as the BMA think it might,
following their report—Q 83), there should be "full consultation between
the medical and pharmacy professions" (p 290). They urge the Government to
consider moving all cannabinoids from Schedule 1 to Schedule 2. Research7.18 As noted in Chapter 3, cannabinoid
pharmacology is currently a lively field of research. However, until Dr Guy's initiative,
no new cannabis-based medicines were in commercial clinical development (Wall Q 134).
As to why this should be so, most of our witnesses point to the "stigma" of
working with a "disreputable" substance and a Schedule 1 controlled drug (e.g.
Austin Mitchell MP Q 132, Pertwee Q 317, Robson Q 482). Others point to the likelihood
that a non-synthetic cannabis-based medicine would be cheap and therefore unprofitable,
and the markets for it small (RPharmSoc p 289; Lader QQ 7, 17)—though Professor
Ashton and the BMA believe that the global market is potentially large (Q 57). Dr Pertwee
believes that drug companies are very interested in the possibility of cannabinoids which
avoid psychotropic effects by acting only on the CB2 receptor (Q 281); they are
"dying to get in there, but they do not know what to do" (Q 295).7.19 Dr Notcutt believes that what puts companies
off research involving a Schedule 1 drug is not the stigma, but the "sheer
difficulty" (Q 414). The principal additional difficulty is the requirement to
obtain a licence from the Home Office (see Box 8). If cannabis were moved to
Schedule 2 to the Regulations, research licences would no longer be required (Q 677).BOX 8: CANNABIS RESEARCH LICENCES Licences to possess any Schedule 1 drug for research may be granted by
the Home Office under section 7 of the Misuse of Drugs Act and Regulation 5 of the Misuse
of Drugs Regulations. The Under-Secretary of State at the Home Office, George Howarth MP,
explained to us the conditions under which licences are granted (Q 662). There must
be a legitimate reason for the research; details of method and timetable; ethical
approval; and safeguards including safe custody and record-keeping. The research would
normally be expected to be conducted at a university hospital or pharmaceutical company;
and the method of administration must allow for control of dosage. According to the Home
Office, there have been a total of 27 applications for cannabis research licences, of
which 25 have been approved and two agreed in principle; no application for a licence has
been refused (HC WA 255, 18 Dec. 1997). The Home Office supplied us with a list of 22 current licences. All are
granted to named researchers, 20 at universities and two in hospitals. Most are for
teaching or testing purposes; only three appear to be for research. Four of the licences
were issued this year, compared with 22 over the previous 24 years; the Home Office
attribute the increase to a Royal Pharmaceutical Society symposium on medical uses of
cannabis in July 1997 (Q 666). There are 80 current research licences for Schedule 1
substances other than cannabis (Q 665). Among our witnesses, cannabis research
licences are or have been held by Dr Pertwee, Dr Schon (see p 303 and
Q 664), Dr Holdcroft (see paragraph 5.29), and Dr Guy (see paragraph 5.44); and
Jo Barnes has a licence "in principle" for the Exeter pilot study (see
paragraph 5.47).7.20 In addition to the lack of commercial
development work, there is little clinical research in this area. Professor Wall
comments, "It is a paradox that a subject of such intense scientific interest should
receive so little clinical attention. One reason...[is] the daunting and excessive
bureaucratic control which artificially separates studies of cannabis from drugs such as
narcotics. The other reason is the general social atmosphere which labels cannabis with
every possible negative attitude" (p 31, cp Q 143). He compares the
attitude to medical use of narcotics before the work of Dame Cicely Saunders (Q 127).
Similarly Dr Lambert says, "The Schedule 1 status of cannabis has made
modern clinical research almost impossible, primarily because of the legal, ethical and
bureaucratic difficulties in conducting trials with patients. In addition, the general
attitude towards cannabis...has not helped"[27].
This is regrettable, since there is "a wide range of possibilities and a massive
opportunity for research". The Royal Pharmaceutical Society blame the
"disappointing" lack of evidence on the "stigma" attached to cannabis,
and the burden of licensing (p 288).7.21 Professor Hall also believes that
research has been chilled by the link with recreational use. He regards this link as
"spurious". He observes, "The recent discovery of the cannabinoid receptor
may help to overcome some of the resistance...by holding out the prospect that the
psychoactive effects...can be disengaged from [the] other therapeutically desirable
effects" (p 222). The Multiple Sclerosis Society believe that the stigma
attached to cannabis as a medicine can be countered by "raising awareness" and
taking the issue seriously, which to some extent has already happened (Q 372); and they
know of numerous volunteers for trials (Q 389).7.22 Dr Holdcroft notes two further difficulties:
the lack of standardised preparations (she produced her own capsules), and the medicolegal
problems of working with cannabis-naive subjects[28].
Dr Notcutt blames the licensing system, and the problem of supply (Q 413); he is
optimistic that Dr Guy's initiative may surmount both obstacles. Austin Mitchell MP
believes that ethical committees "run a mile" from sanctioning clinical research
using a Schedule 1 drug (Q 132). Professor Edwards likewise points to ethical
problems (Q 19); he recommends, before blind trials, "a small series of open
clinical investigations with repeat and careful observations on the individual
patient". The National Drug Prevention Alliance, noting that the prospective markets
may be too small to warrant the commercial cost of trials, suggest that trials might be
grant-aided from public funds (p 279—they regard this as preferable to licensing
without trials).7.23 The Department of Health say, "Both the
Home Office and MCA have always indicated that they are prepared to look sympathetically
at well-founded research proposals in this area" (p 48, cp Q 167). However
Dr Kendall calls for "relaxation of the level of control" over trials
(p 268). Dr Robson, in his review for the Department, says, "Research will only
be possible if the regulations imposed under the Misuse of Drugs Act are made more
flexible". IDMU say (p 229), "The present licensing system and policy has
severely limited research opportunities and should be reviewed"; given the rise in
research activity noted above, the United Kingdom academic community and pharmaceutical
industry may miss opportunities if the research licensing regime is not relaxed.7.24 Yet the Multiple Sclerosis Society believe
that the present system obstructs research more by its effect on attitudes than by
practicalities (Q 388); and it is the impression of Austin Mitchell MP
(Q 132) and Clare Hodges (Q 136) that the Home Office are already more flexible
than they used to be. Professor Radda believes that a good research proposal will
receive a licence without difficulty, and that scientists today are well used to
regulation of this kind (Q 630). Dr Guy says that, although consultation was lengthy
(from application to grant took 4 months—Q 663), the Home Office have been
"most helpful" (p 162).7.25 The BMA report said, "The regulation of
cannabis and cannabinoids should be sufficiently flexible to allow such compounds to be
researched without a Misuse of Drugs Act licence issued by the Home Office". In
evidence, the BMA reported "very positive feedback" from the Department of
Health and the Home Office on the pace of the licensing process (Q 82); but they said
that at present there was serious delay (Q 92). The Home Office responded, saying,
"Applications for research licences are dealt with as expeditiously as the
circumstances allow" (p 149); the Minister gave the time from application to
grant in the last six cases, which averaged seven weeks (Q 663). The BMA hope that
guidelines for trials would help to accelerate the process (Q 92).7.26 The Committee put to the BMA the idea of a
meeting between the Home Office and researchers, and they welcomed it (Q 93). The
Home Office say that they would be happy to hold such a meeting, jointly with the
Department of Health: "It would provide a useful opportunity to highlight some of the
complex issues involved such as the supply of standardised cannabis, and the adoption of
sound methodologies". Work is now in hand to set up such a meeting (Q 686). Medical use and recreational use7.27 "Without pressing the panic button",
Professor Edwards points out that cannabis or preparations of cannabis supplied for
medical use might be diverted to recreational use (Q 20). Professor Hall warns that, if
doctors were allowed to prescribe cannabis, some might be tempted to profit from bogus
prescriptions (Q 761). New Department of Health guidelines on clinical management of drug
abuse are to cover "leakage" of prescribable controlled drugs (such as
methadone) onto the black market; the Department comment that leakage of nabilone is
"highly unlikely", since it is dispensed only by hospital pharmacies in small
amounts (p 217). The BMA report says, "It would be prudent to develop a
labelling system that does not identify prescribed drugs as cannabinoids, and to warn
patients that such drugs should be kept in a place inaccessible to others".
Professor Nathanson added that, ideally, cannabis-based medicines would be developed
which had minimal psychoactive effects (Q 76).7.28 On 23 January 1997, the then Under-Secretary
of State, Home Office, told the House of Commons, "Many of those calling for the
medical use of cannabis are using it as a stalking horse to promote the campaign for its
legalisation" (HC col. 1060). David Copestake, a Methodist Minister who has
researched and written in this field, takes this view; he observes that medical uses were
once touted for tobacco (p 213). The NDPA say the same, claiming that the BMA has
been "hi-jacked" and that the ACT are "very familiar" with lobbyists
for legalisation (p 278). The Christian Institute agree (p 208).7.29 The ACT insist that they are not calling for
general legalisation (p 28). They point out that heroin (diamorphine) may be
prescribed (it is a Class A drug under the Misuse of Drugs Act, yet in Schedule 2 to
the 1985 Regulations). Dr Notcutt observes that there is no evidence that heroin
abuse is thereby encouraged, and lists several other drugs of potential abuse which are
used unlicensed in chronic pain (p 105). The MRC make the same point, and say (as do
several other witnesses), "The question of potential medical uses for cannabis and
its derivatives must be considered quite separately from the question of prohibition of
recreational use" (p 144). According to Professor Hall, there is a
stalking-horse element to the debate on medical use; but this should not be allowed to
influence the argument either way (p 222).7.30 The Department of Health still detect an
element of the stalking-horse. However they acknowledge and support "the genuine
concern of some people to find medicinal products for intractable conditions"
(Q 176).25Hirst R A, Lambert D G and Notcutt W G, op.
cit. Back26A member of the Independent Inquiry into the Misuse of
Drugs Act-see paragraph 6.19.Back27Hirst R A, Lambert D G and Notcutt W G, op. cit. Back28Holdcroft A et al, op. cit.Back
| https://www.druglibrary.org/Schaffer/LIBRARY/studies/hlords/15109.htm |
The Framework to Mitigate the Urban Heat Island Effect for Improving Environment and Protecting Human Health | IIETA
JOURNAL METRICS
CiteScore 2021: 1.8 ℹ CiteScore: CiteScore is the number of citations received by a journal in one year to documents published in the three previous years, divided by the number of documents indexed in Scopus published in those same three years.
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The Framework to Mitigate the Urban Heat Island Effect for Improving Environment and Protecting Human Health
P. Shahmohamadi| A.I. Che-Ani| K.N.A. Maulud| A. Sairi| M.F.I. Mohd-Nor
https://www.witpress.com/elibrary/sdp-volumes/5/4/473
Abstract:
Changes in temperature and precipitation, sea level, fisheries, agriculture, natural ecosystems, and air quality will all directly or indirectly affect human morbidity (illness) or mortality. One of the great challenges facing our current generation of scientists and engineers is how to protect urban population from health stressors associated with summertime heat. As heat-waves are likely to increase in frequency because of global climate change, the most effective interventions, measures and policies to protect the health need to be developed and evaluated. Therefore, this paper is focused on understanding the most important factors of urban heat island (UHI) formation and their effects on urban population health with an emphasis on the considerable growth of both population and rapid urbanization of Tehran, Iran. To achieve this aim, this paper explores literally a conceptual framework about the relationship between UHI and human health. Then, it suggests three important strategies to minimize the impact of UHI on human health: achieving appropriate transportation for mitigating air pollution, providing appropriate landscape, increasing the albedo of building materials.
Keywords:
appropriate landscape, appropriate material, appropriate transportation, human health, natural ventilation, urban heat island
References
[1] Intergovernmental Panel on Climate Change (IPCC), Summary for Policymakers. Climate Change 2007: The Physical Science Basis, Working Group I Contribution to the Intergovernmental Panel on Climate Change Fourth Assessment Report, eds S. Solomon, D. Qin, M. Manning, Z. Chen, M. Marquis, et al., Cambridge University Press: Cambridge, UK, 2007.[2] Intergovernmental Panel on Climate Change (IPCC), potential impacts of climate change: human settlements; energy, transport and industrial sectors; human health; air quality and changes in ultraviolet-B radiation. Working Group II Contribution to the Intergovernmental Panel on Climate Change (A. Izrael, chair,. Geneva WMO/UNEP), p. 34, 1990.[3] Emmanuel, M.R., An Urban Approach to Climate-Sensitive Design; Strategies for the Tropics, Spon Press: London, 2005.[4] Santamouris, M., Energy and Climate in the Urban Built Environment, James & James Publication: London, 2001.[5] Oke, T.R., Boundary Layer Climates, 2nd edn, Methuen and Co. Ltd.: New York, 1987.[6] Oke, T.R., Canyon geometry and the nocturnal urban heat island: comparison of scale model and field observations. Journal of Climatology, 1, pp. 237–254, 1981. doi:10.1002/ joc.3370010304[7] Habibi, S.M. & Hourcade, B., Atlas of Tehran Metropolis, Pardazesh va Barnamerizi-e Shahri Publications: Tehran, Iran, 2005.[8] Bahrainy, H., Application of meteorology of air pollution in urban design of the city of Tehran. Journal of Environmental Studies: Scientific Report Series of Environment, 22(18), pp. 17–31, 1997.[9] Alijani, B. & Safavi, S.Y., Study geographical factors in Tehran air pollution. Geographical Studies Journal, 58, pp. 99–112, 2007.[10] Madanipour, A., Tehran: the Making of a Metropolis, John Wily & Sons: England, 1998.[11] Hastaie, P., Air Pollution Countermeasures in Tehran, http://www.worldbank.org/html/fpd/ transport/utsr/budapest/background/tehran.pdf, 2004.[12] Peterson, J.T., The climate of cities: a survey of recent literature. Climate in Review, ed. G. McBoyle, pp. 264–285, 1973.[13] Alexandri, E. & Jones, P., Sustainable urban future in southern Europe – what about the heat island effect? European Regional Science Association Conference Papers, Vienna, Austria, 2006.[14] Givoni, B., Climate Considerations in Building and Urban Design, John Wiley & Sons: Canada, 1998.[15] Sepehri, J. & Zarei, P., Sport and heat island phenomenon in cities. Proc. of the 1st National Conf. on City and Sport, Tehran, Iran, 2007.[16] Lee, D.O., Urban climates. Progress in Physical Geography, 8(4), pp. 1–31, 1984. doi:10.1177/030913338400800101[17] Hardy, J.T., Climate Change: Causes, Effects, and Solutions, John Wiley & Sons: England, 2003.[18] Wong, N.H. & Chen, Y., Tropical Urban Heat Islands: Climate, Buildings and Greenery, Taylor & Francis Press: London and New York, 2009.[19] World Health Organization (WHO), Heat-waves: risks and responses. Health and Global Environmental Change (Series, No. 2). Geneva: German Weather Service (DWD). London School of Hygiene and Tropical Medicine and WHO/Europe, 2004.[20] Makie, T., Harada, M., Kinukawa, N., Toyoshiba, H., Yamanaka, T. et al., Association of meteorological and day-of-the-week factors with emergency hospital admissions in Fukuoka, Japan. International Journal of Biometeorology, 46(1), pp. 38–41, 2002. doi:10.1007/s00484001-0110-2[21] Hajat, S., Armstrong, B., Gouveia, N. & Wilkinson, P., Comparison of mortality displacement of heat-related deaths in Delhi, Sao Paulo and London. Epidemiology Journal, 15(4), p. 94, 2004.[22] Appelhans, T. et al., Mesoscale controls on particulate matter pollution for a mega-city in a semi-arid mountainous environment: Tehran, Iran. Proc. of the 13th Int. Conf. on Mountain Meteorology & 17th Int. Conf. on Applied Climatology, Canada, 2008.[23] Shafie-Pour, M. & Ardestani, M., Environmental damage costs in Iran by the energy sector. Energy Policy, 35, pp. 4413–4423, 2007. doi:10.1016/j.enpol.2007.03.008[24] Sailor, D.J., Sensitivity of coastal meteorology and air quality to urban surface characteristics, Preprints of the Eighth Joint Conference on the Applications of Air Pollution Meteorology on American Meteorological Society, vol. 8, Boston, MA, pp. 286–293, 1994.[25] Akbari, H., Bretz, S., Kurn, D.M. & Hanford, J., Peak power and cooling energy savings of high-albedo roofs. Energy and Buildings, 25, pp. 117–126, 1997. doi:10.1016/S0378-7788-(96)01001-8[26] Taha, H., Urban climates and heat islands: albedo, evapotranspiration, and anthropogenic heat. Energy and Buildings, 25, pp. 99–103, 1997. doi:10.1016/S0378-7788(96)00999-1[27] Konopacki, S., Gartland, L., Akbari, H. & Rainer, L., Demonstration of Energy Savings of Cool Roofs. A Report Prepared for the U.S. Environmental Protection Agency, Heat Island Project, University of California, Berkeley, 1998.[28] Wong, N.H., A Study of the Urban Heat Island in Singapore. A Report of Heat Island Project, National University of Singapore, 2002.
| https://iieta.org/journals/ijsdp/paper/10.2495/SDP-V5-N4-351-366 |
1957 Chevrolet Bel Air Sedan 2400 specifications, technical data, performance
1957 Chevrolet Bel Air Sedan - full technical specs sheet, including performance data, economy and emissions, dimensions, weight and engine particulars.
Chevrolet Bel Air Sedan, 1957 MY 2400 2402; 1011D
Bel Air, 2400
Chevrolet Bel Air Sedan is an automobile that has a 2 door saloon (sedan) type body with a front located engine driving through the rear wheels.
The Bel Air Sedan forms part of Chevrolet's 2400 family of cars.
Its 4.3 litre engine is a naturally aspirated, overhead valve, 8 cylinder unit that develops 162 bhp (164 PS/121 kW) of power at 4200 rpm, and maximum torque of 348 N·m (257 lb·ft/35.5 kgm) at 2400 rpm.
The engine supplies its power through to the wheels via a 3 speed manual with overdrive transmission. Full specs
Key facts
<table><tbody><tr><th> What body style?</th><td> 2 door sedan/saloon with 4/5 seats</td></tr><tr><th> How long?</th><td> 5080 mm</td></tr><tr><th> What drivetrain?</th><td> naturally aspirated petrol</td></tr><tr><th> What size engine?</th><td> 4.3 litre, 4344 cm 3</td></tr><tr><th> How many cylinders?</th><td> 8, V</td></tr><tr><th> How much power?</th><td> 164 PS/ 162 bhp/ 121 kW@ 4200 rpm</td></tr><tr><th> How much torque?</th><td> 348 Nm/ 257 ft.lb/ 35.5 kgm@ 2400 rpm</td></tr></tbody></table>
1957 Chevrolet Bel Air Sedan
Chevrolet auto insurance tips
Some car insurance will be cheaper if you take a per-usage option, sometimes called pay-per-mile. You need to factor in your driving patterns before opting for pay-as-you-go auto insurance.
<table> 1957 Chevrolet Bel Air Sedan dati<tbody><tr><td> Language Français Deutsch Nederlands Italiano Español English</td><td colspan=3></td></tr><tr><th colspan=4>Carozzerie</th></tr><tr><th> Carrozzeria</th><td colspan=2> 4/5 seater sedan/saloon</td></tr><tr><th> Numero di porte</th><td colspan=2> 2</td></tr><tr><th> Disegno di</th><td colspan=2></td></tr><tr><th colspan=4>Dimensioni e masse</th></tr><tr><th> Passo</th><td> 2921</td><td> 115</td></tr><tr><th> Carreggiata anteriore</th><td> 1473</td><td> 58</td></tr><tr><th> Carreggiata posteriore</th><td> 1494</td><td> 58.8</td></tr><tr><th> Lunghezza</th><td> 5080</td><td> 200</td></tr><tr><th> Larghezza</th><td> 1876</td><td> 73.9</td></tr><tr><th> Altezza</th><td> 1521</td><td> 59.9</td></tr><tr><th> Altezza minima de terra</th><td></td><td></td></tr><tr><th></th><td> 1.74</td><td colspan=2></td></tr><tr><th> Massa veicolo in ordine di marcia</th><td></td><td></td></tr><tr><th> Ripartizione anteriore</th><td colspan=2></td></tr><tr><th> Capacita serbatoio carburante</th><td> 60.6 litres</td><td> 13.3 [16] UK [US] gal.</td></tr><tr><th colspan=3>Aerodinamica</th></tr><tr><th> Coefficiente di resistenza</th><td colspan=2></td></tr><tr><th> area frontale</th><td colspan=2></td></tr><tr><th> CdA</th><td colspan=2></td></tr><tr><th colspan=3>Propulsore</th></tr><tr><th></th><td colspan=2> naturally aspirated petrol</td></tr><tr><th> Costruttore del motore</th><td colspan=2> GM</td></tr><tr><th> Tipo</th><td colspan=2></td></tr><tr><th> Numero dei cilindri</th><td colspan=2> V 8in 90° vee</td></tr><tr><th> Cilindrata</th><td colspan=2> 4.3 litre
4344 cc
(265.087 cu in)</td></tr><tr><th> Alesaggio × Corsa</th><td colspan=2> 95.25 × 76.2 mm
3.75 × 3 in</td></tr><tr><th> Rapporto di alesaggio/corsa</th><td colspan=2> 1.25</td></tr><tr><th> Distribuzione</th><td colspan=2> overhead valve(OHV)
2 Valvole per cilindro
16 Valvole Totale</td></tr><tr><th> Potenza max
(gross)</th><td colspan=2> 164 PS(162 bhp) (121 kW)
a 4200 giri/min</td></tr><tr><th> Coppia max
(gross)</th><td colspan=2> 348 Nm(257 ft·lb) (35.5 kgm)
a 2400 giri/min</td></tr><tr><th> Specific output
(gross)</th><td colspan=2> 27.8 kW/litre
37.8 ps/litre
37.3 bhp/litre
0.61 bhp/cu in</td></tr><tr><th>
(gross)</th><td colspan=2> 80.11 Nm/litre
0.97 ft·lb/cu 3</td></tr><tr><th> Engine construction</th><td colspan=2></td></tr><tr><th> Carter</th><td colspan=2> Carter umido</td></tr><tr><th> Rapporto di compressione</th><td colspan=2> 8:1</td></tr><tr><th> Alimentazione</th><td colspan=2> 1 Rochester 7010647 carburettor</td></tr><tr><th></th><td colspan=2> 1006.7 kPa(146 psi)</td></tr><tr><th> Regime massimi</th><td colspan=2></td></tr><tr><th> Numero supporti di banco</th><td colspan=2> 5</td></tr><tr><th> Raffreddamento</th><td colspan=2> Water</td></tr><tr><th> cilindrata unitaria</th><td colspan=2> 543 cc</td></tr><tr><th> Alimentazione</th><td colspan=2> Normal</td></tr><tr><th> Compressore</th><td colspan=2> N/A</td></tr><tr><th> Intercooler</th><td colspan=2> None</td></tr><tr><th> Catalizzatore</th><td colspan=2> N</td></tr><tr><th colspan=3>Prestazioni</th></tr><tr><th> 0-80km/h</th><td colspan=2></td></tr><tr><th> 0-60mph</th><td colspan=2></td></tr><tr><th> 0-100km/h</th><td colspan=2></td></tr><tr><th> 0-160km/h</th><td colspan=2></td></tr><tr><th> 0-400m</th><td colspan=2></td></tr><tr><th> 0-1000m</th><td colspan=2></td></tr><tr><th> Velocità max.</th><td colspan=2></td></tr><tr><th> Power-to-weight ratio</th><td colspan=2></td></tr><tr><th> Weight-to-power ratio</th><td colspan=2></td></tr><tr><th colspan=3>Consumi/Emissioni</th></tr><tr><th> Consumo</th><td colspan=2></td></tr><tr><th colspan=3> universal fuel consumption (calculated from the above)</th></tr><tr><th> litres/100km</th><td colspan=2></td></tr><tr><th> km/litre</th><td colspan=2></td></tr><tr><th> UK MPG</th><td colspan=2></td></tr><tr><th> US MPG</th><td colspan=2></td></tr><tr><th rowspan=2> Emissioni di CO2</th><td colspan=2></td></tr><tr><td colspan=2></td></tr><tr><th> Carfolio Calculated CO 2 ?</th><td colspan=2></td></tr><tr><th> VED band (UK)</th><td colspan=3></td></tr><tr><th> CO 2Effizienz (DE)</th><td colspan=3></td></tr><tr><th colspan=4>Autotelaio</th></tr><tr><th> Posizione del motore</th><td colspan=3> front</td></tr><tr><th> Engine layout</th><td colspan=3> longitudinal</td></tr><tr><th> Trazione</th><td colspan=3> rear wheel drive</td></tr><tr><th> Distribuzione di coppia</th><td colspan=3> N/A</td></tr><tr><th> Sterzo</th><td colspan=3></td></tr><tr><th> turns lock-to-lock</th><td colspan=3></td></tr><tr><th> diametro di sterzata</th><td colspan=3></td></tr><tr><th> Avantreno</th><td colspan=3></td></tr><tr><th> Retroreno</th><td colspan=3></td></tr><tr><th> Cerchi anteriori</th><td colspan=3> 5J x 14</td></tr><tr><th> Cerchi posteriori</th><td colspan=3> 5J x 14</td></tr><tr><th> Pneumatici anteriori</th><td colspan=3> 7.50-14</td></tr><tr><th> Pneumatici posteriori</th><td colspan=3> 7.50-14</td></tr><tr><th> Freni ant/post</th><td colspan=3> Dr/Dr</td></tr><tr><th> Diametro di freni anteriori</th><td colspan=3> 279 mm</td></tr><tr><th> Diametro di freni posteriori</th><td colspan=3> 279 mm</td></tr><tr><th> Braked area</th><td colspan=3></td></tr><tr><th> Trasmissione</th><td colspan=3> 3</td></tr><tr><th> Inizio rapporto di cambio</th><td colspan=3> 0.7</td></tr><tr><th> Rapporto finale</th><td colspan=3> 4.11</td></tr><tr><th colspan=4>Generalità</th></tr><tr><th> Carfolio.com ID</th><td colspan=3> 308286</td></tr><tr><th> Production total</th><td colspan=3></td></tr><tr><th> Codice di modello</th><td colspan=3> 2402; 1011D</td></tr><tr><th> Codice di serie</th><td colspan=3> 2400</td></tr><tr><th> RACrating</th><td colspan=3> 45.0</td></tr><tr><th> Insurance classification</th><td colspan=3> No information available</td></tr><tr><th> Tax band</th><td colspan=3> No information available</td></tr><tr><td colspan=4> 1957 Chevrolet Bel Air Sedanadded 2013-02-06.
Last modified 2020-02-02.
</td></tr></tbody></table>
1956 Dodge Kingsway D61X-2
4 door sedan/saloon FR 3M 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW 1490 kg
1956 Dodge Kingsway D61X-2
4 door sedan/saloon FR 3OD 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Cabriolet D61X-2
2 door convertible/cabriolet FR 3OD 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Cabriolet D61X-2
2 door convertible/cabriolet FR 3M 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Cabriolet PowerFlite D61X-2
2 door convertible/cabriolet FR 2A 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Custom D61X-3
4 door sedan/saloon FR 3OD 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Custom D61X-3
4 door sedan/saloon FR 3M 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW 1490 kg
1956 Dodge Kingsway Custom Cabriolet D61X-3
2 door convertible/cabriolet FR 3M 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Custom Cabriolet D61X-3
2 door convertible/cabriolet FR 3OD 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Custom Cabriolet PowerFlite D61X-3
2 door convertible/cabriolet FR 2A 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Custom Hardtop D61X-3
4 door sedan/saloon FR 3OD 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Custom Hardtop D61X-3
4 door sedan/saloon FR 3M 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW 1490 kg
1956 Dodge Kingsway Custom Hardtop PowerFlite D61X-3
4 door sedan/saloon FR 2A 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Custom PowerFlite D61X-3
4 door sedan/saloon FR 2A 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Hardtop D61X-2
4 door sedan/saloon FR 3OD 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway Hardtop D61X-2
4 door sedan/saloon FR 3M 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW 1490 kg
1956 Dodge Kingsway Hardtop PowerFlite D61X-2
4 door sedan/saloon FR 2A 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1956 Dodge Kingsway PowerFlite D61X-2
4 door sedan/saloon FR 2A 3975 cm 3/242.6 cuin 160 PS158 bhp118 kW
1958 Dodge Kingsway TorqueFlite
4 door sedan/saloon FR 3A 3982 cm 3/243.0 cuin 167 PS165 bhp123 kW 1575 kg
1955 Ford V-8 Customline Fordor Sedan
4 door sedan/saloon FR 3OD 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Customline Fordor Sedan
4 door sedan/saloon FR 3M 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Customline Fordor Sedan Fordomatic
4 door sedan/saloon FR 3A 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Customline Tudor Sedan
2 door sedan/saloon FR 3M 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Customline Tudor Sedan
2 door sedan/saloon FR 3OD 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Customline Tudor Sedan Fordomatic
2 door sedan/saloon FR 3A 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Club Sedan
2 door sedan/saloon FR 3M 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Club Sedan
2 door sedan/saloon FR 3OD 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Club Sedan Fordomatic
2 door sedan/saloon FR 3A 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Crown Victoria
2 door fixed-head coupé FR 3M 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Crown Victoria
2 door fixed-head coupé FR 3OD 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Crown Victoria Fordomatic
2 door fixed-head coupé FR 3A 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Sunliner
2 door convertible/cabriolet FR 3M 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Sunliner
2 door convertible/cabriolet FR 3OD 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Sunliner Fordomatic
2 door convertible/cabriolet FR 3A 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Town Sedan
4 door sedan/saloon FR 3OD 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Town Sedan
4 door sedan/saloon FR 3M 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Town Sedan Fordomatic
4 door sedan/saloon FR 3A 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Victoria
2 door sedan/saloon FR 3OD 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Victoria
2 door sedan/saloon FR 3M 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Fairlane Victoria Fordomatic
2 door sedan/saloon FR 3A 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Mainline Fordor Sedan
4 door sedan/saloon FR 3OD 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Mainline Fordor Sedan
4 door sedan/saloon FR 3M 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Mainline Fordor Sedan Fordomatic
4 door sedan/saloon FR 3A 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Mainline Tudor Business Sedan
2 door sedan/saloon FR 3M 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Mainline Tudor Business Sedan
2 door sedan/saloon FR 3OD 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Mainline Tudor Business Sedan Fordomatic
2 door sedan/saloon FR 3A 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Mainline Tudor Sedan
2 door sedan/saloon FR 3OD 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Mainline Tudor Sedan
2 door sedan/saloon FR 3M 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Ford V-8 Mainline Tudor Sedan Fordomatic
2 door sedan/saloon FR 3A 4452 cm 3/271.7 cuin 164 PS162 bhp121 kW
1955 Hudson Hornet Custom 6 35560 G-6
4 door sedan/saloon FR 3M 5047 cm 3/308.0 cuin 172 PS170 bhp127 kW
1955 Hudson Hornet Custom 6 35560 G-6
4 door sedan/saloon FR 3M 5047 cm 3/308.0 cuin 162 PS160 bhp119 kW
1955 Hudson Hornet Custom 6 35560 G-6
4 door sedan/saloon FR 3OD 5047 cm 3/308.0 cuin 162 PS160 bhp119 kW
1955 Hudson Hornet Custom 6 35560 G-6
4 door sedan/saloon FR 3OD 5047 cm 3/308.0 cuin 172 PS170 bhp127 kW
1955 Hudson Hornet Custom 6 Automatic 35560 G-6
4 door sedan/saloon FR 4A 5047 cm 3/308.0 cuin 172 PS170 bhp127 kW
1955 Hudson Hornet Custom 6 Automatic 35560 G-6
4 door sedan/saloon FR 4A 5047 cm 3/308.0 cuin 162 PS160 bhp119 kW
1955 Hudson Hornet Custom 6 Hollywood Hardtop 35560 J-6
2 door fixed-head coupé FR 3OD 5047 cm 3/308.0 cuin 162 PS160 bhp119 kW
1955 Hudson Hornet Custom 6 Hollywood Hardtop 35560 J-6
2 door fixed-head coupé FR 3M 5047 cm 3/308.0 cuin 162 PS160 bhp119 kW
1955 Hudson Hornet Custom 6 Hollywood Hardtop 35560 J-6
2 door fixed-head coupé FR 3OD 5047 cm 3/308.0 cuin 172 PS170 bhp127 kW
1955 Hudson Hornet Custom 6 Hollywood Hardtop 35560 J-6
2 door fixed-head coupé FR 3M 5047 cm 3/308.0 cuin 172 PS170 bhp127 kW
1955 Hudson Hornet Custom 6 Hollywood Hardtop Automatic 35560 J-6
2 door fixed-head coupé FR 4A 5047 cm 3/308.0 cuin 172 PS170 bhp127 kW
1955 Hudson Hornet Custom 6 Hollywood Hardtop Automatic 35560 J-6
2 door fixed-head coupé FR 4A 5047 cm 3/308.0 cuin 162 PS160 bhp119 kW
1955 Hudson Hornet Super 6 35560 G-6
4 door sedan/saloon FR 3M 5047 cm 3/308.0 cuin 162 PS160 bhp119 kW
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Horseshoes chaos and its passive control in dissipative nonlinear chemical dynamics | Request PDF
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Horseshoes chaos and its passive control in dissipative nonlinear chemical dynamics
<here is a image 7cdae89b06dc1c1a-d9d5b94e9f44341b>
August 2018
Physica Scripta93(8)
DOI: 10.1088/1402-4896/aacef0
Authors:
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Dagbégnon Luc Olabode
<here is a image c093f60c31fe9333-fda4a78192eccd55>
clément Miwadinou
Institute of Mathematics and Physics
<here is a image 848b4dd3c4b06256-298082f360573c5e>
Vincent A. Monwanou
Institute of Mathematics and Physics
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Jean Bio Chabi Orou
Institute of Mathematics and Physics
Abstract and Figures
This work deals with the passive control of horseshoes chaos in dissipative nonlinear chemical oscillations which concentration dynamics are governed by a forced modified Van der Pol-Duffing oscillator. We considered the dynamics of nonlinear chemical systems subjected to fluctuating hydrodynamic drag forces. The influences of the such parameter of the control force on the depth of asymmetric double well potential are analyzed. The Melnikov method is utilized to analytically determine the domains boundaries where horseshoes chaos appears in chemical oscillations. The effects of the constraint parameter β and of the control parameters in the all directions of passive control force are analyzed. Results of analytical investigations are validated and complemented by numerical simulations for draw the fractal basin of attraction and the efficiency of the control force is discussed.
<here is a image 33c113f0f3e1b463-e5d7afad0173c7f5>
Effect of β on the well of asymmetric potential V(ζ) with the parametersϵ = 0, α = −0.5, and γ = 0.05. …
<here is a image f5724c75917c343b-4ab80bf271064749>
Effect of (a) β, (b) K and (c) U on the well of asymmetric potential V(ζ) with the parameters ϵ = −1, β = 0.05, K = 0.01, U = 0.05, α = −0.5, and γ = 0.05. …
<here is a image 5675fc6ef5db4f0c-49426b65b64fbfd4>
Effect of the direction parameter of control force ϵ on Melnikov criterion for chaotic motions with the parameters μ = 0.0001, α = −0.5, γ = 0.05, β = 0.05, K = 0.01 and U = 0.05. …
<here is a image 6075dbbc068a7194-4dbbcf28520fa09e>
Effect of the parameters (a) β, (b) K and (c) U on Melnikov criterion for chaotic motions with the parameters μ = 0.0001, α = −0.5, γ = 0.05, β = 0.05, ϵ = −1, K = 0.01 and U = 0.05. …
<here is a image 62f54b906544210a-286ab1ea5c06fc49>
+5
Effect of the parameters (a), (b) β, (c) K and (d), (e) U on Melnikov criterion for chaotic motions with the parameters μ = 0.0001, α = −0.5, γ = 0.05, β = 0.05, ϵ = +1, K = 0.01 and U = 0.05. …
Figures - available from: Physica Scripta
<here is a image 175d1bd4b7439d95-754927124da715c1>
<here is a image 7cdae89b06dc1c1a-d9d5b94e9f44341b>
A preview of this full-text is provided by IOP Publishing.
Horseshoes chaos and its passive control in
dissipative nonlinear chemical dynamics
D L Olabodé
1
, C H Miwadinou
1 ,2
, A V Monwanou
1
and J B Chabi Orou
1
1
Laboratoire de Mécanique des Fluides, de la Dynamique Nonlinéaire et de la Modélisation des Systèmes
Biologiques ( LMFDNMSB ) , Institut de Mathématiques et de Sciences Physiques, Porto-Novo, Bénin
2
Département de Physique, ENS-Natitingou, ( UNSTIM ) -Abomey, Bénin
E-mail: clement.miwadinou@imsp-uac.org and hodevewan@yahoo.fr
Received 26 March 2018, revised 16 May 2018
Accepted for publication 25 June 2018
Published 11 July 2018
Abstract
This work deals with the passive control of horseshoes chaos in dissipative nonlinear chemical
oscillations which concentration dynamics are governed by a forced modi fi ed Van der Pol –
Duf fi ng oscillator. We considered the dynamics of nonlinear chemical systems subjected to
fl uctuating hydrodynamic drag forces. The infl uences of the such parameter of the control force
on the depth of asymmetric double well potential are analyzed. The Melnikov method is utilized
to analytically determine the domains boundaries where horseshoes chaos appears in chemical
oscillations. The effects of the constraint parameter β and of the control parameters in the all
directions of passive control force are analyzed. Results of analytical investigations are validated
and complemented by numerical simulations for draw the fractal basin of attraction and the
ef fi ciency of the control force is discussed.
Keywords: forced modi fi ed Van der Pol – Duf fi ng oscillator, nonlinear dissipative chemical
dynamics, passive control of horseshoes chaos, Melnikov ’ s method, basin of attraction
( Some fi gures may appear in colour only in the online journal)
1. Introduction
Nonlinear dynamic phenomena are of great interest in several
fi elds such as physics, mathematics, chemistry, biochemistry,
economics and fi nance, epidemiology, engineering, etc [ 1 –3 ].
A major theme from both academic and industrial persperc-
tives and touching many areas, such as hydrodynamic, aero-
space, biophysics and biochemistry technologies and other is
the analysis of nonlinear dynamic systems. This analysis is
based on the modeling which seems very dif fi cult because of
the complexity of the nonlinear systems. Chaos, since its
discovery in the 20th century, has been one of the most
interesting behaviors discovered in nonlinear dynamic sys-
tems [ 4 –6 ] . Depending on the fi eld of study, chaos is some-
times useful or undesirable, which is why many researchers
are interested in its prediction and / or control. In engineering
for example, it is on the one hand, used to encode information
or to encrypt images [ 7 ] and on the other hand, avoids in the
construction of large infrastructure. It is also noted that, in the
last few decades, despite the many theoretical advances
observed in the nature of chemical oscillations, the only
known chemical oscillators were either of biological origin,
such as the glycolytic systems and oxidase-peroxidase sys-
tems; discovered accidentally, like the Bray and BZ reactions;
or variants of those reactions [ 4 , 8 – 10 ] . Several studies have
shown that the modeling of the dynamics of complex systems
in physics, chemistry, biochemistry, electronics, engineering
and many others leads very often to nonlinear oscillator
equations. However, the most important factors favoring
chaos in a dynamic system being nonlinearity and sensivity to
initial conditions, it should be noted that these known non-
linear dynamic chemical systems have a strong chance of
developing chaotic and strong instabilities behaviors. This is
the case with the chaotic behavior obtained by several
researchers during the analysis of certain chemical reactions
on BZ reactions [ 11 – 14 ] . Most recently, some investigations
have identi fi ed not only period doublings for the route to
chaos but also periodic orbits in chaotic attractors in BZ
chemical reactions [ 15 – 18 ] including chlorite-thiosulfate
reaction and cobalt / manganese / bromide-catalyzed autoxida-
tions of p-xylene and cyclohexanone [ 15 – 20 ] . Through these
examples, it is therefore obvious that rich dynamics and chaos
Physica Scripta
Phys. Scr. 93 ( 2018 ) 085203 (12pp ) https: //doi.org /10.1088 /1402-4896 /aacef0
0031-8949 /18 /085203 + 12$33.00© 2018 IOP Publishing LtdPrinted in the UK1
... Recent studies have used the passive method to control chaotic behavior. For example, Olabodé et al.
[21]
used the passive control technique to suppress the instabilities occurring during regular and chaotic oscillatory states of plasma. These authors have shown that the oscillatory states being sources of instability of the plasma, a passive control technique would be appropriate to regulate both the chaotic oscillations and the high amplitude of the oscillations which can occur respectively in chaotic and non-chaotic states. ...
... It belongs to a category of nonlinear chemical reactions well developed in the scientific literature. We made this choice because it has already been demonstrated that a modified Van der Pol-Duffing oscillator can be used to model the nonlinear chemical oscillations like BZ reactions
[21]
[22][23][24][25][26]. Since the control of regular and irregular motions is an interesting issue in several areas [27], the dynamical behavior of a forced generalized Rayleigh oscillator, which constitutes a new model for describing the nonlinear chemical oscillations, may be investigated. ...
... The generic model for nonlinear oscillations used in this study is based on the kinetic scheme which given by the following chain of equations
[21,
22,28,29]: ...
Dynamics and active control of chemical oscillations modeled as a forced generalized Rayleigh oscillator with asymmetric potential
Article
Aug 2021
ADECHINAN Adébiyi Joseph
<here is a image 4f7e228da5efd980-bf8de14e81dd3970> Y. J. Fernando Kpomahou
Miwadinou H. Clément
Hinvi A. laurent
This paper focuses on the dynamics and active control of chemical oscillations governed by a forced generalized Rayleigh oscillator. The Melnikov method is used to analytically determine the critical parameters for the onset of chaotic motions. The analytical results are confirmed by numerical simulations. The bifurcation structures obtained show that the model displays a rich variety of dynamical behaviors and remarkable routes to chaos. The effects of the control gain parameters on the behavior of the system are analyzed and the results obtained have shown the control efficiency.
... To that end, various analytical methods and numerical tools have been proposed and successfully used in study of nonlinear dynamics of oscillatory systems [4][5][6][7][8][9][10]. Recently, nonlinear chemical oscillations have received attention of many researchers from theoretical and experimental point of view [11][12][13][14][15][16][17][18][19][20][21]
[22]
[23][24][25][26][27]. ...
... e dynamics of the nonautonomous chemical system showed various routes to chaos. Olabodé et al.
[22]
used the Melnikov method and derived analytically the domains boundaries where horseshoe chaos appears in chemical oscillations. ey afterward controlled chaotic oscillations by subjecting the nonlinear chemical system to fluctuation hydrodynamic drag forces. ...
... Shabunin et al. [26] modeled chemical reactions by the forced limit-cycle oscillator and studied synchronization phenomena and transition to chaos. e most theoretical studies on nonlinear dissipative chemical systems in general and on Briggs-Rauscher reaction system in particular have been performed with periodically external excitation [20,
22,
23,27]. However, the aspects of nonlinear dynamics of Briggs-Rauscher reaction system under the influence of the parametric and two external periodic excitations have not been yet studied. ...
Chaotic Behaviors and Coexisting Attractors in a New Nonlinear Dissipative Parametric Chemical Oscillator
Full-text available
Mar 2022
COMPLEXITY
<here is a image 4f7e228da5efd980-bf8de14e81dd3970> Y. J. Fernando Kpomahou
<here is a image 9c3113e7b15826b7-70489589524dce6b> Adomou Alain
<here is a image 74be9ab634cc263d-61f9e87906dd64db> Joseph Adechinan
<here is a image f2ec3f79ed977ab7-0729d530d2823f61> Irénée Vianou Madogni
In this study, complex dynamics of Briggs–Rauscher reaction system is investigated analytically and numerically. First, the Briggs–Rauscher reaction system is reduced into a new nonlinear parametric oscillator. The Melnikov method is used to derive the condition of the appearance of horseshoe chaos in the cases ω = Ω and ω ≠ Ω . The performed numerical simulations confirm the obtained analytical predictions. Second, the prediction of coexisting attractors is investigated by solving numerically the new nonlinear parametric ordinary differential equation via the fourth-order Runge–Kutta algorithm. As results, it is found that the new nonlinear chemical system displays various coexisting behaviors of symmetric and asymmetric attractors. In addition, the system presents a rich variety of bifurcations phenomena such as symmetry breaking, symmetry restoring, period doubling, reverse period doubling, period-m bubbles, reverse period-m bubbles, intermittency, and antimonotonicity. On the contrary, emerging chaotic band attractors and period-1, period-3, period-9, and period-m bubbles routes to chaos occur in this system.
... Recent studies have used the passive method to control chaotic behavior. For example, Olabodé et al.
[21]
used the passive control technique to suppress the instabilities occurring during regular and chaotic oscillatory states of plasma. These authors have shown that the oscillatory states being sources of instability of the plasma, a passive control technique would be appropriate to regulate both the chaotic oscillations and the high amplitude of the oscillations which can occur respectively in chaotic and non-chaotic states. ...
... It belongs to a category of nonlinear chemical reactions well developed in the scientific literature. We made this choice because it has already been demonstrated that a modified Van der Pol-Duffing oscillator can be used to model the nonlinear chemical oscillations like BZ reactions
[21]
[22][23][24][25][26]. Since the control of regular and irregular motions is an interesting issue in several areas [27], the dynamical behavior of a forced generalized Rayleigh oscillator, which constitutes a new model for describing the nonlinear chemical oscillations, may be investigated. ...
... The generic model for nonlinear oscillations used in this study is based on the kinetic scheme which given by the following chain of equations
[21,
22,28,29]: ...
International Journal of Basic and Applied Sciences Dynamics and active control of chemical oscillations modeled as a forced generalized Rayleigh oscillator with asymmetric potential
Full-text available
Aug 2021
<here is a image 74be9ab634cc263d-61f9e87906dd64db> Joseph Adechinan
<here is a image 4f7e228da5efd980-bf8de14e81dd3970> Y. J. Fernando Kpomahou
<here is a image c093f60c31fe9333-fda4a78192eccd55> clément Miwadinou
<here is a image 58828ce9b807f012-7197741e7978fda3> Lambert Cloud. Hinvi
This paper focuses on the dynamics and active control of chemical oscillations governed by a forced generalized Rayleigh oscillator. The Melnikov method is used to analytically determine the critical parameters for the onset of chaotic motions. The analytical results are confirmed by numerical simulations. The bifurcation structures obtained show that the model displays a rich variety of dynamical behaviors and remarkable routes to chaos. The effects of the control gain parameters on the behavior of the system are analyzed and the results obtained have shown the control efficiency.
... The control of undesirable oscillations remains up to now an important activity in many areas of science and engineering in order to ensure the safety of real dynamical systems. To that end, several studies on chaos control in nonlinear oscillatory systems have been performed, viz different control methods [Chacon, 2006;
Olabodé et al., 2018
Olabodé et al., , 2019Liu & Yamaura, 2012;Yamapi et al., 2007;Adéchinan et al., 2022]. Although chaos can be an undesirable phenomenon, it has large practical applications in science but also in engineering and technology. ...
Influence of Amplitude-Modulated Force and Nonlinear Dissipation on Chaotic Motions in a Parametrically Excited Hybrid Rayleigh–Van der Pol–Duffing Oscillator
Mar 2023
INT J BIFURCAT CHAOS
<here is a image 4f7e228da5efd980-bf8de14e81dd3970> Y. J. Fernando Kpomahou
K. J. Agbélélé
N. B. Tokpohozin
<here is a image badf8cabf197856b-2bc9aaa7e2ece808> Arnaud Edouard Yamadjako
The generation and evolution of chaotic motions in a hybrid Rayleigh–Van der Pol–Duffing oscillator driven by parametric and amplitude-modulated excitation forces are investigated analytically and numerically. By using the Melnikov method, the conditions for the appearance of horseshoe chaos in our system are derived in the case where the modulation frequency [Formula: see text] and the forcing frequency [Formula: see text] are the same [Formula: see text]. The obtained results show that the chaotic region decreases and increases in certain ranges of frequency. The numerical simulations based on the basin of attraction of initial conditions validate the obtained analytical predictions. It is also found that in the case where [Formula: see text] is irrational, the increase of amplitude-modulated force accentuates the fractality of the basin of attraction. The global dynamical changes of our model are numerically examined. It is found that our model displays a rich variety of bifurcation phenomena and remarkable routes to chaos. In addition, the presence of the hybrid Rayleigh–Van der Pol damping force reduces the chaotic domain in the absence of amplitude-modulated force. But when the amplitude-modulated force acts on the system, the chaotic oscillations decrease and disappear. Further, the geometric shape of the chaotic attractors considerably decreases in the presence of the amplitude-modulated excitation force. On the other hand, the system presents transient chaos, torus-chaos and torus of different topologies when [Formula: see text] is irrational.
... The purpose is to eliminate the chaotic trajectories and stabilize the system toward one of its equilibrium points. Since OGY (Ott, Grebogi and Yorke) method was introduced (Ott et al. 1990), many effective control methods have been proposed and used for the control of chaotic systems such as linear feedback control (Liu and Liu 2018), time-delayed feedback control (Mahmoud et al. 2017), nonlinear feedback control (Luo et al. 2018), adaptive control (Cheng et al. 2020), sliding mode control (Jang et al. 2002;Yau and Yan 2004;Chang et al. 2008;Ablay 2009;Kocamaz et al. 2014;Alrifai and Zribi 2018;Lin and Zhang 2018;Kızmaz et al. 2019), passive control
(Olabode et al. 2018)
, impulsive control (Rao and Zhong 2020), backstepping design (Njah et al. 2010), neural control (Li 2016) and fuzzy control (Wang and Chen 2019). The sliding mode control is one of the most preferred chaos control methods due to the nature of its robustness. ...
Control of chaotic two-predator one-prey model with single state control signals
Full-text available
J INTELL MANUF
<here is a image f006b42c4799712f-06500a935583f858> Uğur Erkin Kocamaz
Alper Göksu
Harun Taşkın
<here is a image f26c2925cf03edb0-590b15ab0b852c23> Yılmaz Uyaroğlu
In this paper, the complex control dynamics of a predator–prey Lotka–Volterra chaotic system are studied. The main purpose is to control the chaotic trajectories of two-predator one-prey system which was introduced by Samardzija and Greller (Bull Math Biol 50(5):465–491. https://doi.org/10.1007/BF02458847, 1988). Lyapunov based nonlinear control and sliding mode control methods are used. The other purpose of this paper is to present the sliding mode control performances under different sliding surface choices. Based on the sliding mode control and Lyapunov stability theory, four alternative sliding surfaces are constructed to stabilize the chaotic two-predator one-prey model to its zero equilibrium point. The focused control signals realize the control from only one state which provides simplicity in implementation. Numerical simulations are demonstrated to validate the theoretical analyses and compare the effectiveness of proposed controllers for the chaotic Samardzija–Greller system.
... Recently Olabode et al. [1,
2]
studied the van der Pol type equation for nonlinear chemical dynamics. The van der Pol equation was originally derived relating to oscillation problems in physics and electrical engineering by the Dutch physicist Balthasar van der Pol in around 1920 [3]. ...
Numerical verification of the orders of accuracy of truncated asymptotic expansion solutions to the van der Pol equation
<here is a image 6f134f3610eda757-ced688383c842851> Sudi Mungkasi
We propose a numerical method to verify the orders of accuracy of truncated asymptotic expansion solutions to the van der Pol equation. Our proposed method is simpler than an existing method (Deeba and Xie in J Comput Anal Appl 3(2): 165–171, 2001). Our proposed method does not need any technique of a least-squares fit of error data, whereas the existing one does. Numerical simulations confirm that our proposed method works effectively.
Effect of amplitude-modulated force on horseshoe dynamics in Briggs-Rauscher chemical system modeled by a new parametric oscillator with asymmetric potential
<here is a image 4f7e228da5efd980-bf8de14e81dd3970> Y. J. Fernando Kpomahou
<here is a image 9c3113e7b15826b7-70489589524dce6b> Adomou Alain
<here is a image badf8cabf197856b-2bc9aaa7e2ece808> Arnaud Edouard Yamadjako
<here is a image c1a5a72333e4f398-b114a4f9e0a8b0a6> Julien Djossou
In this paper, the effect of amplitude-modulated force on horseshoe dynamics in Briggs–Rauscher chemical system
modeled by a nonlinear parametric asymmetric oscillator is investigated analytically and numerically. By applying Melnikov
method, the homoclinic bifurcation condition of existence of chaotic motion is derived. The domain where appears the horseshoe
chaos decreases when the amplitude-modulated excitation increases. The numerical simulations based on the basin boundaries of
attraction confirm the obtained analytical prediction. In addition, it is found that the increase in amplitude-modulated excitation
provokes the erosion of the basin of attraction and the decrease of the strangeness of the chaotic attractors. It is also found that
the initial conditions affect the fractal geometric shape of the chaotic attractors. The global dynamical changes are numerically
examined by evaluating the effect of amplitude-modulated force on the bifurcation diagrams. The obtained results show that
the amplitude-modulated excitation induces in the system a rich variety of bifurcation phenomena such as symmetry breaking,
symmetry restoring, period-doubling and reverse period-doubling bifurcations, antimonotonicity, intermittency, remerging chaotic
band attractors, period-m bubbles, chaos and remarkable routes to chaos. Moreover, the variation of amplitude-modulated excitation
has a real impact on the geometry of the chaotic attractors. Further, for large amplitude-modulated excitation, the chaotic motion
disappears, and regular behavior takes place in the chemical system. On the other hand, for certain values of the system parameters,
the new chemical system displays transient chaos.
Chaos, coexisting attractors and chaos control in a nonlinear dissipative chemical oscillator
CHINESE J PHYS
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Adebiyi Joseph Adechinan
<here is a image 4f7e228da5efd980-bf8de14e81dd3970> Y. J. Fernando Kpomahou
<here is a image fc5989e937e3bdc2-573c991ece0c235b> L. A. Hinvi
<here is a image c093f60c31fe9333-fda4a78192eccd55> clément Miwadinou
In this paper, chaos, coexisting behaviors of attractors and passive control in a dissipative chemical system modeled by a nonautonomous generalized mixed Rayleigh-Liénard oscillator are investigated. The condition of the appearance of horseshoe chaos is derived using the Melnikov method. The analytical results are confirmed by numerical simulations. The bifurcation mechanisms obtained show that the chemical model displays various bifurcations such as period doubling, period windows, period bubbling, symmetry-breaking, reverse period windows, chaos, chaotic bubbling, intermittency, antimonotonicity. Furthermore, the chemical system exhibits monostability and bistability phenomena as well as the coexisting of attractors and hysteresis phenomenon. It is also found that the system presents remarkable routes to chaos. The effects of control gain parameter on the chaotic behavior of the system are analyzed and the obtained results have shown the control efficiency.
Resonance, chaos and coexistence of attractors in a position dependent mass‐driven Duffing‐type oscillator
Aug 2021
J Kor Phys Soc
<here is a image fc5989e937e3bdc2-573c991ece0c235b> L. A. Hinvi
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Aime A Koukpemedji
<here is a image 848b4dd3c4b06256-298082f360573c5e> Vincent A. Monwanou
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Jean Bio Chabi Orou
This paper addresses the dynamics of a position-dependent mass-driven Duffing-type oscillator (PDM oscillator) subjected to periodic excitation. The approximate equation of the PDM oscillator is considered to analyze the harmonic oscillations and the possible resonance states. The Amplitudes and frequencies of possible resonances are found by using the harmonic balance method and the multiple scales method. The harmonic resonance, primary resonance, order 3, 5 superharmonic resonances and order 3, 5 subharmonic resonances are obtained. The stability conditions for each of these resonances have also been obtained. Chaotic oscillations, multistability, hysteresis, and coexisting attractors have been found using the bifurcation diagram, the Lyapunov exponents, the phase portraits, and the basin of attraction. The effects of the PDM parameter \(\xi \) and of the external excitation have been analyzed. Results obtained by using the approximate equation of the system have been compared to the dynamics obtained with the exact equation of the PDM oscillator. The analytical investigations have been complemented and validated using the numerical simulations.
Nonlinear Dynamics of the Quadratic-Damping Helmholtz Oscillator
COMPLEXITY
<here is a image 30c27cce612f6e08-4d0f6ee9159472bb> Raymond Fangnon
Cyrille Ainamon
<here is a image 848b4dd3c4b06256-298082f360573c5e> Vincent A. Monwanou
J. B. Chabi Orou
In this paper, the Helmholtz equation with quadratic damping themes is used for modeling the dynamics of a simple prey-predator system also called a simple Lotka–Volterra system. From the Helmholtz equation with quadratic damping themes obtained after modeling, the equilibrium points have been found, and their stability has been analyzed. Subsequently, the harmonic oscillations have been studied by the harmonic balance method, and the phenomena of resonance and hysteresis are observed. The primary and secondary resonances have been researched by the multiple-scale method, and the conditions of stability of the amplitudes of oscillations are determined. Chaos is detected analytically by the Melnikov method and numerically using the basin of attraction, the bifurcation diagram, the Lyapunov exponent, the phase portrait, and the Poincaré section. The effects of all the parameters of the system are analyzed in detail, and special emphasis is placed on the new parameters. Through this analysis, the complex phenomena such as hysteresis, bistability, amplitude jump, resonances, and chaos have been obtained. The control of the parameters and the necessary conditions to control the aforementioned phenomena have been found.
Modeling nonlinear dissipative chemical dynamics by a forced modified Van der Pol-Duffing oscillator with asymmetric potential: Chaotic behaviors predictions
Full-text available
Apr 2018
CHINESE J PHYS
<here is a image c093f60c31fe9333-fda4a78192eccd55> clément Miwadinou
<here is a image 848b4dd3c4b06256-298082f360573c5e> Vincent A. Monwanou
<here is a image bdbf1fc04403c481-64814263152fb940> Julien Yovogan
J. B. Chabi Orou
This paper addresses the issues of nonlinear chemical dynamics modeled by a modified Van der Pol-Duffing oscillator with asymmetric potential. The Melnikov method is utilized to analytically determine the domains boundaries where Melnikov’s chaos appears in chemical oscillations. Routes to chaos are investigated through bifurcations structures, Lyapunov exponent, phase portraits and Poincaré section. The effects of parameters in general and in particular the effect of the constraint parameter β which shows the difference between a nonlinear chemical dynamics order two differential equation and ordinary Van der Pol-Duffing equation are analyzed. Results of analytical investigations are validated and complemented by numerical simulations.
Melnikov Chaos in a Modified Rayleigh-Duffing Oscillator with 6 Potential
Aug 2015
INT J BIFURCAT CHAOS
<here is a image c093f60c31fe9333-fda4a78192eccd55> clément Miwadinou
<here is a image 848b4dd3c4b06256-298082f360573c5e> Vincent A. Monwanou
<here is a image 58828ce9b807f012-7197741e7978fda3> Lambert Cloud. Hinvi
J. B. Chabi Orou
The chaotic behavior of the modified Rayleigh-Duffing oscillator with $
\phi^6$ potential and external excitation which modeles ship rolling motions
are investigated both analytically and numerically. Melnikov method is applied
and the conditions for the existence of homoclinic and heteroclinic chaos are
obtained. The effects of nonlinear damping on roll motion of ships are analyzed
in detail. As it is known, nonlinear roll damping is a very important parameter
in estimating ship reponses. The predictions are tested numerical simulations
based on the basin of attraction. We conclude that certains quadratic damping
effects are contrary to cubic damping effect.
Modeling, Stability, Synchronization, and Chaos and Their Applications to Complex Systems
Feb 2014
ABSTR APPL ANAL
<here is a image 1afa237ba1ef7a04-66067e1e4cd92f76> R. Yamapi
<here is a image 092aaab442a3adf8-7d27089f2cfceb9f> Giovanni Filatrella
M. A. Aziz-Alaoui
<here is a image 13065fa46ef7b1ae-e0a44993892fe223> Herve Kadji
Active and passive control of zinc phthalocyanine photodynamics
Sep 2013
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Divya Sharma
<here is a image 15d43088167cabe9-8f4f4e5b7116f6dc> Annemarie Huijser
Janne Savolainen
Jennifer L. Herek
In this work we report on the ultrafast photodynamics of the photosensitizer zinc phthalocyanine (ZnPc) and manipulation thereof. Two approaches are followed: active control via pulse shaping and passive control via strategic manipulation in the periphery of the molecular structure. The objective of both of these control experiments is the same: to enhance the yield of the functional pathway and to minimize loss channels. The aim of the active control experiments is to increase the intersystem crossing yield in ZnPc, which is important for application in photodynamic therapy (PDT). Pulse shaping allowed an improvement in triplet to singlet ratio of 15% as compared to a transform-limited pulse. This effect is ascribed to a control mechanism that utilizes multiphoton pathways to higher-lying states from where intersystem crossing is more likely to occur. The passive control experiments are performed on ZnPc derivatives deposited onto TiO2, serving as a model system of a dye-sensitized solar cell (DSSC). Modification of the anchoring ligand of the molecular structure resulted in an increased rate for electron injection into TiO2 and slower back electron transfer, improving the DSSC efficiency.
Regular and chaotic behaviors of plasma oscillations modeled by a modified Duffing equation
Article
Full-text available
Feb 2008
PHYS SCRIPTA
<here is a image 13065fa46ef7b1ae-e0a44993892fe223> Herve Kadji
J. B. Chabi Orou
<here is a image 6e8395254a7c6f44-4fd6285c9b6f721d> Paul Woafo
The regular and chaotic behavior of plasma oscillations governed by a modified Duffing equation is studied. After establishing that equation and focusing on its quadratic and cubic nonlinearities, the harmonic balance method and the fourth-order Runge–Kutta algorithm are used to derive regular and chaotic motions, respectively. A strong chaotic behavior, exhibited by the system in that event when the system is subjected to an external periodic excitation is reported as the nonlinear quadratic term varies.
Nonlinear Oscillations in Physical Systems
Book
Dec 1986
Chihiro Hayashi
On the dynamics of Rayleigh beams resting on fractional-order viscoelastic Pasternak foundations subjected to moving loads
Article
Dec 2016
CHAOS SOLITON FRACT
<here is a image e1011b5fcf66932e-1755d7bf5779dd6c> Lionel Merveil Anague Tabejieu
<here is a image 30686347f2337b21-b54794049ef01516> B.R. Nana Nbendjo
<here is a image 6e8395254a7c6f44-4fd6285c9b6f721d> Paul Woafo
The standard averaging method is used to provide an analytical explanation on the effects of spacing loads, load velocity, order of the fractional viscoelastic property of shear layer material on the amplitude of the beam. The geometric nonlinearity is taken into account in the model. The analysis shows that, when the moving loads are uniformly distributed upon all the length of the structure, it vibrates the least possible. Moreover, as the order of the derivative increases, the resonant amplitude of the beam vibration decreases. In other hand, by means of Melnikov technique, a necessary condition for onset of horseshoes chaos resulting from heteroclinic bifurcation is derived analytically. We point out the critical weight of moving loads and order of the fractional derivative above which the system becomes unstable.
Chemical chaos in the chlorite-thiosulfate reaction
Article
Apr 1984
<here is a image 8fb49b549f31bc5e-25bd65d0b2d3a536> Jerzy Maselko
<here is a image 38421d1f1ec51549-1a4d3be57d758cca> Irving R Epstein
Sustained aperiodic oscillation, or chemical chaos, has been observed to occur in the reaction between chlorite and thiosulfate at pH 4 in a flow reactor via two different routes. In the first, chaotic behavior is found between successive regions of increasingly complex periodic oscillation as the residence time is increased. The second route occurs only at higher [ClO2⁻]0. At high flow rates, a periodic low frequency oscillation is observed. On decreasing the flow rate, bursts of a second higher frequency oscillation appear, the system becomes quasiperiodic, chaotic and then finally periodic at the higher frequency. Both types of chaos are analyzed in terms of an experimentally determined cubic next amplitude map for the system.
Asymmetric Duffing equation and the appearance of
Article
May 1987
G. Cicogna
<here is a image 91f71b1eb5a00b2a-89f31ed5399295a2> F. Papoff
Apr 2012
Comm Nonlinear Sci Numer Simulat
<here is a image 13065fa46ef7b1ae-e0a44993892fe223> Herve Kadji
<here is a image 30686347f2337b21-b54794049ef01516> B.R. Nana Nbendjo
| https://www.researchgate.net/publication/325985312_Horseshoes_chaos_and_its_passive_control_in_dissipative_nonlinear_chemical_dynamics |
Hooded Grebe | Podiceps gallardoi
Only discovered in 1974 the Hooded Grebe is found in regions across Argentina and they come from the only taxonomic family within the order Podicipediformes
20. Hooded Grebe
Podiceps gallardoi
Overview
About
Only discovered in 1974 the Hooded Grebe is found in regions across Argentina and possibly Chile.
They come from the only taxonomic family within the order Podicipediformes, which date back at least 25-35 million years.
Since it’s discovery, the population has dropped by as much as 95% in some areas and there are thought to be between 800 and 1,000 individuals left – but the population trend now is stable due to active conservation actions. .
Climate change is dramatically impacting these birds. The high elevation lakes, where they breed in the Argentinian summer, are drying up as less and less snow falls during the winter. The grebes feed on the milfoil plant ( Myriophillum sp.) which grows in the lakes, so climate change is causing rapid declines in a key food source. Hooded Grebes also have very low reproductive rates, producing only 1 chick in each breeding season. As a result, they are highly susceptible to predation by the invasive American mink and Kelp Gulls which eat the eggs and the juveniles. The mink can kill large numbers of adults in a day, potentially wiping out entire local populations. In addition, introduced salmonids compete for the grebe’s food and change the structure of the lakes where Hooded Grebes live. These threats are exacerbated by the altered weather conditions caused by climate change.
However, recent conservation action, such as controlling invasive mink, has stabilized the population, and since 2014 the Hooded Grebes reproductive success rate seems to be increasing.
Order: Podicipediformes
Family: Podicipedidae
Population: 800-1000
Trend: stable
Size: 32cm
EDGE Score
EDGE Score: 5.59 (?)
ED Score: 15.67 (?)
GE / IUCN Red List (?)
NE Not Evaluated DD Data Deficient LC Least Concern NT Near Threatened VU Vulnerable EN Endangered CR Critically Endangered EW Extinct in the Wild EX Extinct
Distribution
They are found predominantly in the Patagonian province of Santa Cruz, Argentina. The lakes used for breeding are found in the interior of the state whilst the hooded grebe can be found wintering at three estuaries on the Atlantic coast.
Habitat and Ecology
They are found in basaltic lakes during the breeding season, and their currently only recorded wintering sites are estuaries on the Atlantic coast of Argentina. The breeding season is from October to March when it can be found in colonies of up to 130 pairs. The breeding lakes must feature aquatic vegetation where this species can build floating nests. Their diet consists mainly of aquatic invertebrates.
Source: BirdLife International and Handbook of the Birds of the World (2017) Bird species distribution maps of the world. Version 6.0. Available at http://datazone.birdlife.org/species/requestdis
Threats
This wordcloud illustrates the threats facing this species. The size of each word indicates the extent of a species range that is affected by that threat (larger size means a greater area is affected). The colour of the word indicates how much that threat impacts the species (darker shades of red mean the threat is more severe).
Volcanoes
Habitat change
Livestock
Mining
Invasive species
Native species
a
a
a
a
a
a
a
Large area affected
Least severe Most severe Severity unknown
Source: The IUCN List of Threatened Species. Version 2017.1. Available at: http://www.iucnredlist.org
Survival Blueprint
Download the survival blueprint for this species below. Each survival blueprint is compiled by an EDGE fellow working on the species with input from collaborators and stakeholders. The survival blueprint provides a status review (information on the distribution, protection status, habitat & ecology, threat and stakeholder analysis) and more information on the action programme listed here.
Vision (30-50 years)
Recover Hooded Grebe populations numbers and occupancy area to similar levels known in the 1980’s
Goal (5-10 years)
Recover important population by controlling major threats and by creation of new protected areas.
Objectives Priority Expansion and consolidation of invasive species control programmes Critical Understand biological characteristic fundamental for its conservation (e.g. migration patterns) Critical Creation of protected areas in breeding grounds (national and provincial) Critical Creation of protected areas in the winter grounds (national and provincial) Critical Reinforcement of the educational/divulgation programme at local, provincial, national and international level High Consolidation of local network of local leaders and local participant for the protection of important areas (winter and summer) High Promotion of sustainable activities (e.g. ecotourism) High Promotion of scientific research to different component of the ecosystem. Medium
Projects
Mapping the mysterious migration route of the Critically Endangered Hooded Grebe
Locations: Santa Cruz province, Patagonia, Argentina
Active dates: 2017 - ongoing
Find out more
Fellows
Kini Ignacio Roesler
Project name: Unraveling the major gap for Hooded Grebe conservation: migration and movements
Project site: Santa Cruz Province, Argentina
Active: 2015 - ongoing
| http://www.edgeofexistence.org/species/hooded-grebe/ |
Titus 2 Expositor's Dictionary of Texts
Expositor's Dictionary of Texts
Titus 2:1
But speak thou the things which become sound doctrine:
Sound in Patience
Titus 2:2
The Apostle Paul has himself been described by a great Biblical student as 'Paul the undiscourageable'. And, indeed, he is worthy of the name, and there is no better way of studying the significance of his teaching than by watching his own life. He is his own best commentary on his own counsels. His purposes were frequently broken by tumultuous shocks. His plans were destroyed by hatred and violence. His course was twisted here, diverted there, and wrenched a hundred times from its appointed goings by the mischievous plots of wicked men. The little Churches he had founded were in chronic disturbance and unrest. They were often infested with puerilities, and sometimes they were honeycombed by heresies which consumed their very life. And yet how sound and noble his patience! With what fruitful tenderness he waits for his lagging pupils! His very reproofs are given, not with the blind, clumsy blows of a street mob, but with the quiet, discriminating hand of a surgeon. This man, more than most men, had proved the hygienic value of endurance, and he, more than most men, was competent to counsel his fellow-believers to discipline themselves to the 'soundness of patience'.
I. Let us, therefore, look a little more closely at the virtue. This virtue of patience is to be exercised in seasons of waiting. This is certainly the hardest and most exacting exercise. I suppose that the rarest form of courage is displayed when we are compelled to sit still, and things are happening in which we can take no part. Action would reduce the tension and bring relief, but action is impossible. The acutest strain is not in the fighting, but in perilous waiting when fighting is impossible. It is in seasons like these that the finest courage and the ripest patience display their superlative glory. 'Although the fig-tree shall not blossom, neither shall fruit be in the vines: the labour of the olive shall fail, and the fields shall yield no meat; the flocks shall be cut off from the fold, and there shall be no herd in the stalls; yet will I rejoice in the Lord, I will joy in the God of my salvation.' This is surely a supreme instance of the virtue of being 'sound in patience'.
II. But the virtue of patience is also to be exercised in seasons of activity. The army needs patience in waiting; it also needs patience in fighting. Impatience can spoil the waiting, and impatience can spoil the fighting. Impatient action defeats its own ends. An impatient shot registers a very erratic mark. An impatient batsman throws away the game. Yes, we require patience in the field as well as in the pavilion. And so it is a general principle in life; patience is not something to be called up merely in hours of enforced indolence; it is not a stand-by in emergencies; it is the virtue which endows every moment with promise, and which makes the most commonplace action healthily effective.
Now let me mention two or three conditions in life in which this 'sound patience' would operate with splendid effectiveness.
1. First of all, then, we need a 'sound patience' when we are
in the presence of oppressive mysteries.
2. We need a 'sound patience'
in the presence of burdensome disappointment.
3. We need a 'sound patience'
in the presence of a loitering progress.
—J. H. Jowett,
The Transfigured Church,
p. 149.
Titus 2:2
In my very young years I had a gravity and stayed-ness of mind and spirit, not usual in children; insomuch that when I saw old men behave lightly and wantonly towards each other, I had a dislike thereof raised in my heart.'
—George Fox's
Journal.
A School for Womanhood
Titus 2:4
The suggestion of my text is 'that they may teach'. That is characteristic of the Bible. It is eminently a teaching book. The word rendered 'teach' is rendered in the Revised Version 'train'. But perhaps its most literal translation would be 'school'—'that they may
school
'. This sacred book would put us all to school, and it would keep us there Are young women the only ones who need instruction? The first verse bids Titus, the Bishop of Crete, 'speak the things which become sound doctrine,' or 'healthful teaching,' and instead of this being required only for young women it is imparted also to old men, aged women, young men and servants. But, in the instance before us, we are interested to know who are to be the instructors, 'That
they
may teach the young women'. Who are the 'they'? The reply is found in the previous verse. It is 'the aged women'. Women are best taught by women. Nor must we fail to notice the
method
of this teaching. It is to be the teaching of example, which is so proverbially better than precept. There must, however, be verbal instruction, and God's Apostles today must not forget in teaching all to 'teach the young women'.
I. Has not the Church too often forgotten to teach such? And yet the influence of women is incalculable. In view of the multiplied and multiplying influence of their sex, it is indeed right that the Christian pulpit should 'teach the young women'.
II. Let me remind you also that woman owes her influence to Christ That woman's nature was equally honourable with man's nobody believed in the pagan world; but as Augustine well said: 'The Saviour gave abundant proof of this in being born of a woman'. He, and He alone, has placed woman on the crowning slope of honour.
III. Consider the elements of character which give to young women their highest influence. (1) To brighten home with love—this is what the Apostle would first teach the young women. (2) Another lesson Paul would have young women taught is 'to be discreet'. The R.V. renders this 'to be sober-minded'. It might be read 'self-restrained'. In another place the original word is translated 'temperate'. Sober-mindedness is certainly a lesson which young women need today. Does not the age demand that the other meaning of this word, 'temperate,' be urged upon young women? The life of woman is often blasted through lack of self-restraint (3) A further apostolic lesson for young women is to be 'chaste' (4) 'Keepers at home' is again an indoctrination of St. Paul. The R.V. gives it as 'workers at home'. Home duties are the first of duties. (5) The next quality urged is 'good,' or as the R. V. has it 'kind'.
What if young women who name the name of Christ and profess His hallowed service omit or forget these homely duties? 'The word of God' will be 'blasphemed 'or evil spoken of.
—Dinsdale T. Young,
Messages for Home and Life,
p. 17.
Titus 2:6
'I have delivered up my son to you,' Cromwell wrote in 1649 to the Mayor of Hursley; 'and I hope you will counsel him; he will need it; and indeed I believe he likes well what you say and will be advised by you. I wish he may be serious; the times require it.' In the next year (1650) he again wrote to the same friend: 'I hope you give my son good counsel; I believe he needs it. He is in the dangerous time of his age; and it's a very vain world. O how good it is to close with Christ betimes!—there is nothing else worth the looking after.'
Reference.—II. 7.—
Expositor
(5th Series), vol. vi. p. 382.
Adorning the Doctrine
Titus 2:10
The universal test of religion is character, and that standard of judgment is a just standard. If the world is to be won for Christ it must be won by the unconscious evangelism of homely virtues and the upright, generous lives of the followers of Christ. Where you have a good life going out in the inspiration and power of Christianity you have an evidence of Christianity. As a sceptic once said: 'There is not an argument for Christianity that I do not see through except one. I cannot make out how it was my mother was so good a woman.'
I. The life that adorns the Gospel is the real evidence of Christianity. Christ implicitly rested the demonstration of His religion on the conduct of His disciples. The only evidence for Christ is that of Christians. We may treat that thought with effortless familiarity; but it is a wonderfully important thought full of thrust and moment. It means this, that Christians
must
be better than other men; if not, Christianity breaks down. Most of us are advocates for Christianity without being Christians. 'Christian is that Christian does.' You may know the truth of Christ, you may feel at times rapturously ecstatic. But what is it all for? All for this, to make us like Christ. Your religious life is not across the seas of far ideals and undiscovered truths—your religious life consists in putting goodness into homely outward shape. There are still men like Bulstrode in
Middlemarch,
who could not conceive that there was any relation between his business and religion, who thought that 'the Lord's cause' had no connection with his shop at all.
II. How are we to be
induced
to adorn the Gospel of God? A preacher may stand up and say to his congregation 'Be good,' until the crack of doom. There is nothing more futile. It is not good advice that we need; it is good motive, or momentum to carry us past the place of danger. We need some principle of life, some flow of inspiration, that is large enough to influence the whole nature And that, as I understand it, is the crux of our holy religion. To be a Christian means to be in touch with Christ, to let Christ help us. Live so near to Christ that He has some chance of beautifying your life; submit yourself to the power of His Spirit. He means to be your comrade, your Saviour. But He cannot unless you will. When the Gospel of Christ grips a man's soul it entails the saving of a man's whole life.
—B. J. Snell,
The All-Enfolding Love,
p. 129.
References.—II. 10.—Spurgeon,
Sermons,
vol. xli. No. 2416. W. L. Watkinson,
Christian World Pulpit,
vol. xlix. p. 284. A. Maclaren,
Expositions of Holy Scripture
—
Titus,
p. 132. II. 11.—
Expositor
(4th Series), vol. i. p. 140;
ibid.
vol. vi. p. 421. II. 11-14.—Spurgeon,
Sermons,
vol. xxxii. No. 1894. II. 11-15.—J. A. Alexander,
The Gospel of Jesus Christ,
p. 221. II. 17.—A. Maclaren,
Expositions of Holy Scripture—Titus,
p. 149.
That Blessed Hope ( an Advent Sermon )
Titus 2:13
I fear that this great truth—the coming again of the Lord—is largely a neglected truth.
Since the Lord Jesus Christ departed into the heavens, and men are really touched by matters spiritual, you will find, if you study the history of the great majority of the professing Christians, that they have almost entirely, if not quite, ignored the coming of the Lord Jesus Christ as a Person to fulfil a great historical event. They think of that as a merely emotional dream of certain enthusiasts; and if they do admit that He is coming again in glory, they simply think of it as a general idea—that there will be some day a manifestation of judgment and glory; but with the details they have not the slightest possible interest
I. The Second Advent as a Matter of Reason.
—I ask you, as a matter of reason, is it likely that the Great High God, Who has, as we are told in the opening of the Epistle to the Hebrews, appointed His Son to be Heir of all things, would allow His retirement from the earth as if defeated, and never see to it that His purpose was completely fulfilled? When the Lord Jesus Christ left this world, He passed up from the Mount of Olives and from the sight of a few humble followers, who claimed Him in their hearts as King. But the world at large ignored Him entirely, and Satan might well have been said to have gained a magnificent victory, if nothing further took place historically with regard to the Jesus of Nazareth. Consequently, we may expect, on the very ground of reason, that there must be a further return of Christ in majesty and glory to claim the kingdoms of this world for Himself and His father. Otherwise, throughout the hosts of hell there might be an acclamation cry, 'We have beaten the Lord, that God of your heaven'. They have not beaten Him! They never can! And it is because we believe the Word of the living God, and expect our God is to have a triumphant victory in all matters connected with the history of this world, that we, some of us at least, are now 'looking for that blessed hope,' and we seem to see the dawn of that wondrous day when Christ shall take to Himself His great power and reign, when the kingdoms of this world shall become the Kingdom of our Lord and of His Christ
II. What Saith the Scripture?
—We must inquire what is revealed to us in the Scripture with regard to this historical fact, of which we are expecting the fulfilment In what manner will the Lord Jesus Christ return? Our text speaks of it as 'the glorious appearing of our Saviour Jesus Christ'. He is to come 'in like manner' as He went up. And the Lord Jesus Christ, our Blessed Saviour, who went up to heaven as Jesus, the Perfect Man, to claim our places there and prepare them for us, in the presence of God and the angels, is coming back to 'receive the kingdom' according to His own parable. He comes to be King, and His title is to be 'the Lord Himself.
III. Christ and the Church.
—What will it be to Christ when He looks upon His Church, and says, 'My beloved, My beloved!' That is my Saviour's joy, my Saviour's reward for all His pains. 'For the joy that was set before Him, He endured the cross, despising the shame, and is set down at the right hand of the throne of God,' henceforth waiting till His enemies are crushed, and His saints are ready to meet Him, and the cry goes up from earth as well as from heaven above: 'My Lord, my God'. Not only will it be a satisfaction to His own soul; He will see God satisfied, too. When He was upon earth, there was one thought in His mind. 'I have glorified Thee upon the earth... I came not to seek my own glory, but the glory of Him that sent Me.' I can imagine (oh, so feebly!) the wondrous feeling of my Lord and Master as He looks upon that perfected Bride—gathered in all ages from earth—how He turns back for a moment to His Father's throne, and says, 'Father, I have glorified Thee; I have glorified Thee!'
IV. What Shall we Say to these Things?
—I ask you to think that we are to get ready. A little child said to its mother, 'Hadn't we better begin to pack up for heaven?' Are you beginning to pack up for glory? Are you getting ready, for that wondrous moment when all our beloved ones shall meet us—not only our own beloved on earth, but our dearly beloved Lord—to meet Him in the air and be like Him, because we see Him as He is. I beseech you to be getting ready, 'for in such an hour as ye think not the Son of Man cometh'. Get ready, and help others. It is an honour to be called of God to go out and hasten the time when the Bride shall be ready to meet her Lord. Work your work while yet it is day; you will not have long to win souls for Jesus. Are we ready to receive Him? He will come in a moment, in the twinkling of an eye. May our prayer be, 'Come, Lord Jesus; come quickly!'
References.—II. 13.—H. Alford,
Sermons on Christian Doctrine,
p. 266. D. L. Moody,
The Fulness of the Gospel,
p. 82. C. D. Bell,
The Power of God,
p. 197.
Expositor
(4th Series), vol. x. p. 109. II. 13, 14.—J. Keble,
Sermons for the Sundays After Trinity,
p. 372. II. 14.—Spurgeon,
Sermons,
vol. ii. No. 70. A. Maclaren,
After the Resurrection,
p. 241. G. A. Sowter,
From Heart to Heart,
p. 212.
Expositor
(5th Series), vol. ix. p. 437;
ibid.
(6th Series), vol. i. p. 367. A. Maclaren,
Expositions of Holy Scripture
—
Titus,
p. 171;
ibid.
p. 180.
Titus 2:15
'I met the society [at Norwich] at seven,' says Wesley, in his journal for September, 1759, 'and told them in plain terms, that they were the most ignorant, self-conceited, self-willed, fickle, untractable, disorderly, disjointed society, that I knew in the three kingdoms. And God applied it to their hearts: so that many were profited; but I do not find that one was offended.'
Reference.—II. 15.—H. D. M. Spence,
Voices and Silences
p. 9.
Titus 2:2
That the aged men be sober, grave, temperate, sound in faith, in charity, in patience.
Titus 2:3
The aged women likewise, that
they be
in behaviour as becometh holiness, not false accusers, not given to much wine, teachers of good things;
Titus 2:4
That they may teach the young women to be sober, to love their husbands, to love their children,
Titus 2:5
To be
discreet, chaste, keepers at home, good, obedient to their own husbands, that the word of God be not blasphemed.
Titus 2:6
Young men likewise exhort to be sober minded.
Titus 2:7
In all things shewing thyself a pattern of good works: in doctrine shewing uncorruptness, gravity, sincerity,
Titus 2:8
Sound speech, that cannot be condemned; that he that is of the contrary part may be ashamed, having no evil thing to say of you.
Titus 2:9
Exhort
servants to be obedient unto their own masters,
and
to please
them
well in all
things
; not answering again;
Titus 2:10
Not purloining, but shewing all good fidelity; that they may adorn the doctrine of God our Saviour in all things.
Titus 2:11
For the grace of God that bringeth salvation hath appeared to all men,
Titus 2:12
Teaching us that, denying ungodliness and worldly lusts, we should live soberly, righteously, and godly, in this present world;
Titus 2:13
Looking for that blessed hope, and the glorious appearing of the great God and our Saviour Jesus Christ;
Titus 2:14
Who gave himself for us, that he might redeem us from all iniquity, and purify unto himself a peculiar people, zealous of good works.
Titus 2:15
These things speak, and exhort, and rebuke with all authority. Let no man despise thee.
Nicoll - Expositor's Dictionary of Texts Text Courtesy of BibleSupport.com . Used by Permission. Bible Hub
| https://www.biblehub.com/commentaries/edt/titus/2.htm |
JCM | Free Full-Text | Dissecting Relations between Depression Severity, Antidepressant Use, and Metabolic Syndrome Components in the NHANES 2005& ndash;2020
We aimed to dissect the complex relations between depressive symptoms, antidepressant use, and constituent metabolic syndrome (MetS) components in a representative U.S. population sample. A total of 15,315 eligible participants were included from 2005 to March 2020. MetS components were defined as hypertension, elevated triglycerides, reduced high-density lipoprotein cholesterol, central obesity, and elevated blood glucose. Depressive symptoms were classified as mild, moderate, or severe. Logistic regression was used to evaluate the relationship between depression severity, antidepressant use, individual MetS components and their degree of clustering. Severe depression was associated with the number of MetS components in a graded fashion. ORs for severe depression ranged from 2.08 [95%CI, 1.29–3.37] to 3.35 [95%CI, 1.57–7.14] for one to five clustered components. Moderate depression was associated with hypertension, central obesity, raised triglyceride, and elevated blood glucose (OR = 1.37 [95%CI, 1.09–1.72], 1.82 [95%CI, 1.21–2.74], 1.63 [95%CI, 1.25–2.14], and 1.37 [95%CI, 1.05–1.79], respectively). Antidepressant use was associated with hypertension (OR = 1.40, 95%CI [1.14–1.72]), raised triglyceride (OR = 1.43, 95%CI [1.17–1.74]), and the presence of five MetS components (OR = 1.74, 95%CI [1.13–2.68]) after adjusting for depressive symptoms. The depression severity and antidepressant use were associated with individual MetS components and their graded clustering. Metabolic abnormalities in patients with depression need to be recognized and treated.
Dissecting Relations between Depression Severity, Antidepressant Use, and Metabolic Syndrome Components in the NHANES 2005–2020
by Ziying Lin 1 , Yap-Hang Chan 1 and Bernard Man Yung Cheung 1,2,3,*
1
Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong, China
2
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pokfulam, Hong Kong, China
3
Institute of Cardiovascular Science and Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2023 , 12 (12), 3891; https://doi.org/10.3390/jcm12123891
Received: 20 March 2023 / Revised: 26 May 2023 / Accepted: 5 June 2023 / Published: 7 June 2023
(This article belongs to the Section Endocrinology & Metabolism )
Abstract
We aimed to dissect the complex relations between depressive symptoms, antidepressant use, and constituent metabolic syndrome (MetS) components in a representative U.S. population sample. A total of 15,315 eligible participants were included from 2005 to March 2020. MetS components were defined as hypertension, elevated triglycerides, reduced high-density lipoprotein cholesterol, central obesity, and elevated blood glucose. Depressive symptoms were classified as mild, moderate, or severe. Logistic regression was used to evaluate the relationship between depression severity, antidepressant use, individual MetS components and their degree of clustering. Severe depression was associated with the number of MetS components in a graded fashion. ORs for severe depression ranged from 2.08 [95%CI, 1.29–3.37] to 3.35 [95%CI, 1.57–7.14] for one to five clustered components. Moderate depression was associated with hypertension, central obesity, raised triglyceride, and elevated blood glucose (OR = 1.37 [95%CI, 1.09–1.72], 1.82 [95%CI, 1.21–2.74], 1.63 [95%CI, 1.25–2.14], and 1.37 [95%CI, 1.05–1.79], respectively). Antidepressant use was associated with hypertension (OR = 1.40, 95%CI [1.14–1.72]), raised triglyceride (OR = 1.43, 95%CI [1.17–1.74]), and the presence of five MetS components (OR = 1.74, 95%CI [1.13–2.68]) after adjusting for depressive symptoms. The depression severity and antidepressant use were associated with individual MetS components and their graded clustering. Metabolic abnormalities in patients with depression need to be recognized and treated.
Keywords:
metabolic syndrome components
;
depressive symptoms
;
antidepressant use
;
survey
1. Introduction
Metabolic syndrome (MetS) is defined as a clustering of conditions that include hypertension, dyslipidemia (raised triglycerides and reduced high-density lipoprotein-cholesterol [HDL-C]), central obesity, and elevated fasting glucose. MetS is a key risk factor for cardiovascular diseases and is associated with increased all-cause mortality [ 1 , 2 , 3 , 4 , 5 ]. MetS as a major public health threat has been observed with increasing prevalence worldwide in recent decades [ 6 ].
Psychiatric conditions are associated with increased risks of premature death from cardiovascular diseases. Studies showed that an increased risk of MetS is present in psychiatric conditions, including depression [ 7 , 8 , 9 ]. Depression is now believed to be the result of an interaction of multiple risk factors, including genetics, development, and environment [ 10 , 11 , 12 ]. The convergence of evidence suggests that, despite the presence of multiple risk factors, the final pathologic pathway of depression occurs in multiple but interacting regions of the human brain, involving the prefrontal cortex and its connections to many subcortical structures [ 13 , 14 , 15 , 16 ]. Connections have been found between cortico-limbic circuits and shared physiological functions in chronic stress exposure and depression [ 17 , 18 , 19 ]. These processes involve disruptions in circadian rhythm function, affective state regulation, drive and motivation, intention formation, and behavioral execution. As a logical consequence of these disruptions, individuals may experience symptoms such as decreased energy levels, apathy, anhedonia, and changes in appetite and sleep patterns [ 12 , 20 ]. The unhealthy lifestyle and poor adherence to treatment associated with these changes may be potential mediating mechanisms between depressive patients and the presence of MetS [ 21 , 22 ]. Furthermore, underlying pathophysiological mechanisms, such as dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, impaired thalamocortical rhythm and immune function, and genetic predisposition, may have a long-term effect on depression and MetS in a bidirectional manner [ 23 , 24 , 25 , 26 ]. Thus, depression and MetS, both cardiovascular risk factors, may exert bidirectional influences through complex behavioral and psycho-neuroendocrine pathways.
Although the link between depression and MetS has been established, the association between gradated depression severity and the individual components of MetS and the clustering of these components has not been well characterized [
7
,
12
]. Antidepressants may also directly influence metabolic dysregulation, independent of depressive symptoms [
27
]. Given that the MetS is a syndromal conglomeration of various metabolic abnormalities, describing its individual components and the clustering of its components may be a more robust way to determine the independent and synergistic effect between depression and MetS rather than using the dichotomous definition of MetS. Therefore, the present study aimed to dissect the complex associations between the severity of depressive symptoms, antidepressant use, and individual MetS components, as well as their degree of clustering in a representative non-institutionalized population sample, the U.S. National Health and Nutrition Examination Survey (NHANES).
2. Methods
2.1. Study Population
NHANES is a cross-sectional national survey designed to collect information on health and nutrition in the U.S. non-institutionalized civilian population [
28
]. It is a stratified, complex, multistage, probabilistic survey conducted continuously in two-year cycles since 1999. Specific weights are assigned to participants to account for their different sampling probabilities and non-response rates. NHANES was approved by the CDC Institutional Review Board, and all participants provided written informed consent. Depression was evaluated using the World Health Organization Composite International Diagnostic Interview (CIDI) in NHANES 1999–2004 and Patient Health Questionnaire-9 (PHQ-9) in NHANES 2005–2020, respectively [
29
,
30
]. In our study, we combined multiple years of NHANES data, from 2005 to March 2020, to yield the available NHANES sample size. We extracted the participants’ information, including demographic characteristics, examination results, prescription information, and laboratory tests.
2.2. Definitions of MetS Components, Depressive Symptoms, and Antidepressant Use
MetS components were defined according to the National Cholesterol Education Program’s Adult Treatment Panel III criteria: (1) hypertension: systolic blood pressure at least 130 mm Hg or diastolic blood pressure at least 85 mm Hg or taking hypertension medications; (2) raised triglyceride: triglyceride level greater than 150 mg/dL; (3) reduced HDL-C: HDL-C level less than 40 mg/dL in men or less than 50 mg/dL in women; (4) central obesity: waist circumference greater than 102 cm in men or 88 cm in women; (5) raised blood glucose: fasting plasma glucose level at least 100 mg/dL or taking diabetes medications [
5
]. MetS was defined as having at least three of the above five components [
5
].
Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), the instrument most widely used in primary care settings to screen for depression [ 12 , 31 ]. It assesses symptoms of a major depressive episode in the past two weeks, with a score ranging from 0–27. Depression severity was classified as normal (0–4), mild (5–9), moderate (10–14), and severe (15–27) [ 31 ]. A score of 10 or above (moderate or severe depressive symptoms) is the standard cut-off for identifying possible major depression [ 32 ].
The information of antidepressant use was extracted from NHANES prescription information files [
28
]. The information on medication use was collected during household interviews. Participants were asked if they have taken medications in the past thirty days. The participants were asked to show containers of all drugs when they answered “yes” to the question or report the drug name if the containers were not available. All prescription medication data were processed and categorized using the Multum Lexicon Plus database. The category of “antidepressants” was listed in the second level category whose first level category was “psychotherapeutic agents” [
33
,
34
]. Antidepressant use in our study was defined as the use of at least one antidepressant agent in the prior thirty days.
2.3. Definitions of Potential Confounders
Participants’ demographic and socioeconomic information were collected by the self-reported questionnaires. Participants’ age was stratified into three groups of 20–44 years old, 45–64 years old, and ≥65 years old. Race/ethnicity was classified into non-Hispanic Whites, non-Hispanic Blacks, Mexican Americans, other Hispanic, and other race. Education levels were categorized into four groups: less than high school, high school, some college, and college or higher. Family income-to-poverty ratio was categorized as less than 130%, 130–349%, and 350% or more. Health insurance was classified as uninsured and insured status. Marital status was categorized into three groups: married or living with partner, widowed or divorced or separated, and never married. The information on body mass index (BMI) was extracted from the examination data. Participants with a BMI of 25 kg/m
2
or more were defined as overweight and over 30 kg/m
2
as obese. The lifestyle factors, including physical activity, smoking status, and alcohol consumption were defined. Physical activity was collected during a household interview. Moderate activity was defined as work or recreational activity that resulted in a slight increase in breathing or heart rate for at least ten minutes. Vigorous activity was defined as activity that resulted in a large increase in breathing or heart rate for at least ten consecutive minutes. Participants who have smoked 100 cigarettes in their lifetimes and currently smoke cigarettes every day or some days were defined as current smokers. Those who have ever smoked 100 or more cigarettes or not and do not smoke now were defined as former or never smokers. Alcohol consumption was classified according to self-reported average daily numbers of standard drinks. Moderate drinkers were defined as drinking fewer than four alcoholic drinks per day for women or five alcoholic drinks per day for men. Heavy drinkers were defined as having four or more drinks a day for women or five or more drinks a day for men.
2.4. Statistical Analysis
All analyses were performed accounting for NHANES’ complex survey design, including appropriate NHANES sampling weights, strata, and primary sampling units, as these factors affect the precision of the estimates. All estimates and 95% confidence intervals (CIs) were weighted to be nationally representative. Participants’ characteristics were compared using adjusted Pearson’s chi-squared test.
Binomial logistic regression was used to evaluate the association between depressive symptoms and antidepressant use with individual MetS components among all participants. Multinomial logistic regression was used to evaluate the association between depressive symptoms and antidepressant use with the number of clustered MetS components among all participants. Models were adjusted for the potential confounders. Models for sensitivity analyses were additionally adjusted for antidepressant use or depressive symptoms. Because the parallel assumption was not met in the ordinal logistic regression models, multinomial logistic regression models were used to test the odds ratios of groups with more MetS components to the group without MetS components by the severity of depressive symptoms and antidepressant use. The association was reported as odds ratio (OR) and 95%CIs. Statistical significance was assessed at 2-sided
p
values < 0.05. All analyses were performed using SPSS 26.0 (IBM Corp., Armonk, NY, USA).
3. Results
A total of 15,315 participants were included in the final studied population (equivalent to approximately 200 million U.S. adults). Amongst them, 15.4%, 4.6%, and 2.3% presented with mild, moderate, and severe depressive symptoms during the study period, respectively. Of all included participants, 82.9% had one or more MetS components, and more than 50% had central obesity and elevated blood glucose.
Baseline characteristics of all participants by individual MetS component and according to the degree of clustering are shown in Table 1 , Table 2 , and Table S1 , respectively. Prevalence estimates of individual MetS components (A) and their clustered presence (B) according to depression severity are shown in Figure 1 . Prevalence estimates for all five subgroups of abnormal components increased with depression severity. The proportions of participants with any depressive symptom amongst those with hypertension, raised triglyceride, reduced HDL-C and central obesity were significantly higher than those in the corresponding normal subgroups. This was not the case in those with raised blood glucose. More participants used antidepressants in these five subgroups compared to corresponding normal subgroups. The prevalence of depressive symptoms and antidepressants increased with the number of MetS components in an individual ( p < 0.001). More women than men experienced depressive symptoms, whether mild (18.0% vs. 12.8%), moderate (6.0% vs. 3.3%), or severe (2.8% vs. 1.8%) ( Table S2 ). More than twice as many women, compared to men, used antidepressants (17.6% vs. 7.4%) ( Table S2 ). In each of the men and women subgroups, there was a significant positive association between the severity of depression and the number of MetS components ( Table S3 ).
Figure 1. Prevalence of individual ( A ) and clustered ( B ) MetS components by depressive symptoms.
Table 1. Characteristics of participants by individual MetS components a .
Table 2. Characteristics of participants by the clustered number of MetS components a .
As shown by multivariable models in Table 3 , Tables S4 and S5 , compared with subjects without depression, those with depression had a higher risk of developing raised triglyceride: ORs for mild, moderate, and severe depression were 1.30 (95%CI [1.12–1.52]), 1.63 (95%CI [1.25–2.14]), and 1.44 (95%CI [1.05–1.97]), respectively. Those with moderate depression were more likely to have hypertension (OR = 1.37 [95%CI, 1.09–1.72]), central obesity (OR = 1.82 [95%CI, 1.21–2.74]) and raised blood glucose (OR = 1.37 [95%CI, 1.05–1.79]) ( Table 3 ). Interestingly, the association between moderate depression and hypertension was not statistically significant after adjustment for antidepressant use ( Table S4 , Model 2). Furthermore, increased depression severity was associated with increased clustering of MetS components in a graded fashion ( Table 3 ). Compared with subjects without depression, those with mild depression had a higher risk of having five MetS components (OR = 1.82 [95%CI, 1.25–2.67], versus none). Similarly, those with moderate and severe depression had more than 4-fold (OR = 4.31 [95%CI, 2.45–7.60]) and 3-fold risk (OR = 3.35 [95%CI, 1.57–7.14]) of having five MetS components, respectively. These findings remained similar after adjustment for antidepressant use. Gender-specific analyses are shown in Figure S1 and Table S8 .
Table 3. Odds ratios for individual and clustered MetS components by depressive symptoms a .
Prevalence estimates of individual MetS components (A) and their clustered presence (B) stratified by antidepressant use are shown in Figure 2 . The prevalence of each individual MetS component was higher amongst antidepressant users compared to non-users. Independent of the severity of depression, antidepressant use was associated with hypertension (OR = 1.40 [95%CI, 1.14–1.72]) and raised triglyceride (OR = 1.43 [95%CI, 1.17–1.74]) ( Table 4 , Tables S6 and S7 ). Such associations were not statistically significant for HDL-C, central obesity, and elevated blood glucose. Furthermore, antidepressant use was associated with the degree of clustering of MetS components (five MetS components versus none: OR = 1.74 [95%CI, 1.13–2.68]). Gender-specific analyses are shown in Figure S2 and Table S9 .
Figure 2. Prevalence of individual ( A ) and clustered ( B ) MetS components by antidepression use.
Table 4. Odds ratios for individual and clustered MetS components by antidepressant use a .
4. Discussion
Our study provides a comprehensive evaluation of the association between depression severity and antidepressant use with individual MetS components as well as their degree of clustering in the U.S. national survey over 15 years. Greater depression severity was not only associated with individual MetS components but their greater degree of clustering in a graded fashion. In addition, the use of antidepressants was further associated with greater degrees of clustering of MetS components, independently of the severity of depressive symptoms. It was also individually associated with higher risks of hypertension and elevated triglyceride.
Although relations between depression and MetS had been described earlier [ 7 ], the current study provides unique insights into the complex relations between gradated severity of depression and each constituent component of MetS among the non-institutionalized U.S. population. One previous study using the NHANES 2009–2010 dataset showed that 41% of depressed individuals (PHQ-9 score ≥ 10) fulfilled the criteria of MetS, which ties in with the estimate of 46% in our study [ 35 ]. Our findings indicate that persons with more severe depression could be at increased vulnerability to the clustering of MetS components. An excess two-fold increase in cardiovascular risk associated with MetS compared with the general population, including mortality, warrants a routine screening for depressed persons, especially those who have moderate or severe depression [ 2 ]. While the mechanism behind the association remains not entirely clear, depression has been reported to be intricately associated with MetS components through behavioral and psycho-neuroendocrine pathways. For example, depressive symptoms can affect individuals’ lifestyle behaviors, such as physical inactivity, heavy smoking, alcohol consumption, and unhealthy dietary patterns, thereby contributing to MetS development [ 22 , 36 , 37 ]. In addition, increasing studies suggest that the HPA axis hyperactivation is an inherent feature in different psychiatric patients that plays an important role by multiple paths, including increased glucocorticoid sensitivity and lipid storage, in the linkage between depression and MetS development [ 7 , 38 , 39 ]. Furthermore, systemic inflammatory stress has been implicated in depression, and inflammation is a cardinal metabolic derangement that is seen in MetS [ 25 , 35 , 40 , 41 , 42 ]. The activation of the HPA axis and inflammation response may affect the development of both disorders, and this influence could be long term [ 12 , 43 ]. Hence, clinicians need to adopt a holistic view of patients’ mental and physical health when managing depression, considering these interconnected factors in their treatment plans.
Interestingly, our findings showed a stronger association between the presence of individual MetS components and moderate depression, as compared to severe depression. Furthermore, antidepressant use was associated with an increase in certain MetS components, such as elevated triglyceride levels and hypertension, independent of depression severity. This might raise the possibility of a distinct role played by antidepressants, independent of their impact on depressive symptoms, in modulating certain MetS components. For instance, tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) have been associated with hypertension and abdominal obesity, while selective serotonin reuptake inhibitors (SSRIs) have been shown to be associated with increased weight and dyslipidemia [ 44 , 45 , 46 , 47 ]. Antidepressants were shown to have pleiotropic effects across biological systems on processes such as immunity, oxidation, and inflammation [ 48 , 49 ]. Studies found that antidepressant treatment improved glycemic control in those patients with diabetes [ 50 ]. However, there is no evidence of increased or decreased cardiac events resulting from antidepressant use in meta-analyses or large randomized trials (sample size > 200 participants) [ 51 , 52 , 53 ]. Whether there is a genuine detrimental effect of antidepressants on MetS is uncertain. Alternatively, it is possible that the excess risks observed in MetS components and their clustering associated with antidepressant use in our study could have reflected a sample with higher pre-treatment depression severity that mandated antidepressant treatment. In fact, the abolishment of a positive association between depression severity and hypertension by including antidepressant use in the multivariable model may indicate potential protection of effective antidepressant therapy by ameliorating the harmful effects of depression on MetS. Thus, it is crucial for healthcare providers to closely monitor metabolic indicators in patients undergoing antidepressant treatment. Regular screening for MetS components and tailored interventions might be required to counteract potential adverse metabolic effects of antidepressants.
Interestingly, our results showed potential gender differences in the association between depressive symptoms and antidepressant use with MetS. Studies have consistently found that depression is more common in women than men, as was the case in our study [ 54 , 55 ] . The potential behavioral and biological mechanisms involved in the sex differences for developing individual MetS components and their combination ought to be further investigated in future studies.
Strengths and Limitations
Our study, drawing on the recent 15 years of nationally representative U.S. data, emphasizes the need for healthcare providers to recognize the complex relationship between depression severity, antidepressant use, and individual MetS components and the degree of their clustering. Moreover, integrated care models that address both mental and physical health conditions concurrently might be beneficial in managing this dual burden of disease. Nevertheless, there were several important limitations. First, we could not infer direct causality based on the current results due to the cross-sectional nature. Second, the study data were also subject to response bias, as participants self-reported medication use. Medication compliance was not assessed. Third, our study did not delve into the potential effects of different categories of antidepressants on MetS components. Future research could benefit from a more nuanced exploration of this aspect, examining the differential metabolic impacts of various antidepressant classes and their potential underlying mechanism. Lastly, self-reported depressive symptoms may subject to response bias, and they may differ from the clinical features of depression assessed by a medical doctor. Future research to corroborate our findings is needed.
5. Conclusions
The severity of depressive symptoms was associated with individual MetS components and their clustering in the U.S. general population. The findings highlight the importance of an individualized approach in the management of cardiometabolic risk in patients with depression. Whether antidepressant treatment may result in tangible impacts on MetS in depressive persons will require further investigation.
Supplementary Materials
The following supporting information can be downloaded at:
https://www.mdpi.com/article/10.3390/jcm12123891/s1
, Figure S1: Prevalence of individual (A) and clustered (B) MetS components by depressive symptoms in men and women; Figure S2: Prevalence of individual (A) and clustered (B) MetS components by antidepression use in men and women; Table S1: Characteristics of participants by individual MetS components; Table S2: Characteristics of participants by sex; Table S3: Depressive symptoms and antidepressant use by clustered and individual MetS components in men and women; Table S4: Odds ratios for individual and clustered MetS components by depressive symptoms in men and women; Table S5: Beta values and
p
values for models of depressive symptoms; Table S6: Odds ratios for individual and clustered MetS components by antidepressant use; Table S7: Beta values and
p
values for models of antidepressant use; Table S8: Odds ratios for individual and clustered MetS components by depressive symptoms in men and women; Table S9: Odds ratios for individual and clustered MetS components by antidepressant use in men and women.
Author Contributions
Z.L.: conceptualization, methodology, formal analysis, visualization, writing—original draft; Y.-H.C.: methodology, visualization, validation, writing—review and editing; B.M.Y.C.: conceptualization, methodology, validation, writing—review and editing, supervision. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
NHANES protocol was approved by the Research Ethics Review Board of National Center for Health Statistics. All participants provided informed consent prior to participating in NHANES. The Ethical Approval Code/Number is available from the published NCHS Ethics Review Board (ERB) Approval online ( https://www.cdc.gov/nchs/nhanes/irba98.htm#print (accessed on 5 April 2023)).
Informed Consent Statement
Informed consent was obtained from all subjects involved in NHANES.
Data Availability Statement
Data used in this study are available from the published NHANES database ( https://www.cdc.gov/nchs/nhanes/index.htm (accessed on 2 October 2022)).
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Prevalence of individual ( A ) and clustered ( B ) MetS components by depressive symptoms.
Figure 2. Prevalence of individual ( A ) and clustered ( B ) MetS components by antidepression use.
Table 1. Characteristics of participants by individual MetS components a .
Characteristic Total ( n = 15,315) Hypertension p Value Raised Triglyceride p Value Reduced HDL-C p Value Central Obesity p Value Raised Blood Glucose p Value ( n = 6952, 40.0 [38.7–41.3]) ( n = 3783, 24.4 [23.4–25.4]) ( n = 4259, 27.0 [25.8–28.2]) ( n = 8780, 56.3 [54.9–57.7]) ( n = 8493, 51.9 [50.5–53.4]) Age, years <0.001 <0.001 <0.001 <0.001 <0.001 20–44 45.5 (44.0–47.0) 20.1 (18.8–21.6) 39.1 (36.6–41.6) 49.2 (47.1–51.2) 37.5 (35.9–39.2) 31.9 (30.1–33.7) 45–64 36.4 (35.2–37.6) 46.1 (44.6–47.7) 41.7 (39.3–44.1) 35.7 (33.8–37.6) 39.9 (38.6–41.3) 42.7 (41.1–44.3) ≥65 18.2 (17.2–19.2) 33.7 (32.1–35.4) 19.2 (17.7–20.9) 15.1 (13.7–16.7) 22.5 (21.3–23.8) 25.5 (24.1–26.8) Women 50.6 (49.7–51.6) 48.3 (46.9–49.7) <0.001 43.0 (40.9–45.0) <0.001 54.5 (52.6–56.5) <0.001 60.0 (58.6–61.5) <0.001 43.0 (41.6–44.5) <0.001 Race/ethnicity <0.001 <0.001 <0.001 <0.001 <0.001 Non-Hispanic White 67.8 (65.4–70.1) 69.1 (66.2–71.9) 71.5 (68.8–74.0) 66.7 (63.7–69.6) 69.8 (67.1–72.4) 67.8 (65.3–70.3) Non-Hispanic Black 10.8 (9.6–12.2) 14.0 (12.2–16.0) 5.2 (4.4–6.2) 9.1 (7.8–10.6) 11.3 (9.9–13.0) 9.8 (8.6–11.1) Mexican American 8.4 (7.2–9.7) 5.8 (4.8–7.0) 10.2 (8.7–11.9) 10.0 (8.5–11.7) 8.4 (7.1–10.0) 9.1 (7.8–10.7) Other Hispanic 5.7 (4.8–6.6) 4.6 (3.8–5.6) 5.7 (4.5–7.1) 6.9 (5.8–8.2) 5.3 (4.5–6.3) 5.7 (4.8–6.7) Other race 7.3 (6.6–8.2) 6.5 (5.6–7.5) 7.4 (6.4–8.6) 7.3 (6.2–8.6) 5.1 (4.4–5.9) 7.6 (6.7–8.6) Education <0.001 <0.001 <0.001 <0.001 <0.001 <High school 15.1 (14.0–16.3) 17.3 (16.0–18.7) 18.3 (16.7–20.0) 18.9 (17.3–20.6) 15.7 (14.5–17.0) 17.4 (16.1–18.8) High school 23.5 (22.3–24.8) 27 (25.4–28.8) 25.1 (22.9–27.5) 24.7 (22.6–26.9) 24.6 (23.3–26.0) 25.6 (24.1–27.2) Some college 31.0 (29.8–32.3) 31 (29.1–32.9) 32.1 (30.0–34.3) 33.0 (30.8–35.2) 33.3 (31.8–34.9) 29.6 (28–31.4) College or higher 30.4 (28.4–32.4) 24.7 (22.6–26.9) 24.5 (22.1–27.1) 23.4 (21.2–25.9) 26.3 (24.3–28.5) 27.3 (25.3–29.5) Family income-to-poverty ratio 0.05 0.09 <0.001 <0.001 0.16 <130% 20.0 (18.6–21.4) 19.3 (17.7–21.1) 21.2 (19.4–23.2) 25.2 (23.3–27.2) 20.4 (18.9–22.0) 19.8 (18.4–21.3) 130–349% 36.1 (34.8–37.5) 37.7 (35.9–39.5) 36.8 (34.7–38.9) 38.5 (36.4–40.7) 38.0 (36.1–39.8) 37.2 (35.5–38.9) ≥350% 43.9 (42.0–45.9) 42.9 (40.6–45.4) 42.0 (39.6–44.5) 36.3 (33.3–39.4) 41.6 (39.3–44.0) 43.0 (40.8–45.3) Health insurance 82.9 (81.7–84.0) 88.0 (86.8–89.1) <0.001 82.5 (80.5–84.3) 0.54 80.0 (78.3–81.7) <0.001 85.7 (84.4–86.9) <0.001 84.8 (83.6–86.0) <0.001 Marital status <0.001 <0.001 0.54 <0.001 <0.001 Married/Living with Partner 64.3 (62.6–65.9) 65.3 (63.3–67.2) 67.3 (64.7–69.9) 64.5 (62.0–67.0) 65.7 (63.6–67.8) 66.7 (64.7–68.7) Widowed/Divorced/Separated 17.7 (16.7–18.7) 24.3 (22.7–25.9) 19.1 (17.4–21.0) 18.1 (16.6–19.7) 20.6 (19.2–22.0) 20.7 (19.2–22.2) Never married 18.1 (16.8–19.4) 10.5 (9.5–11.6) 13.5 (11.8–15.4) 17.3 (15.4–19.4) 13.7 (12.4–15.0) 12.6 (11.3–14.1) BMI, kg/m 2 <0.001 <0.001 <0.001 <0.001 <0.001 Normal (<25) 29.6 (28.5–30.7) 18.7 (17.6–19.9) 13.0 (11.6–14.4) 13.7 (12.3–15.3) 4.8 (4.1–5.6) 18.4 (17.3–19.6) Overweight (25–<30) 33.2 (32.4–34.1) 32.3 (30.9–33.8) 35.4 (33.6–37.2) 30.6 (28.7–32.6) 31.3 (29.9–32.7) 34.0 (32.8–35.3) Obese (≥30) 37.2 (36.1–38.4) 49.0 (47.3–50.6) 51.6 (49.5–53.7) 55.7 (53.4–58.0) 63.9 (62.4–65.4) 47.6 (46.1–49.1) Physical activity <0.001 0.04 0.17 <0.001 0.17 Little/None 49.9 (48.5–51.3) 52.5 (50.7–54.3) 48.3 (46.0–50.7) 51.3 (49.3–53.4) 51.6 (50.1–53.2) 50.6 (48.9–52.3) Moderate 25.3 (24.2–26.4) 26.1 (24.5–27.7) 27.3 (25.2–29.6) 25.0 (23.1–27.1) 26.4 (25.1–27.7) 25.4 (24.0–26.9) Vigorous 24.9 (23.8–26) 21.4 (20–22.9) 24.3 (22.5–26.3) 23.6 (21.9–25.5) 22.0 (20.7–23.2) 24.0 (22.7–25.4) Current smoking 19.7 (18.5–20.8) 17.3 (16.0–18.7) <0.001 22.7 (21–24.5) <0.001 24.8 (22.9–26.8) <0.001 17.2 (16.0–18.5) <0.001 18.4 (17.2–19.8) 0.01 Alcohol consumption <0.001 <0.001 <0.001 <0.001 <0.001 Non-drinker 21.3 (20.1–22.6) 26.8 (25.2–28.5) 23.5 (21.7–25.4) 26.5 (24.6–28.5) 24.8 (23.3–26.4) 23.3 (21.8–24.8) Moderate drinker 62.8 (61.1–64.4) 59.4 (57.2–61.5) 57.6 (54.9–60.2) 55.5 (53.2–57.9) 60.0 (58.1–61.8) 61.7 (59.8–63.6) Heavy drinker 15.9 (15–16.8) 13.8 (12.6–15.2) 18.9 (17.0–20.9) 18.0 (16.4–19.7) 15.2 (14.2–16.4) 15.0 (13.8–16.3) Depressive symptoms 0.01 <0.001 <0.001 <0.001 0.08 Normal 77.6 (76.6–78.6) 76.0 (74.5–77.5) 72.7 (70.7–74.7) 73.1 (71–75.2) 74.7 (73.3–76.0) 76.7 (75.2–78.2) Mild 15.4 (14.6–16.3) 16.0 (14.7–17.3) 18.0 (16.4–19.8) 17.4 (15.6–19.3) 17.1 (15.9–18.3) 15.7 (14.5–17.0) Moderate 4.6 (4.2–5.1) 5.4 (4.7–6.2) 6.1 (5.2–7.3) 6.1 (5.3–7.1) 5.5 (4.9–6.2) 5.0 (4.4–5.7) Severe 2.3 (2–2.6) 2.6 (2.1–3.2) 3.1 (2.5–3.8) 3.4 (2.7–4.1) 2.7 (2.4–3.2) 2.6 (2.2–3.0) Antidepressants use 12.6 (11.8–13.4) 16.5 (15.4–17.8) <0.001 17.2 (15.3–19.3) <0.001 14.6 (13–16.3) 0.003 16.3 (15.2–17.4) <0.001 13.7 (12.8–14.8) <0.001
Abbreviations: BMI, body mass index; HDL-C, high-density lipoprotein-cholesterol; MetS, metabolic syndrome. a Prevalence estimates [% (95%CI)] are weighted to be nationally representative.
Table 2. Characteristics of participants by the clustered number of MetS components a .
Characteristic Total ( n = 15,315) None One Two Three Four Five p Value ( n = 2230, 17.1 [16.1–18.2]) ( n = 3322, 23.3 [22.3–24.3]) ( n = 3701, 23.2 [22.2–24.2]) ( n = 3483, 20.7 [19.8–21.6]) ( n = 1801, 10.8 [10.1–11.6]) ( n = 778, 4.9 [4.5–5.4]) Age, years 20–44 45.5 (44.0–47.0) 71.9 (69.4–74.3) 56.8 (54.4–59.1) 40.8 (38.2–43.5) 32.0 (29.6–34.4) 26.5 (23.9–29.3) 20.6 (16.8–24.9) <0.001 45–64 36.4 (35.2–37.6) 23.7 (21.4–26.1) 31.9 (29.7–34.2) 39.0 (36.6–41.4) 40.3 (38.3–42.4) 47.6 (44.6–50.6) 47.8 (43.5–52.1) ≥65 18.2 (17.2–19.2) 4.4 (3.5–5.6) 11.3 (9.8–13) 20.2 (18.4–22.1) 27.7 (25.5–30) 25.9 (23.9–27.9) 31.6 (27.7–35.8) Women 50.6 (49.7–51.6) 53.7 (50.8–56.5) 48.8 (46.3–51.4) 50.6 (48.4–52.8) 49.3 (47.1–51.5) 50.5 (46.6–54.4) 54.3 (50.0–58.6) 0.08 Race/ethnicity Non-Hispanic White 67.8 (65.4–70.1) 68.5 (65.7–71.2) 65.7 (62.6–68.7) 65.8 (62.8–68.7) 68.1 (64.9–71.2) 70.2 (66.8–73.4) 77.6 (73.6–81.2) <0.001 Non-Hispanic Black 10.8 (9.6–12.2) 10.3 (8.9–11.8) 11.1 (9.6–12.9) 11.9 (10.4–13.6) 12.0 (10.4–14) 8.7 (7.3–10.4) 5.7 (4.3–7.6) Mexican American 8.4 (7.2–9.7) 7.0 (5.9–8.3) 8.8 (7.4–10.5) 9.0 (7.5–10.8) 8.5 (7.2–10.0) 8.8 (7.1–10.8) 6.9 (5.2–9.2) Other Hispanic 5.7 (4.8–6.6) 5.4 (4.2–6.8) 6.3 (5.2–7.6) 6.0 (5.0–7.2) 5.1 (4.2–6.1) 5.3 (4.3–6.6) 5.4 (3.8–7.6) Other race 7.3 (6.6–8.2) 8.9 (7.5–10.5) 8.0 (6.9–9.3) 7.3 (6.2–8.5) 6.3 (5.2–7.6) 6.9 (5.5–8.7) 4.3 (2.6–7.2) Education <High school 15.1 (14.0–16.3) 9.6 (8.1–11.3) 13.2 (11.6–15.0) 16.5 (14.9–18.1) 17.7 (16.0–19.6) 17.5 (15.4–19.9) 20.7 (17.9–23.9) <0.001 High school 23.5 (22.3–24.8) 18.0 (15.8–20.4) 22.3 (20.1–24.7) 23.8 (21.6–26.2) 26.5 (24.5–28.5) 27.9 (24.7–31.3) 24.4 (21.1–28.1) Some college 31.0 (29.8–32.3) 30.4 (27.7–33.1) 29.9 (27.7–32.1) 30.9 (28.9–33) 31.7 (29.7–33.9) 32.3 (28.9–35.9) 33.8 (29.3–38.7) College or higher 30.4 (28.4–32.4) 42.1 (38.8–45.5) 34.6 (31.8–37.6) 28.8 (26–31.7) 24.1 (21.9–26.4) 22.3 (19.2–25.8) 21 (16.9–25.8) Family income-to-poverty ratio <130% 20.0 (18.6–21.4) 18.1 (16.3–20.0) 19.2 (17.2–21.3) 19.7 (17.8–21.7) 22.0 (19.8–24.5) 20.8 (18.3–23.5) 21.4 (18.4–24.7) <0.001 130–349% 36.1 (34.8–37.5) 31.1 (28.4–33.8) 35.8 (33.6–38.0) 37.1 (34.8–39.5) 37.8 (35.2–40.6) 39.2 (36.1–42.5) 37.0 (32.7–41.5) ≥350% 43.9 (42.0–45.9) 50.9 (47.5–54.2) 45.1 (42.5–47.7) 43.2 (40.2–46.2) 40.1 (36.9–43.5) 40.0 (36.4–43.7) 41.6 (36.6–46.8) Health insurance 82.9 (81.7–84) 79.5 (76.9–81.8) 80.8 (78.8–82.6) 82.4 (80.5–84.2) 85.7 (84.0–87.2) 85.7 (83.6–87.6) 89.1 (86.5–91.2) <0.001 Marital status Married/Living with Partner 64.3 (62.6–65.9) 58.3 (55.6–61.0) 64.1 (61.6–66.5) 65.2 (62.6–67.8) 66.7 (64.1–69.3) 66.4 (62.5–70.0) 66.1 (61.4–70.4) <0.001 Widowed/Divorced/Separated 17.7 (16.7–18.7) 9.5 (8.2–11.0) 15.1 (13.5–16.8) 18.8 (17.1–20.6) 21.9 (20.1–23.9) 23.1 (20.2–26.3) 23.4 (20–27.3) Never married 18.1 (16.8–19.4) 32.1 (29.6–34.8) 20.8 (18.6–23.2) 16.0 (14.1–18.0) 11.3 (9.9–12.9) 10.5 (8.6–12.9) 10.5 (8.0–13.8) BMI, kg/m 2 Normal (<25) 29.6 (28.5–30.7) 74.8 (72.5–77.0) 41.8 (39.6–44.0) 20.6 (19.0–22.2) 8.3 (7.1–9.8) 4.0 (3.1–5.0) 1.8 (1.1–3.0) <0.001 Overweight (25–<30) 33.2 (32.4–34.1) 23.3 (21.2–25.6) 38.6 (36.6–40.6) 41.7 (39.2–44.1) 32.4 (30.4–34.5) 26.0 (23.4–28.8) 22.0 (18.4–26.2) Obese (≥30) 37.2 (36.1–38.4) 1.8 (1.3–2.7) 19.6 (17.8–21.5) 37.8 (35.5–40.2) 59.3 (56.7–61.8) 70.0 (67.3–72.7) 76.2 (72–79.9) Physical activity Little/None 49.9 (48.5–51.3) 48.4 (45.4–51.4) 47.4 (45.1–49.7) 50.9 (48.5–53.3) 50.5 (48.2–52.9) 50.7 (47.3–54.0) 57.1 (52.3–61.8) <0.001 Moderate 25.3 (24.2–26.4) 23.9 (21.9–26.1) 24.2 (22.2–26.3) 25.1 (23.0–27.3) 26.2 (24.1–28.5) 28.8 (26.2–31.5) 23.9 (19.7–28.7) Vigorous 24.9 (23.8–26) 27.7 (25.4–30.2) 28.4 (26.0–31.0) 24.0 (21.9–26.2) 23.2 (21.3–25.3) 20.6 (18.0–23.4) 19.0 (15.6–22.9) Current smoking 19.7 (18.5–20.8) 20.4 (18.3–22.6) 20.3 (18.4–22.3) 19.6 (17.7–21.8) 19.2 (17.5–21.0) 18.6 (16.1–21.3) 18.8 (15.8–22.2) 0.80 Alcohol consumption Non-drinker 21.3 (20.1–22.6) 15.4 (13.3–17.7) 16.4 (14.9–18.1) 22.0 (20.3–23.8) 24.6 (22.5–26.9) 27.7 (25.1–30.5) 33.9 (30.0–38.1) <0.001 Moderate drinker 62.8 (61.1–64.4) 68.9 (65.8–71.7) 67.5 (65.2–69.7) 62.2 (60.0–64.3) 58.0 (55.2–60.7) 57.2 (53.6–60.8) 53.9 (49.0–58.8) Heavy drinker 15.9 (15–16.8) 15.7 (14.0–17.7) 16.1 (14.4–17.9) 15.8 (14.2–17.5) 17.4 (15.5–19.4) 15.1 (12.8–17.7) 12.1 (9.4–15.6) Depressive symptoms Normal 77.6 (76.6–78.6) 83.0 (81.1–84.8) 79.4 (77.4–81.3) 77.6 (75.6–79.5) 76.3 (74.2–78.2) 72.8 (69.6–75.8) 67.0 (63.0–70.8) <0.001 Mild 15.4 (14.6–16.3) 12.9 (11.2–14.7) 14.4 (12.9–16.1) 15.7 (14.2–17.4) 16.3 (14.6–18.1) 17.3 (14.9–20.0) 20.2 (17.1–23.6) Moderate 4.6 (4.2–5.1) 3.2 (2.5–4.1) 4.0 (3.1–5.1) 4.3 (3.6–5.1) 4.9 (4.1–5.9) 6.4 (5.0–8.1) 9.3 (6.9–12.4) Severe 2.3 (2.0–2.6) 1.0 (0.7–1.4) 2.2 (1.7–2.8) 2.4 (1.8–3.2) 2.5 (2.0–3.2) 3.5 (2.6–4.7) 3.5 (2.4–5.1) Antidepressants use 12.6 (11.8–13.4) 7.5 (6.1–9.2) 9.6 (8.1–11.2) 11.6 (10.1–13.2) 15.5 (14.0–17.1) 18.4 (15.9–21.2) 23.9 (19.9–28.3) <0.001
Abbreviations: BMI, body mass index; MetS, metabolic syndrome. a Prevalence estimates [% (95%CI)] are weighted to be nationally representative.
Table 3. Odds ratios for individual and clustered MetS components by depressive symptoms a .
Individual MetS Components Depressive symptoms Hypertension Raised triglyceride Reduced HDL-C Central obesity Raised blood glucose Normal 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Mild 1.12 (0.97–1.29) 1.30 (1.12–1.52) 1.05 (0.90–1.24) 1.08 (0.89–1.32) 1.12 (0.95–1.32) Moderate 1.37 (1.09–1.72) 1.63 (1.25–2.14) 1.22 (1.00–1.49) 1.82 (1.21–2.74) 1.37 (1.05–1.79) Severe 1.23 (0.82–1.84) 1.44 (1.05–1.97) 1.18 (0.87–1.59) 1.00 (0.63–1.61) 1.36 (0.98–1.90) Clustered Number of MetS Components Depressive symptoms One Two Three Four Five Normal 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Mild 1.15 (0.94–1.41) 1.23 (0.96–1.58) 1.25 (0.96–1.62) 1.34 (0.99–1.83) 1.82 (1.25–2.67) Moderate 1.52 (1.00–2.31) 1.69 (1.09–2.62) 1.90 (1.24–2.91) 2.63 (1.52–4.55) 4.31 (2.45–7.60) Severe 2.08 (1.29–3.37) 2.11 (1.24–3.62) 2.21 (1.18–4.12) 3.04 (1.68–5.51) 3.35 (1.57–7.14)
Abbreviations: HDL-C, high-density lipoprotein-cholesterol; MetS, metabolic syndrome. Model was adjusted for: age, sex, race, education, family income-to-poverty ratio, insurance, marital status, physical activity, BMI, smoking status, and alcohol consumption. a The values of odds ratio (95%CI) with boldface indicates statistical significance ( p < 0.05).
Table 4. Odds ratios for individual and clustered MetS components by antidepressant use a .
Individual MetS Components Hypertension Raised triglyceride Reduced HDL-C Central obesity Raised blood glucose Antidepressant use 1.40 (1.14–1.72) 1.43 (1.17–1.74) 1.01 (0.84–1.22) 1.14 (0.88–1.48) 1.03 (0.88–1.21) Clustered Number of MetS Components One Two Three Four Five Antidepressant use 1.07 (0.78–1.47) 1.04 (0.75–1.44) 1.32 (0.88–1.97) 1.44 (0.99–2.09) 1.74 (1.13–2.68)
Abbreviations: HDL-C, high-density lipoprotein-cholesterol; MetS, metabolic syndrome. Model was adjusted for: age, sex, race, education, family income-to-poverty ratio, insurance, marital status, physical activity, BMI, smoking status, alcohol consumption, and depressive symptoms. a The value of odds ratio (95%CI) with boldface indicates statistical significance ( p < 0.05).
MDPI and ACS Style
Lin, Z.; Chan, Y.-H.; Cheung, B.M.Y.
Dissecting Relations between Depression Severity, Antidepressant Use, and Metabolic Syndrome Components in the NHANES 2005–2020. J. Clin. Med. 2023, 12, 3891.
https://doi.org/10.3390/jcm12123891
AMA Style
Lin Z, Chan Y-H, Cheung BMY.
Dissecting Relations between Depression Severity, Antidepressant Use, and Metabolic Syndrome Components in the NHANES 2005–2020. Journal of Clinical Medicine. 2023; 12(12):3891.
https://doi.org/10.3390/jcm12123891
Chicago/Turabian Style
Lin, Ziying, Yap-Hang Chan, and Bernard Man Yung Cheung.
2023. "Dissecting Relations between Depression Severity, Antidepressant Use, and Metabolic Syndrome Components in the NHANES 2005–2020" Journal of Clinical Medicine12, no. 12: 3891.
https://doi.org/10.3390/jcm12123891
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Molecules | Free Full-Text | Chemical and Antimicrobial Analyses of Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood, an Endemic of the Western Balkan
A comprehensive study on essential oil and different solvent extracts of Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood (Lamiaceae) from Montenegro is reported. The gas chromatography-mass spectrometry analysis of the essential oil revealed a total of 43 components with bicyclogermacrene (23.8%), germacrene D (8%), (E)-caryophyllene (7.9%) and spathulenol (5.5%) as the major ones. Sesquiterpenoid group was found to be the most dominant one (64.8%), with 19.9% of the oxygenated forms. In the crude methanol extract of the investigated plant, obtained by Sohhlet exraction, the total phenol content was 14.7 ± 0.4 mg of GA/g, the total flavonoids were 0.29 ± 0.03% expressed as hyperoside percentage, whereas the total tannins content was 0.22 ± 0.04% expressed as pyrogallol percentage. For the antimicrobial activity determination, the following microorganisms have been used: methicillin-susceptible Staphylococcus aureus (MSSA (American Type Culture Collection (ATCC) 29213)) and methicillin-resistant S. aureus (MRSA (clinical strain)), Escherichia coli (ATCC 25922), carbapenem-susceptible Klebsiella pneumoniae (clinical strain), carbapenem-resistant K. pneumoniae (clinical strain) and Candida albicans (ATCC 14053). The essential oil showed high potency against MSSA and MRSA, both at high (~5 × 105 CFU/mL) and low (~5 × 103 CFU/mL) inoculum. With respect to MSSA, the minimal inhibitory concentration (MIC) value was 0.307 mg/mL, with bactericidal activity obtained at 0.615 mg/mL, while, in the case of MRSA, the MIC and minimal bactericidal concentration (MBC) values were 0.076 and 0.153 mg/mL, respectively. Regarding anti-Candida albicans activity, the MIC value was 2.46 mg/mL without reaching fungicidal activity. In addition to the observed essential oil efficacy, different solvent extracts were analyzed for their antimicrobial activity. Similarly to the essential oil, thehighest efficacy was observed against both MSSA and MRSA strains, at high and low inoculums, in the case of the 1,2-dichloroethane and methanol extracts. A potent fungicidal activity has been also found for the n-hexane and 1,2-dichloroethane extracts. It can be concluded that Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood provides a wide range of application in different fields such as phytochemistry, pharmacology, toxicology or pharmacognosy.
Chemical and Antimicrobial Analyses of Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood, an Endemic of the Western Balkan
by Vanja Tadić 1,† , Alessandra Oliva 2,† , Mijat Božović 3,4,* , Alessia Cipolla 2 , Massimiliano De Angelis 2 , Vincenzo Vullo 2 , Stefania Garzoli 5 and Rino Ragno 4,5,*
Molecules 2017 , 22 (9), 1395; https://doi.org/10.3390/molecules22091395
Abstract
:
Sideritis romana
purpurea
E
Staphylococcus aureus
S. aureus
Escherichia coli
Klebsiella pneumoniae
K. pneumoniae
Candida albicans
5
3
Candida albicans
n
Sideritis romana
purpurea
Keywords:
Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood
essential oil
solvent extracts
GC-MS
flavonoids
phenols
tannins
antimicrobial activity
Graphical Abstract
1. Introduction
Essential oils (EOs) have been known since antiquity to possess different biological activities, notably antibacterial and antifungal, or antioxidant properties [ 1 , 2 ]. Generally, these activities depend on the chemical composition of EO that is determined by the plant genotype, but also greatly influenced by several factors such as geographical origin and environmental and agronomic conditions [ 3 , 4 , 5 ]. Many EOs and their ingredients have an unexpectedly large range of applications. Their cosmetic use is probably the most ancient one, both for their functional, perfume and preservative properties [ 6 ]. They have been widely used as food flavors [ 7 ], and possessing antioxidant and antimicrobial activities serve as natural additives in foods and food products [ 8 ]. Known for their antiseptic (i.e., bactericidal, virucidal and fungicidal), medicinal properties and their fragrance, EOs are used in embalmment, preservation of foods and as antimicrobial, analgesic, sedative, anti-inflammatory, spasmolytic and local anesthetic remedies [ 9 ].
Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood (SP) is an endemic of the Western Balkan. Although numerous scientific studies related to different Sideritis species confirmed biological effects of their active compounds [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], such studies considering this species are rather rare. To the best of our knowledge, there is only one report for SP collected in Greece [ 21 ]. Herein, we report for the first time a comprehensive study on its chemical composition and the related antimicrobial activity from material collected in Montenegro.
Taxonomic Characterization and Uses of SP
Purple ironwort [synonyms: S. purpurea Tal. ex Benth., Hesiodia purpurea (Tal. ex Benth.) Sojàk] from Lamiaceae family is a densely villous-lanate annual that grows up to 30 cm. Its stem is eglandular, and leaves are 10–25 × 5–12 mm, oblong-ovate, dentate or crenate-dentate. Verticillasters are usually 6-flowered and distant. Calyx is 6–10 mm, 2-lipped; upper tooth is broadly ovate, lower lanceolate, all with a straight, pungent apex. Purple (or rarely white) corolla is 7–10 mm, equaling or slightly exceeding calyx, with the upper lip of 4–5 × 1–2 mm ( Figure 1 ) [ 22 ].
It inhabits dry, rocky places or abandoned meadows and arid grasslands, but can also be found on the edges of irrigation ditches or alleys, usually at lower altitudes. To the best of our knowledge, there is no particular report on any traditional use of this subspecies. However, different biological activities of other Sideritis species have been investigated by numerous authors [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. A review work [ 23 ] on genus Sideritis has reported that these plants have been traditionally used for tea preparation, as flavoring agents, and in folk medicine in the Mediterranean and Balkan regions as anti-inflammatory, antiulcerative, antimicrobial, anticonvulsant, antispasmodic, antioxidant, vulnerary, analgesic and carminative agents. According to the authors, diterpenes, flavonoids and EOs occurring in almost each species are the compounds mainly responsible for the observed in vivo and in vitro pharmacological activities. Sideritis is used in Turkish folk medicine as beverage in brew form for its high antibacterial, carminative, diuretic and digestive properties [ 24 ]. The species from this genus are used for its vulnerary properties to heal cuts and wounds of the skin [ 25 ], while, in some Italian regions, the decoy of the exsiccated leaves is used to wash the unconcealed parts of the body in case of fright in order to soothe anxiety [ 26 ].
2. Results and Discussion
2.1. EO and Solvent Extractions
SP essential oil (SPEO) isolated by hydrodistillation from the crushed dried plant material was obtained as a yellow liquid with a yield of 0.015% w / w (calculated per weight of dried material).
Solvent extracts yields are shown in Table 1 and Table 2 . In general, the methanol extracts furnished the highest yields.
2.2. EO Chemical Analysis
Detected components and their percentages according to their relative retention indices (RI) are given in Table 3 . A total of 43 components was determined, representing 90.4% of the EO. The major components were bicyclogermacrene (23.8%), germacrene D (8%), (E or β, but one throughout the text)-caryophyllene (7.9%) and spathulenol (5.5%). Sesquiterpenoid group was found to be the most dominant one (64.8%), with 19.9% of the oxygenated forms. Mono- and diterpene fractions were present only with oxygenated forms: 4.4% and 5.7%, respectively.
Many studies have been performed on the chemical composition of EOs from different Sideritis species, explaining the polymorphism among the populations, as well as the existence of new species, chemical varieties and hybrids. Numerous studies have reported the influence of the geographical location, season, climatological variations, plant variety and experimental conditions on EO composition of Sideritis species, and a possible existence of chemotypes or ecotypes has also been noted [ 27 , 28 , 29 , 30 ]. The most common terpene group of constituents among Sideritis species is almost absent, since some species are rich in monoterpenoids, while others are characterized by the prevalence of sesquiterpenoid fraction, or even diterpenes [ 21 , 31 ]. According to the most prevalent compounds, some authors classified Sideritis species into six main groups: monoterpene hydrocarbon-rich, oxygenated monoterpene-rich, sesquiterpene hydrocarbon-rich, oxygenated sesquiterpene-rich, diterpene-rich and others [ 31 ].
High content of monoterpene hydrocarbons has been reported in many studies, with α-pinene, β-pinene, sabinene, myrcene or limonene as the main ones [ 27 , 30 , 31 , 32 , 33 ]. Thus, some Greek endemic S. clandestina subspecies are rich in α- and β-pinene [ 21 ], as well as S. congesta and S. argyrea EOs [ 34 ]. The Spanish endemic S. ibanyezii has been found to be rich in sabinene and α-pinene [ 32 , 35 ], and the same monoterpenes along with fenchone and cineole were in prevalence in S. pusilla from the Iberian Peninsula [ 36 ]. Limonene was found as the major compound in S. perfoliata [ 34 ], and the prevalence of myrcene has been reported for S. syriaca [ 37 ].
Oxygenated derivatives are not common as main constituents among Sideritis species. Oxygenated forms of monoterpenes are characteristic constituents only in several species: S. arguta, S. libanotica and S. romana [ 31 , 38 ]. Oxygenated sesquiterpenes predominate in EOs of S. phlomoides and S. taurica [ 31 ], while in the group rich in sesquiterpenes, β-caryophyllene, germacrene D and calamene have been identified as the main constituents [ 19 ]. Thus, the Greek endemic S. euboea was dominated by the presence of sesquiterpenes, with the oxygenated sesquiterpene valeranone being the main component, followed by β-caryophyllene and γ-muurolene [ 21 ]. Sesquiterpenoids β-caryophyllene and nerolidol dominated in S. scardica [ 37 ], while germacrene D and bicyclogermacrene were found in prevalence in S. montana, S. curvidens and S. raeseri [ 31 , 37 , 39 ]. S. lanata was also characterized by the abundance of sesquiterpenes, with spathulenol and β-phellandrene being the major metabolites [ 21 , 31 ], while S. condensata provided an EO with high proportions of β-caryophyllene and α-pinene [ 34 ]. S. perfoliata and S. dichotoma are rich in diterpenes [ 40 ], as well as an Greek endemic S. clandestina subsp. peloponnesiaca with the labdane derivative isoabienol being the major diterpene constituent [ 21 ]. S. lanata formed a distinct group with the occurrence of a fatty acid as main constituent in the EO [ 31 ].
21
romana
31
38
2.3. Total Phenolic, Flavonoid and Tannin Contents
Medicinal plants are known to produce diverse substances possessing antioxidant properties that have the ability to protect the human body against cellular oxidation [ 41 ]. Antioxidant compounds as different classes of secondary metabolites like polyphenolic acids, different groups of flavonoids, including flavonols, flavons, flavanones, flavanonols, isoflavonoids, antocyanidis, derivatives of flavan 3-ols (tannins), flavan-3,4-diols, are well known to be able to scavenge free radicals and thus inhibit the oxidative mechanisms that lead to degenerative diseases [ 42 ].
Phenolic compounds are a class of antioxidants that act as free radical terminators and their bioactivities may be related to their abilities to chelate metals, inhibit lipoxygenase and scavenge free radicals [ 43 ]. The phenol content of a plant depends on a number of intrinsic (genetic, extracting solvent) and extrinsic (environmental, handling and development stage) factors [ 44 ]. Total phenolic content (TPC) in the methanol SP extract (F) using the Folin–Ciocalteu’s reagent was expressed in terms of gallic acid equivalent (mg of GA/g of extract) and it was 14.7 ± 0.4. Similar results were obtained with S. lycia and S. libanotica being 16.05–18.04 and 9.16–10.49 mg GA/g, respectively [ 45 ], while higher TPC has been reported for S. raeseri (15.3 to 34.1 mg GA/g), S. scardica (188.5 ± 12.9 mg GA/g), S. amasiaca , S. serratifolia (from 402.5 ± 2.5 to 321.1 ± 0.5 mg GA/g), S. condensata and S. eryhrantha samples (from 247.62 ± 1.91 to 217.61 ± 0.95 mg GA/g) [ 20 , 39 , 46 , 47 , 48 ]. It is well-known that phenolic compounds contribute to quality and nutritional value in terms of modifying color, taste, aroma, and flavor and also in providing health beneficial effects. They also serve in plant defense mechanisms to counteract reactive oxygen species in order to survive and prevent molecular damage and damage by microorganisms, insects, and herbivores [ 49 , 50 , 51 ].
Although a group of compounds of relatively homogenous structure, the flavonoids exhibit wide range of activities, antimicrobial being one among others. Flavonoids were found to reduce blood-lipid and glucose and to enhance human immunity, as well. These compounds among others that contain hydroxyls are responsible for the radical scavenging effect [ 39 , 52 ]. The content of flavonoids (TFC) in the menthanol SP extract (F) was expressed as hyperoside percentage, and the TFC value was calculated as 0.29 ± 0.03%. Comparing with available literature data, this content is similar to that reported for S. raeseri and S. scardica [ 20 , 46 ]. It has been reported that light intensity, temperature and altitude could influence the biosynthesis of flavonoids [ 53 ].
Tannins are generally defined as naturally occurring polyphenolic compounds of high molecular weight. They have been accorded an important role in protecting plant tissues from herbivore attack [ 54 ]. Dietary supplementation of these compounds reduces the oxidative damage to cell membrane lipid, protein and nucleic acid due strong quenching property of free radicals [ 55 ]. Thus, these compounds also provide protection from cardiovascular, immune/autoimmune diseases and brain dysfunctions viz. Parkinson’s, Alzheimer’s, Huntington’s diseases [ 56 ]. The content of tannins, expressed as pyrogallol percentage, in the methanol SP extract (F) was presented as the mean value of three determinations, resulting as 0.22 ± 0.04%, which is quite lower than in the case of S. scardica [ 20 ].
2.4. Antimicrobial Activity
The SPEO antimicrobial potency, compared with that of each reference compound, is shown in Table 4 . The EO showed high activity against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA), both at high (~5 × 10 5 CFU/mL) and low (~5 × 10 3 CFU/mL) inoculum. In fact, with respect to MSSA, the minimal inhibitory concentration (MIC) value was 0.307 mg/mL, with bactericidal activity obtained at 0.615 mg/mL; in the case of MRSA, even stronger activity was observed, with the MIC and minimal bactericidal concentration (MBC) values of 0.076 and 0.153 mg/mL, respectively.
In contrast, no effect was found for E. coli , carbapenem-susceptible and carbapenem-resistant K. pneumoniae , with the MIC values for both pathogens >2.46 mg/mL. Regarding the antifungal activity of SPEO, the MIC value was 2.46 mg/mL for C. albicans , without reaching fungicidal activity (MBC > 2.46 mg/mL).
In addition to observed activity of SPEO against Gram(+) microorganisms and C. albicans , SP extracts have been investigated as well. With the aim to assess the antimicrobial efficacy, the extracts were analysed against MSSA, MRSA and C. albicans . The results are shown in Table 5 . Similarly to the activity of SPEO, the highest efficacy was observed against both MSSA and MRSA strains, at high and low inoculum, for the extracts C and F , with bactericidal activity achieved at 3.09 mg/mL and 2.90 mg/mL, respectively. The extract A was bactericidal against MSSA and MRSA at high inoculum at the concentration of 4.74 mg/mL, whereas D had only a slight activity (i.e., 2 log10 CFU/mL reduction compared to the initial inoculum) against high inoculum of MRSA at 1.3 mg/mL, thus showing bacteriostatic effect.
Furthermore, the potent fungicidal activity has been found for both B and C extracts, with the absence of growth at the concentration 0.75 mg/mL and 3.09 mg/mL, respectively. Our assumption was that the mentioned extracts, obtained at room temperature using non-polar extragens ( n -hexane and 1,2-dichloroethane) might have resemblance of EO, taking into account that non-polar terpenoids, phenylpropanoids and, in some samples, diterpenoids are constituents of EOs. The extracts A , D and F lacked to show any effect against C. albicans . High resistance of each tested microorganisms has been shown in the case of the extracts E , G and H .
There are several reports on the antimicrobial activity of different Sideritis species. For instance, a strong inhibitory effect against Staphylococcus epidermidis was shown by S. trojana EO [ 57 ]. According to the authors, a higher content of oxygenated terpenes derivatives in this EO may be responsible for the better antimicrobial activity. Some Spanish Sideritis species showed great antimicrobial efficacy against Gram(+) bacteria and C. albicans fungal strain, with the lack of any activity against Gram(−) bacterial strains [ 58 ]. Similar results with a significant activity on Gram(+) bacteria were achieved with EOs of S. curvidens and S. lanata [ 59 ]. Six Sideritis taxa of Greek origin have been also analysed confirming this rule. S. aureus was found as the most sensitive strain, whereas E. coli , K. pneumoniae and P. aeruginosa were resistant to the tested oils [ 21 ]. S. lanata EO exhibited the best antimicrobial activity even comparable to the reference antibiotics in the case of S. aureus and M. luteus . Interestingly, one strain of C. albicans was more sensitive compared with the other that was resistant to all tested oils. The EOs of two S. clandestine subspecies exhibited good antifungal activity [ 21 ]. However, some authors reported the same activity on both Gram(+) and Gram(−) bacteria, as well as C. albicans , explaining it by the presence of α- and β-pinene as the main EO constituents [ 60 ]. Interestingly, the higher activity against Gram(−) strains has been reported for S. italica , particularly against P. aeruginosa [ 13 ].
Aside from EOs, Sideritis solvent extracts were also reported to possess significant antimicrobial activity. Considerable potency was reported for methanolic extracts of Turkish S. ozturkii and S. caesarea [ 61 ]. Good activity against S. aureus was shown for hexane extract of S. scardica [ 62 ]. Moreover, its EO, the ethanol extract and its different fractions, as well as the CO 2 -supercritical and conventional extracts have been analyzed on a series of bacterial and yeast strains [ 19 ]. Results indicated strong to moderate potency of all investigated extracts, with Gram(+) bacterial strains being more susceptible than the Gram(−) ones, with the exception of Pasteurella multocida and Haemophilus sp. The strongest antibacterial activity was reported against Corynebacterium pseudotuberculosis for the ethyl-acetate and n -butanol fractions, as well as for the EO. Interestingly, the mentioned solvent extracts exhibited moderate activity against MRSA with MIC values 0.64 mg/mL, while E. coli and K. pneumoniae proved to be the most resistant. According to the authors, the observed activity might be attributed to the presence of different terpenoids types, including diterpenes that have been reported to display important biological activities [ 19 , 63 ].
However, SP seems to be less investigated. To the best of our knowledge, there is only one report for the antimicrobial activity of its EO. In that study, the strong activity was found against S. aureus and Micrococcus luteus with MIC values of 0.006 mg/mL, whereas the good activity was reported against S. epidermidis and C. albicans (the MIC value of 0.024 mg/mL). That study also revealed the resistance of Enterococcus faecalis , E. coli , P. aeruginosa and K. pneumoniae strains [ 21 ]. As expected, due to similar EO chemical compositions, the results herein presented are mainly in agreement with those previously reported. The observed antimicrobial activities might be very interesting when considering their possible use as a part of the treatment of infections caused by MSSA, MRSA and C. albicans . The predominance of sesquiterpenoids (64.8%) could be addressed for the antimicrobial activity, particularly in the case of the opportunistic pathogen S. aureus strains. At least, this could be partly attributed to the ( E )-caryophyllene content that has already demonstrated good activity against S. aureus [ 64 , 65 , 66 ]. Other main compounds bicyclogermacrene and germacrene D are known for their antimicrobial activity [ 67 , 68 ], whereas the spathulenol content could also have a synergy to the exhibited activity [ 69 ]. However, considering the phytocomplex, EO’s trace compounds could also be important as they could act synergistically and/or with antagonistic effects to the antimicrobial actions [ 64 , 70 , 71 ].
3. Materials and Methods
3.1. Plant Material
Aerial parts ( herba ) of wild growing SP were collected in June 2014 in a suburban area Šteke (42°40′94′′ N, 19°17′41.1′′ E) at an altitude of 134 m and about 5 km from Podgorica city (Montenegro) during the time of flowering. Air-drying of the collected plant was performed in a shady place for approximately 20 days, packed in paper bags and kept in a dark and cool place. A voucher specimen (No. DB-SP/01) has been deposited at the University of Montenegro, Department of Biology.
Taxonomic identification was performed by M.B. (the author) and was conducted according to the official European flora [ 22 ].
3.2. EO Extraction
Fifty grams of semi-crushed air-dried plant material and 800 mL of distilled water were subjected to hydrodistillation for 3 h using a Clevenger-type apparatus to produce EO. The accumulated oil/water double phase was extracted 3 times with 20 mL of diethyl ether. The organic layers were dried over anhydrous sodium sulfate (Na 2 SO 4 ), filtered and deprived of the solvent in vacuo to furnish a yellow pale oil. Prepared SP oil (SPEO) was stored in a tightly closed dark vial until further analysis.
3.3. Solvent Extraction
A
A
n
B
C
D
E
In addition, shape-dried powdered SP samples were extracted in Soxhlet apparatus for 24 h according to the standard procedure. Ten grams of each sample was separately extracted with 300 mL of 3 different solvents. Methanol, acetone and diethyl-ether were used, and obtained extracts were labelled as F , G and H , respectively. After the mixtures were evaporated in vacuum, the final extracts were stored in glass vials in refrigerator until further use.
3.4. EO Chemical Analysis
2
m/z
72
72
3.5. Determination of Total Phenols Content (TPC)
TPC was determined by the Folin–Ciocalteu method. In addition, 100 μL of methanolic solution of an SP dry extract (F) (15.63, 7.81 and 3.96 μg/mL final quantity) was mixed with 0.75 ml of Folin–Ciocalteu reagent (previously diluted 10-fold with distilled water) and allowed to stand at 22 °C for 5 min; 0.75 mL of sodium bicarbonate (60 g/L) solution was added to mixture. After 90 min at 22 °C, the absorbance was measured at λ max 725 nm. Gallic acid (0–100 mg/L) was used for calibration of a standard curve. The calibration curve showed the linear regression at r > 0.99, and the results were expressed as milligrams of gallic acid equivalents per gram of plant extract dry weight (mg GAE/g DW). Triplicate measurements were taken and data were presented as mean ± standard deviation (SD) [ 73 ].
3.6. Determination of Total Tannins Content (TTC)
74
max
A
1
A
2
w
w
T
T
C
=
62.5
×
(
A
1
−
A
2
)
×
m
2
A
3
×
m
1
(1)
m
1
m
2
A
3
3.7. Determination of Total Flavonoid Content (TFC)
TFC expressed as hyperoside was calculated using the method described in the Deutsches Arzneibuch, DAB 10. Briefly, the plant extract (F) was extracted with acetone/HCl under reflux condenser; the AlCl 3 complex of the flavonoid fraction extracted by ethyl acetate was measured by UV-Vis Spectrophotometer HP 8453 at λ max 425 nm. The content of flavonoid, expressed as hyperoside percentage, presented the mean ± standard deviation of three determinations.
3.8. Bacterial Strains and Growth Media
For the antimicrobial activity determination, the following microorganisms have been used: methicillin-susceptible Staphylococcus aureus (MSSA (ATCC 29213)) and methicillin-resistant S. aureus (MRSA (clinical strain)), Escherichia coli (ATCC 25922), carbapenem-susceptible Klebsiella pneumoniae (clinical strain), carbapenem-resistant K. pneumoniae (clinical strain) and Candida albicans (ATCC 14053).
After bacterial storage on cryovial bead preservation system (Microbank; Pro-Lab Diagnostics, Richmond Hill, Ontario, ON, Canada) at −80 °C, inoculum was prepared by spreading one cryovial bead on blood agar plate and incubated overnight at 37 °C. One colony was re-suspended in 5 mL tryptic soy broth (TSB) and incubated at 37 °C without shaking. Overnight cultures were then adjusted to a turbidity of 0.5 McFarland, corresponding to ≈ 1 × 10 8 CFU/mL.
3.9. Antimicrobials Agents and EO/Extracts Solutions Preparation
Antimicrobial agents used as reference were provided as purified powder by the manufacturer (Sigma Aldrich, Milan, Italy). Stock solutions at different concentrations were prepared in sterile and pyrogen-free 0.9% saline or water, according to the manufacturer’s instructions.
SPEO and SP extracts were dissolved in 50% dimethylsulphoxide (DMSO) or water, as appropriate, in order to obtain complete solubilization. Used concentration of DMSO did not interfere with bacterial and fungal viability.
3.10. Antimicrobial Assay
Given that the starting solutions were limpid, both minimal inhibitory and bactericidal concentrations (MICs/MBCs) of each reference compound and EO were determined. In contrast, the starting solution of SP extracts was opalescent; thus, only the MBCs were evaluated.
Two-fold serial dilutions of each antimicrobial agent, SPEO and SP extracts were prepared in 2 mL Mueller Hinton broth (MHB) in borosilicate glass tubes and incubated for 24 h at 37 °C. The MIC value was defined as the lowest concentration of antibiotic that completely inhibited visible growth whereas bactericidal activity was defined as ≥3-log10 CFU/mL reduction of the initial bacterial count after 24 h of incubation [ 75 ]. Cation-adjusted Mueller Hinton (CAMHB) and Sabouraud broth were used for bacteria and fungi, respectively.
The following antimicrobial agents were used as references: vancomycin (VAN, Sigma Aldrich, purity >99%) and rifampin (RIF, Sigma Aldrich, purity ≥97%) for Gram-positive microorganisms, meropenem (MEM, Sigma Aldrich, purity ≥98%) for Gram-negative bacteria, and fluconazole (FLU, Sigma Aldrich, purity ≥98%) for fungi.
The used bacterial inoculum was ~5 × 10 3 CFU/mL. Given the high effect observed against MSSA and MRSA, we tested the EO and SP extracts even at higher inoculum (~5 × 10 5 CFU/mL), which represents the likely bacterial amount in case of systemic infections [ 76 ].
All the experiments were performed in duplicate.
4. Conclusions
Plants have provided the source of inspiration for novel drug compounds. Their extracts and EOs have been shown as useful alternative antimicrobial substances, and numerous studies are continuously published on their uses and applications. In this context, investigations on SP are rather rare. Thus, to initially fulfill this gap in this work, we report for the first time a comprehensive study on EO’s chemical composition and its related antimicrobial activity, as well as of different solvent extracts from SP material collected in Montenegro.
E
C. albicans
Although present in SP, different phenolic compounds, flavonoids and tannins obviously had not shown the same antimicrobial activity as its EO. Generally, derivatives of 2-phenylchromen-4-one (bioflavonoids) and 2-phenyl-3,4-dihydro-2 H -chromen-3-ol (tannins), as subgroups within the larger flavonoid group, are considered to be the main groups of active constituents, and, in many national and international pharmacopoeias, these groups of compounds are used for their standardization and quality control. Thus, besides the determination of EO contents, its chemistry profile and antimicrobial potential, we performed the characterization of the plant material in terms of other secondary metabolites.
Bearing in mind the numerous findings on Sideritis species, it can be concluded that SP provides a wide range of application in different fields such as phytochemistry, pharmacology, toxicology or pharmacognosy.
Acknowledgments
The authors are thankful to Branka Knežević for proofreading the paper and Dušan Matković and Predrag Jovanović for the help in field work.
Author Contributions
R.R. and M.B. conceived and initiated the work. M.B. harvested plant material, performed the extraction experiments and drafted the manuscript. V.T. performed the chemical analyses experiments. A.O., A.C., M.D.A. and V.V. performed the microbiology experiments. S.G. contributed with reagents/materials/analysis tools. All of the authors critically edited the manuscript before submission.
Conflicts of Interest
The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
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Sample Availability: Samples of the essential oils and extract are not available from the authors.
Figure 1. Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood in full blossom on its natural habitat in Šteke locality near Podgorica city (Montenegro) (photo by Mijat Božović).
Figure 1. Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood in full blossom on its natural habitat in Šteke locality near Podgorica city (Montenegro) (photo by Mijat Božović).
Table 1. Maceration extraction: final extracts yield (in grams).
Table 1. Maceration extraction: final extracts yield (in grams).
Sample Name Solvent Yield (Grams) A methanol 0.76 B n -hexane 0.03 C 1,2-dichloroethane 0.03 D ethyl-acetate 0.05 E chloroform 0.02
Table 2. Soxhlet extraction: final extracts yield %.
Table 2. Soxhlet extraction: final extracts yield %.
Sample Name Solvent Yield % 1 F methanol 0.254 G acetone 0.176 H diethyl-ether 0.191
1 calculated per plant material weight.
Table 3. Chemical composition of SPEO. Values are in weight %.
Table 3. Chemical composition of SPEO. Values are in weight %.
# 1 Compound Name KI 2 % # 1 Compound Name KI 2 % 1 1,8-cineole 1026 0.3 23 viridiflorol 1592 0.8 2 camphor 1141 0.3 24 8-cedren-13-ol 1688 1.1 3 trans -chrysanthenyl acetate 1235 0.2 25 myristic acid 1770 1.1 4 α-terpinyl acetate 1346 3.1 26 isopropyl tetradecanoate 1828 1.7 5 γ-ylangene 1374 0.2 27 hexahydrofarnesyl acetone 1848 6.9 6 α-copaene 1377 1 28 (5 E ,9 E )-farnesyl acetone 1913 0.5 7 β-bourbonene 1387 0.4 29 phytol 1942 0.9 8 β-( E )-demascenone 1383 0.5 30 palmitoleic acid 1953 0.5 9 β-elemene 1384 0.6 31 palmitic acid 1959 7.6 10 ( E or β)-caryophyllene 1417 7.9 32 isopropyl hexadecanoate 2024 0.6 11 endo -arbazol 1433 0.2 33 manool 2056 0.9 12 aromadendrene 1439 0.3 34 epi -manool 2059 0.3 13 α-humulene 1452 0.4 35 octadecanol 2077 0.6 14 β-farnesene 1454 0.4 36 phytol acetate 2218 1.9 15 γ-muurolene 1478 0.9 37 3α-hydroxy manool 2297 0.9 16 germacrene D 1484 8 38 3-deoxy estradiol 2300 0.8 17 bicyclogermacrene 1500 23.8 39 torulosol 2360 0.8 18 10-epi-italicene ether 1515 1.6 40 pentacosane 2500 0.7 19 δ-cadinene 1522 1 41 hexacosane 2600 0.5 20 spathulenol 1577 5.5 42 heptacosane 2700 0.1 21 caryophyllene oxide 1582 2 43 nonacosane 2900 1.1 22 globulol 1590 1.5 Unidentified compounds 9.6
1 # indicates the compound identification number; 2 Kovats index, experimentally determined.
Table 4. Activity of SPEO against different bacterial and fungal strains detected through microbroth dilution.
Table 4. Activity of SPEO against different bacterial and fungal strains detected through microbroth dilution.
Microorganism MIC Low Inoculum ° (mg/mL) MBC Low Inoculum ° (mg/mL) MIC High Inoculum § (mg/mL) MBC High Inoculum § (mg/mL) Activity MIC Reference Antimicrobial (mg/L) MSSA (ATCC 29213) 0.307 0.615 0.307 0.615 Bactericidal 0.5 (VAN)–0.03 (RIF) MRSA * 0.076 0.153 0.076 0.153 Bactericidal 1 (VAN)–0.06 (RIF) E. coli (ATCC 25922) >2.46 >2.46 - - No effect 0.125 (MEM) CS K. pneumoniae * >2.46 >2.46 - - No effect 0.25 (MEM) CR K. pneumoniae * >2.46 >2.46 - - No effect 16 (MEM) C. albicans (ATCC 14053) 2.46 >2.46 - - Fungistatic 0.25 (FLU)
° Low inoculum: 5 × 10 3 CFU/mL; § High inoculum: 5 × 10 5 CFU/mL; * clinical strain; MSSA: methicillin-susceptible S. aureus ; MRSA: methicillin-resistant S. aureus ; CS: carbapenem-susceptible; CR: carpabenem-resistant; ATCC: American Type Culture Collection; MIC: Minimal Inhibitory Concentration Value; MBC: Minimal Bactericidal Concentration Value; CS: carbapenem-susceptible; CR: carbapenem-resistant; VAN: vancomycin; RIF: rifampin; MEM: meropenem; FLU: fluconazole.
Table 5. Activity of different Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood extracts against methicillin-susceptible S. aureus , methicillin-resistant S. aureus and C. albicans. Low and high inoculum are 5 × 10 3 and 5 × 10 5 colony forming units (CFU)/mL, respectively.
Table 5. Activity of different Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood extracts against methicillin-susceptible S. aureus , methicillin-resistant S. aureus and C. albicans. Low and high inoculum are 5 × 10 3 and 5 × 10 5 colony forming units (CFU)/mL, respectively.
Sample Name MBC MSSA (ATCC 29213) Low Inoculum (mg/mL) MBC MSSA (ATCC 29213) High Inoculum (mg/mL) MBC MRSA ° Low Inoculum (mg/mL) MBC MRSA ° High Inoculum (mg/mL) MBC C. albicans (ATCC 14053) Low Inoculum (mg/mL) Antibacterial Activity Antifungal Activity A 18.99 4.74 4.74 4.74 >18.99 Bactericidal No effect B >0.75 >0.75 >0.75 >0.75 0.75 No effect Fungicidal C 3.09 3.09 3.09 3.09 3.09 Bactericidal Fungicidal D >1.30 * >1.30 >1.30 >1.30 ** >1.30 Bacteriostatic No effect E # >0.89 >0.89 >0.89 >0.89 >0.89 No effect No effect F 2.90 2.90 2.90 2.90 >5.80 Bactericidal No effect G >5.25 >5.25 >5.25 >5.25 >5.25 No effect No effect H >3.07 >3.07 >3.07 >3.07 >3.07 No effect No effect
° clinical strain; * 1log10 CFU/mL reduction compared to the initial inoculum was observed; ** 2log10 CFU/mL reduction compared to the initial inoculum was observed; MSSA: methicillin-susceptible S. aureus ; MRSA: methicillin-resistant S. aureus; MBC: Minimal Bactericidal Concentration; # solubilisation of this extract was not optimal.
Tadić, Vanja, Alessandra Oliva, Mijat Božović, Alessia Cipolla, Massimiliano De Angelis, Vincenzo Vullo, Stefania Garzoli, and Rino Ragno. 2017. "Chemical and Antimicrobial Analyses of Sideritis romanaL. subsp. purpurea(Tal. ex Benth.) Heywood, an Endemic of the Western Balkan" Molecules22, no. 9: 1395.
https://doi.org/10.3390/molecules22091395
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Intracellular metabolism of inorganic arsenic. | Download Scientific Diagram
Download scientific diagram | Intracellular metabolism of inorganic arsenic. from publication: Methylated Arsenicals: The Implications of Metabolism and Carcinogenicity Studies in Rodents to Human Risk Assessment | Monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) are active ingredients in pesticidal products used mainly for weed control. MMA(V) and DMA(V) are also metabolites of inorganic arsenic, formed intracellularly, primarily in liver cells in a metabolic process... | Arsenicals, Carcinogens and DMA | ResearchGate, the professional network for scientists.
Intracellular metabolism of inorganic arsenic.
Methylated Arsenicals: The Implications of Metabolism and Carcinogenicity Studies in Rodents to Human Risk Assessment
Monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) are active ingredients in pesticidal products used mainly for weed control. MMA(V) and DMA(V) are also metabolites of inorganic arsenic, formed intracellularly, primarily in liver cells in a metabolic process of repeated reductions and oxidative methylations. Inorganic arsenic is a k...
Contexts in source publication
Context 1
... uptake of trivalent inorganic arsenic (arsenite) is more extensive than that of pentavalent inorganic arsenic (arse- nate) ( Bertolero et al., 1987;Delnomdedieu et al., 1995;Fischer et al., 1985;Georis et al., 1990;Males et al., 1998;Styblo et al., 1999b) (Figure 2). As V i is hardly taken up into cells. ...
Context 2
... et al. (2000) found that the DMA III -GSH moiety compromised the cell viability of rat hepatocytes at micromolar concentrations (LC 50 = 14.5 μM). However, the reactive trivalent arsenicals are more likely to interact with cellular macromolecules and to produce a toxic effect than the glutathione conjugate, as cytotox- icity in vitro occurs at DMA III concentrations of approximately 0.5 μM (Cohen et al., 2002b). Sakurai et al. (1998) suggested that the cytotoxic mechanism of inorganic arsenic compounds (As III i and As V i ) might differ from that of MMA V and DMA V . ...
It has been suggested that there is an association between environmental, low-level arsenic exposure and the risk of diabetes mellitus (DM), but little research has been conducted. Here, the glucose tolerance status and urinary creatinine adjusted total arsenic concentrations were analyzed in 3,602 subjects ≥ 20 yr of age who were registered for th...
The mechanism of arsine (AsH3) toxicity is not completely understood, but hemoglobin (Hb) has long been recognized as a necessary component of the overall mechanism of AsH3-induced hemolysis. In this study, the role of Hb in AsH3-induced hemolysis was investigated. The purpose was to determine whether exposure to AsH3 altered the structure of the h...
Bezoars were introduced into Western medicine by Arabian doctors during the twelfth century. They were used as antidotes to arsenic, the poison used most commonly in European courts. The use of bezoars was widespread during the sixteenth century, and their value was ten times more than their weight in gold. These were rare and expensive items and m...
Factors impacting on the excess arseniasis prevalence due to indoor combustion of high arsenic coal in a hyperendemic village
Hong Meng
Hui Du
[...]
Jian-Hua Shen
A few villages in Southwest Guizhou, China represented a unique case of arseniasis due to indoor combustion of high arsenic-content coal. The present study is aimed to analyze the contribution of possible factors or of their combination to excess prevalence of arseniasis in the exposed population.
An epidemiological investigation was conducted in a...
Citations
... Inorganic arsenic has an extensive distribution in the environment [14][15][16]. The kidney is the most susceptible of all organ systems to iAs exposure
[17,
18]. There is evidence that exposure to iAs is associated with renal disease. ...
Arsenite Exposure to Human RPCs (HRTPT) Produces a Reversible Epithelial Mesenchymal Transition (EMT): In-Vitro and In-Silico Study
Kalli Schaefer
Donald A. Sens
The human kidney is known to possess renal progenitor cells (RPCs) that can assist in the repair of acute tubular injury. The RPCs are sparsely located as single cells throughout the kidney. We recently generated an immortalized human renal progenitor cell line (HRTPT) that co-expresses PROM1/CD24 and expresses features expected on RPCs. This included the ability to form nephrospheres, differentiate on the surface of Matrigel, and undergo adipogenic, neurogenic, and osteogenic differentiation. These cells were used in the present study to determine how the cells would respond when exposed to nephrotoxin. Inorganic arsenite (iAs) was chosen as the nephrotoxin since the kidney is susceptible to this toxin and there is evidence of its involvement in renal disease. Gene expression profiles when the cells were exposed to iAs for 3, 8, and 10 passages (subcultured at 1:3 ratio) identified a shift from the control unexposed cells. The cells exposed to iAs for eight passages were then referred with growth media containing no iAs and within two passages the cells returned to an epithelial morphology with strong agreement in differential gene expression between control and cells recovered from iAs exposure. Results show within three serial passages of the cells exposed to iAs there was a shift in morphology from an epithelial to a mesenchymal phenotype. EMT was suggested based on an increase in known mesenchymal markers. We found RPCs can undergo EMT when exposed to a nephrotoxin and undergo MET when the agent is removed from the growth media.
... Arsenic trioxide (AS2O3) belongs to the class of trivalent arsenic. Chronic exposure to As2O3 has detrimental effects on health as it causes reduced white blood cell (WBC) count (Kyle and Pearse, 1965;Kannan et al., 2001), depletes antioxidant enzymes and causes hepatotoxicity
(Cohen et al., 2006;
Yasmin et al., 2011). Adverse effects of As2O3 are usually treated with chelators such as 2,3-dimercapapto-1propanesulfonate (DMPS) (Flora et al., 2007). ...
Haematological and biochemical changes in arsenic trioxide-induced toxicity in Wistar rats treated with methanol extract of Parquetina nigrescens leaf.: Effects of methanol extract of Parquetina nigrescens leaf on some physiological indices in Wistar rats.
Oore-oluwapo Daramola
This study was designed to investigate the phytochemical composition and protective effects of methanol extract of Parquetina nigrescens leaf (MEPL) in male Wistar rats. Phytochemical screening, in vitro antioxidant assay, gas chromatography-mass spectrometry (GC-MS) and LD50 were determined. Forty male Wistar rats were grouped into eight and orally treated for 54 days as follows: Group 1 (10% tween 80), Group 2 (3 mg/kg As2O3) Groups 3, 4 and 5 (250, 500 and 1000 mg/kg MEPL) and groups 6, 7 and 8, (250 mg/kg+As2O3, 500 mg/kg+As2O3 and 1000 mg/kg+As2O3). The animals were sacrificed on day 55 under anaesthesia. Blood was collected by cardiac puncture for heamatological studies. Liver concentrations of malondialdehyde (MDA), superoxide dismutase (SOD), aspartate aminotransferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) activities were determined spectrophotometrically. Liver histology was also assessed. Flavonoids, tannin, alkaloids, saponin, and anthraquinone were present in MEPL, also, MEPL scavenged 2,2 diphenyl-1-picrylhydrazyl hydrate (DPPH) and Azino-bis-3-ethylbenzthiazoline-6-sulphonic acid radical (ABTS+). The IC50 of MEPL required to chelate metal was also low. The GC-MS revealed the presence of 24 essential oil. The LD50 was > 5000 mg/kg. Packed cell volume and red blood cell count were significantly reduced in 1000 mg/kg MEPL group, white blood cell count and SOD activity reduced (P<0.05) in 3 mg/kg As2O3 when compared with control but increased in groups co-treated with As2O3 and 250, 500 or 1000 mg/kg + As2O3. MDA concentration, AST, ALT and ALP activities increased significantly in 3 mg/kg As2O3 group but decreased (P<0.05) in groups co-treated with As2O3 and 250, 500 or 1000 mg/kg. The methanol extract of Parquetina nigrescens leaf in male Wistar rats has antioxidant, hepatoprotective and white blood cell protective effects.
... Niveles moderados de arsénico activan la vía EGFR (receptor del factor de crecimiento epidérmico) en pulmones y otros órganos diana de la carcinogénesis por arsénico, como el hígado 69,
80
. Además, el arsénico inducido por las ROS activa la vía de señalización Wnt-βcatenina (que se ha demostrado que promueve el cáncer de pulmón), y estimulan la angiogénesis a través de AKT y ERK1/2 81-83 . ...
Cáncer de pulmón y arsénico: Pulmón y arsénico
INTRODUCCIÓN: Esta revisión surge partir del primer estudio citogenético, realizado en Marcos Juárez(Provincia de Córdoba, Argentina), en donde la población había estado bebiendo agua que contenía más de0,13 mg/l (0,13 ppm) de arsénico. En este trabajo llamó la atención la relación entre el cáncer de pulmón yel contenido de arsénico en el agua de consumo, debido a que las causas de muerte de esta población entrelos años 1970-1988 mostraron un significativo aumento, siendo este hallazgo similar a otras investigacionesposteriores sobre el tema. La literatura revisada muestra que la exposición al arsénico ejerce efectosdeletéreos para la salud, principalmente a través de la inducción de estrés oxidativo, alteraciones en lametilación del ADN, modificación de histonas y expresión de mi ARN; por lo que sería interesantedeterminar la presencia y consecuencia de estas alteraciones en las poblaciones afectadas por lacontaminación del agua con arsénico, sin perder de vista otros agentes ambientales. Comprender comoactúa y la promoción de la carcinogénesis relacionada con los procesos de biotransformación del arsénicosería importante para la detección y tratamiento en las personas afectadas.
... Similar to ATO, realgar is also a kind of mined ore that contains arsenic. Currently, it is widely accepted that the benefit and risk of arsenic are solely dependent on the chemical forms of arsenic rather than the arsenic content alone
[17]
. Realgar's monoclinic crystal structure is cradle-type with an octatomic ring spatially and includes approximately 90% As4S4, of which the crystalline form is α-As4S4. ...
Realgar (As4S4), a traditional Chinese medicine, induces acute promyelocytic leukemia cell death via the Bcl-2/Bax/Cyt-C/AIF signaling pathway in vitro
Full-text available
Sep 2022
Ruiming Zhang
Xuewei Yin
Nana Li
Ruirong Xu
Acute promyelocytic leukemia (APL) is a specific subtype of acute myelogenous leukemia (AML) characterized by the proliferation of abnormal promyelocytes. Realgar, a Chinese medicine containing arsenic, can be taken orally. Traditional Chinese medicine physicians have employed realgar to treat APL for over a thousand years. Therefore, realgar may be a promising candidate for the treatment of APL. Nevertheless, the underlying mechanism behind realgar therapy is largely unclear. The present study aimed to investigate the effect of realgar on cell death in the APL cell line (NB4) in vitro and to elucidate the underlying mechanism. In this study, after APL cells were treated with different concentrations of realgar, the cell survival rate, apoptotic assay, morphological changes, ATP levels and cell cycle arrest were assessed. The expression of Bcl-2, Bax, Cytochrome C (Cyt-C) and apoptosis-inducing factor (AIF) at the mRNA and protein levels were also measured by immunofluorescence, quantitative PCR (qPCR) and Western blotting. We found that realgar could significantly inhibit APL cell proliferation and cell death in a time- and dose-dependent manner. Realgar effectively decreased the ATP levels in APL cells. Realgar also induced APL cell cycle arrest at the S and G2/M phases. Following realgar treatment, the mRNA and protein levels of Bcl-2 were significantly downregulated, whereas the levels of Bax, Cyt-C, and AIF were significantly upregulated. In summary, realgar can induce APL cell death via the Bcl-2/Bax/Cyt-C/AIF signaling pathway, suggesting that realgar may be an effective therapeutic for APL.
... . Simultaneously, these compounds were divided into two groups according to their reported mutagenicity in a bacterial reverse mutation test (Ames test): mutagenic and nonmutagenic compounds39,43,44,53,64,67,82,83,85,88,89,91,93,111,[118][119][120][121][122][123][124]
[125]
[126][127][128][129][130][131] . The results of the quantitative analysis of γ-H2AX immunostaining in the rat bladder urothelium are shown in ...
Early detection of urinary bladder carcinogens in rats by immunohistochemistry for γ-H2AX: a review from analyses of 100 chemicals
In safety evaluations of chemicals, there is an urgent need to develop short-term methods to replace long-term carcinogenicity tests. We have reported that immunohistochemistry for γ-H2AX, a well-established biomarker of DNA damage, can detect bladder carcinogens at an early stage using histopathological specimens from 28-day repeated-dose oral toxicity studies in rats. Given the markedly low level of γ-H2AX formation in the bladder urothelium of untreated rats, an increase in γ-H2AX-positive cells following chemical exposure can be relatively easy to identify. Among the 100 compounds examined to date, bladder carcinogens can be detected with high sensitivity (33/39; 84.6%) and specificity (58/61; 95.1%). As expected, γ-H2AX formation levels tended to be high following exposure to genotoxic bladder carcinogens, whereas nongenotoxic bladder carcinogens also increased the number of γ-H2AX-positive cells, probably through secondary DNA damage associated with sustained proliferative stimulation. γ-H2AX formation in the bladder urothelium reflects species differences in susceptibility to bladder carcinogenesis between rats and mice and shows a clear dose-dependency associated with the intensity of tumor development as well as high reproducibility. Some of the bladder carcinogens that showed false-negative results in the evaluation of γ-H2AX alone could be detected by combined evaluation with immunostaining for bladder stem cell markers, including aldehyde dehydrogenase 1A1. This method may be useful for the early detection of bladder carcinogens, as it can be performed by simple addition of conventional immunostaining using formalin-fixed paraffin-embedded tissues from 28-day repeated-dose toxicity studies in rodents, which are commonly used in safety evaluations of chemical substances.
... •-), singlet oxygen ( 1 O 2 ), hydroxyl radical (HO • ), hydrogen peroxide (H 2 O 2 ), and dimethyl As radical [(CH 3 ) 2 As • ], leading to the damage of DNA and proteins responsible for altering the cellular architecture, permeability, and cell survival
[3]
. As has been found to activate a series of downstream signaling cascades and to further disrupt signaling related to cell growth, proliferation, and apoptosis [1]. ...
Glucogallin Attenuates RAW 264.7 Cells from Arsenic Trioxide Induced Toxicity via the NF-ҡB/NLRP3 Pathway
Chronic arsenic (As) poisoning is mostly due to subsoil water contaminated with As and its salts. Exposure to As has been found to cause an elevation in reactive oxygen species (ROS), leading to the damage of DNA and proteins, and it also causes immunotoxicity. Treatment regimens are primarily based on chelation therapy and amino acid and vitamin supplementations. Recent studies have established that natural products display effective and progressive relief from arsenicosis without any side effects. β-glucogallin (BGG), a gallo-tannin natural product, is reported to possess anti-oxidant and anti-inflammatory properties. In the present study, we aim to observe the protective role of BGG against As-induced cytotoxicity, apoptosis, mitochondrial dysfunction, and the underlying mechanisms in RAW 264.7 macrophage cells. We found that BGG alleviates As-induced ROS, apoptosis, and mitochondrial dysfunction in RAW 264.7 macrophage cells. Thus, BGG can be used therapeutically to prevent As-induced toxicity.
... Studies show that inorganic arsenic salts are rapidly and nearly completely absorbed after ingestion (ATSDR 2005;Schuhmacher-Wolz et al. 2009). After absorption, inorganic arsenic is quickly distributed and taken up by cells, where it can accumulate in skin, hair, and nails and can pass into the brain, placenta, and breast milk (ATSDR 2005;
Cohen et al. 2006;
WHO 2001;Schuhmacher-Wolz et al. 2009). It is then metabolized and can be methylated into the forms DMA and MMA. ...
Arsenic exposure and prevalence of human papillomavirus in the US male population
Humairat H. Rahman
Arsenic is a known carcinogen and is naturally available in earth’s crust. Inorganic arsenic is an environmental pollutant with immunosuppressive properties. Human papillomavirus (HPV) is considered one of the most common sexually transmitted diseases in the United States. HPV is linked to several types of cancers in males, including oral, anal, and penile cancer. However, limited information is available on the effect of arsenic on HPV in males. The purpose of this study was to examine the association of urinary arsenic species (speciated and total) and the prevalence of HPV infection in the male population. HPV prevalence in males was analyzed using the 2013–2014 and 2015–2016 National Health and Nutrition Examination Survey (NHANES) dataset. Logistic regression analysis was used to examine associations of seven types of urinary arsenic species (arsenous acid, arsenic acid, arsenobetaine, arsenocholine, dimethylarsinic acid (DMA), monomethylarsonic acid (MMA), total arsenic acid) with HPV risk for male participants aged 18–59 years (N = 1516). Demographic characteristics were included in the logistic regression model for each arsenic variable. All statistical analyses were conducted by using the software R (version 4.2.0). Increasing DMA was positively associated with the prevalence of low-risk HPV (odds ratio (OR): 1.075, 95% confidence interval (CI): 1.025, 1.128) in addition to the sum of total toxic arsenic species (TUA1) including arsenous acid, arsenic acid, DMA, and MMA (OR: 1.068, 95% CI: 1.022, 1.116). High-risk HPV strains were found to be positively associated with arsenic acid (OR: 1.806, 95% CI: 1.134, 2.876) and total arsenic minus the sum of the two organic arsenic species arsenobetaine and arsenocholine (TUA2) at quartile 3 (Q3) level (OR: 1.523, 95% CI: 1.102, 2.103). The logistic regression models also showed that race and marital status were significant factors related to high-risk HPV. Our study reported that DMA and TUA1 are associated with low-risk HPV and arsenic acid is associated with high-risk HPV infections in males. Future research is required to confirm or refute this finding.
... Furthermore, human exposure to As occurs by various industrial processes and polluted air [7]. Moreover, As induces skin lesions
[8]
, neurodegenerative disorders [9], diabetes mellitus [10], and cancer [11]. Epidemiological researches have confirmed that chronic As exposure predisposes an individual to many cardiovascular diseases (CVDs) such as hypertension and arteriosclerosis [12,13]. ...
... Hypertension is the main risk factor associated with CVDs [14]. Toxic elements such as As, cadmium, and mercury increase blood pressure
[8]
. For example, a high prevalence of hypertension was reported in As-contaminated areas [15]. ...
Melatonin improves arsenic-induced hypertension through the inactivation of the Sirt1/autophagy pathway in rat
Arsenic (As), a metalloid chemical element, is classified as heavy metal. Previous studies proposed that As induces vascular toxicity by inducing autophagy, apoptosis, and oxidative stress. It has been shown that melatonin (Mel) can decrease oxidative stress and apoptosis, and modulate autophagy in different pathological situations. Hence, this study aimed to investigate the Mel effect on As-induced vascular toxicity through apoptosis and autophagy regulation. Forty male rats were treated with As (15 mg/kg; oral gavage) and Mel (10 and 20 mg/kg, intraperitoneally; i.p.) for 28 days. The systolic blood pressure (SBP) changes, oxidative stress markers, the aorta histopathological injuries, contractile and relaxant responses, the level of apoptosis (Bnip3 and caspase-3) and autophagy (Sirt1, Beclin-1 and LC3 II/I ratio) proteins were determined in rats aorta. The As exposure significantly increased SBP and enhanced MDA level while reduced GSH content. The exposure to As caused substantial histological damage in aorta tissue and changed vasoconstriction and vasorelaxation responses to KCl, PE, and Ach in isolated rat aorta. The levels of HO-1 and Nrf-2, apoptosis markers, Sirt1, and autophagy proteins also enhanced in As group. Interestingly, Mel could reduce changes in oxidative stress, blood pressure, apoptosis, and autophagy induced by As. On the other hand, Mel led to more increased the levels of Nrf-2 and HO-1 proteins compared with the As group. In conclusion, our findings showed that Mel could have a protective effect against As-induced vascular toxicity by inhibiting apoptosis and the Sirt1/autophagy pathway.
... Various studies have reported that arsenic-induced toxicity leads to severe damage to the vital organs of the system (Yamamoto et al., 1995;Wanibuchi, et al., 1996;
Cohen, et al., 2006)
. Arsenic exposure usually damages the glycolysis pathway, which causes disrupted ATP synthesis (Helleday et al., 2000). ...
Phytoremedial effect of Asparagus racemosus on sodium arsenite-induced toxicity in Charles Foster rats
Arsenic poisoning has recently resulted in significant health problems in the exposed population. In India, the Indo-Gangetic plains are the region where the arsenic threat has increased. In Bihar, it is estimated that 10 million people are exposed to arsenic poisoning. The present study aims to develop a novel drug as an antidote against arsenic-induced toxicity in rats. In the present study, arsenic in sodium arsenite at a dose of 8 mg/kg body weight per day was induced (Group-II) in Charles Foster rats at 2 or 6 months to observe chronic exposure. In the arsenic pretreated group (Group-III), Asparagus racemosus was administered at a dose of 400 mg/kg body weight per day for 8 weeks. Normal control group (Group I) was taken without any treatment. After completion of the entire experiment, the animals were sacrificed, and their blood samples were obtained for hematological and biochemical evaluation. At the same time, vital tissues, such as the liver and kidney, were fixed in preservatives for the histopathological study. The study showed that the hematological levels, such as RBC, WBC, platelet counts and hemoglobin percentage, were significantly restored by administering A. racemosus (Group-III), against the arsenic-exposed group. Furthermore, biochemical parameters such as SGPT, SGOT, ALP, bilirubin, urea, uric acid and creatinine were significantly recovered (p<0.05) against arsenic-induced toxicity. The histopathological study also showed remarkable restoration in hepatocytes and nephrocytes by A. racemosus against arsenic-induced toxicity. Therefore, it can be concluded from the entire study that A. racemosus has a significant antidote effect against arsenic-induced toxicity.
... Most of the ingested and inhaled 'As' gets absorbed through the gastrointestinal tract and lungs into the bloodstream (Bruce et al. 2015). Absorption may involve two mechanisms viz., trivalent 'As' via diffusion
(Cohen et al. 2006
) and pentavalent 'As' via energy-dependent transport system (Lindgren et al. 1984).The trivalent arsenicals bind to the sulfhydryl (-SH) groups of dihydrolipoamide inhibits pyruvate dehydrogenase (Bergquist et al. 2009) either, directly attacking -SH groups or indirectly through the generation of reactive oxygen species (ROS) (Chen et al. 1998). Arsenic interferes with enzymes namely, catalase (CAT) ( Exposure to 'As' and its metabolites methyl arsonic acid (MMA) [III] suppresses the N-methyl D-asparate receptors in the hippocampus, which play a pivotal role in synaptic plasticity, learning and memory, leading to neurobehavioral disorders and cognitive dysfunction (Petrick et al. 2000). ...
Nanocurcumin Restores Arsenic Induced Disturbances in Neuropharmacological Activity in Wistar Rats
The present study was carried out to examine the ameliorative potential of nanocurcumin against arsenic induced (sub-chronic) alterations in central nervous system in male Wistar rats. Nanocurcumin was synthesised and the hydrodynamic diameter, zeta potential and particle size were ~ 76.60 nm, (-) 30 mV and 95nm, respectively. Experimental rats sub-chronically exposed to sodium (meta) arsenite (As; 10 mg.kg − 1 ; 70 days; p.o ) induced significant ( p < 0.05) reduction in superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione and favoured free radical generation and induced lipid peroxidation in brain tissue. Further, sub-chronic arsenic exposure resulted in significant ( p < 0.05) decrease in voluntary- and involuntary motor activities and enhanced anxiety levels. However, experimental rats receiving nanocurcumin (15 mg.kg − 1 ; p.o ) showed significant ( p < 0.05) recovery in enzymatic - and non-enzymatic antioxidant defence system and restoration of redox balance and overcome arsenic induced depression in motor activities and elevated anxiety levels. Further, Arsenic induced elevation in pro-inflammatory cytokines, cyclooxygenase-2 activity and prostaglandin-E 2 in brain and angiotensin-II levels (plasma) was significantly ( p < 0.05) reduced in experimental rats receiving nanocurcumin. Additionally, quantitative real -time polymerase chain reaction revealed a fivefold decrease in Nox 2 expression in brain following nanocurcumin administration. Thus, the study concludes that nanocurcumin can serve as a potential therapeutic candidate to counter arsenic induced redox imbalance and neuropharmacological disturbances and there exists a vast scope to exploit its utility after appropriate clinical modelling.
| https://www.researchgate.net/figure/Intracellular-metabolism-of-inorganic-arsenic_fig1_7045822 |
Pakistan: more war always means more victims - ICRC
The latest fighting in Pakistan's North-Western Frontier Province (NWFP) has caused civilian casualties and massive displacement. Hundreds of thousands have fled in recent days. Tens of thousands inside the conflict areas are in danger, not only from the fighting but also because they are virtually cut off from basic health care, food, water and sanitation. ICRC head of delegation Pascal Cuttat explains the organization's response to the crisis.
Pakistan: more war always means more victims
The latest fighting in Pakistan's North-Western Frontier Province (NWFP) has caused civilian casualties and massive displacement. Hundreds of thousands have fled in recent days. Tens of thousands inside the conflict areas are in danger, not only from the fighting but also because they are virtually cut off from basic health care, food, water and sanitation. ICRC head of delegation Pascal Cuttat explains the organization's response to the crisis.
© REUTERS
A young bomb victim lies bandaged in a Peshawar hospital in the North-Western Frontier Province.
© REUTERS/Faisal Mahmood
A couple fleeing military operations in Buner arrive with their infant at a police checkpoint near Takht Bai.
© REUTERS/Mian Kursheed
Civilians packed in a vehicle flee a military offensive in the North-Western Frontier Province.
Pascal Cuttat, head of ICRC delegation in Pakistan
Is the current crisis different from other recent crises in Pakistan?
The conflict between the government and the Taliban has escalated rapidly over the last two weeks and has generated a humanitarian crisis. Over 500,000 internally disp laced persons (IDPs) from the Swat, Dir and Buner districts have now joined another 500,000 who had already left their homes in Bajaur and Swat in the preceding months, bringing the total number of IDPs to over a million. The geographical extent of the conflict zone is now wider. The number of troops deployed is larger. Consequently, the impact on the civilian population is much greater. The ICRC has never seen so many people affected within such a short timeframe in the recent history of Pakistan. More war always means more victims.
What differentiates the ICRC from other humanitarian agencies currently responding to the crisis?
One important point is that under our mandate and our principles of neutrality and independence, we speak to all parties and make representations to all parties whenever necessary. Over the last year, the ICRC has established solid lines of communication with both the armed forces and insurgent groups. Today, in the midst of a crisis, this is allowing us unique access to those in charge of operations on the ground – on both sides. This privileged access allows us to be present in the conflict zone – we entered Buner on 13 May, the first humanitarian organization to do so – and to help people in areas few other agencies can reach. This is our real strength. Another significant difference is the added value of the Red Cross/Red Crescent Movement, in this case our partnership with the Pakistan Red Crescent Society (PRCS), a highly competent local organization that has been able to rapidly mobilize its staff and volunteers in many of the affected areas.
What is the role of international humanitarian law in this conflict?
The protection of civilians and their right to assistance in such difficult times, as stipulated under international humanitarian law (IHL), are at the core of the ICRC's mandate. As always when a conflict erupts, we have reminded all parties to the conflict of their obligations under IHL. In particular, we have reminded them of their obligation to respect and protect civilians and people no longer taking part in the hostilities, and to so conduct their operations as to spare civilians the effects of the fighting. We will continue to remind the Pakistani forces and the armed opposition of these obligations and to make representations aimed at enhancing the protection of civilians whenever necessary.
Given its mandate, its reliance on neutral and independent humanitarian action and its network of contacts in the region, how can the ICRC best help people affected by the crisis?
Major efforts – by, among others, the Pakistani government and the international community – are under way to assist IDPs in North-West Frontier Province. We are carrying a fair proportion of this workload by providing water, sanitation and health care in PRCS-run camps. We talk to everybody involved. In addition, we will be endeavouring to help people who are not in the spotlight today simply because it is more difficult for aid workers and journalists to reach them. I’m talking about the weak, the wounded and the sick who remain in conflict areas. They include people who have lost contact with their families because they had to flee the war so suddenly.
What are the ICRC's operational objectives for the coming weeks and months?
We aim to respond swiftly and efficiently, so as to bring health care, food, water and sanitation to those most in need, and to preserve the dignity of all civilians affected by the conflict.
The PRCS is a crucial partner for the ICRC. To give one example, the PRCS has just delivered food and other essential assistance to more than 13,000 people in the conflict-hit areas of Malakand and Lower Dir, distributing the aid in several IDP camps it runs with the support of the ICRC.
The ICRC works very closely with the PRCS at all stages, from the planning of operations to implementation. We are part of the same Movement and we are in this together.
| https://www.icrc.org/en/doc/resources/documents/interview/pakistan-interview-150509.htm |
WikiGenes - Re - rex
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Re
-
rex
Mus musculus
Synonyms:
Den, Ri, denuded, riccioli
Manen,
C.A. et al. , Euteneuer,
B. et al. , Michael,
S.K. et al. , Giblin,
M.F. et al. , Brade,
L. et al. , et al.
Lindner , Simon , Dhen , Seifert , Edelman , Ballantyne , Rogers ,
Disease relevance of Re
This mutation exhibits corneal opacity as well as abnormal skin and hair development resembling rex denuded (Re(den)) and bareskin (Bsk) [1] .
Later, the denuded areas developed a keratosis which was prone to infection [2] .
To investigate the nature of this protection, dogs and rabbits were immunized with purified glycolipid prepared by phenol -chloroform-petroleum ether extraction of the "Re" mutant of Salmonella minnesota 595 and opsonophagocytic and bactericidal tests were carried out using lapine peritoneal granulocytes and serum factors [3] .
Results from receptor-binding assays conducted with B16 F1 murine melanoma cells indicated that receptor-binding affinity was reduced to approximately 1% of its original levels after Re incorporation into the cyclic Cys4,10, D-Phe7-alpha-MSH4-13 analog [4] .
In all of the in vitro assays, these synthetic compounds exhibited high activities comparable to those of a reference lipid A prepared from Escherichia coli O8:K27 Re-mutant strain F515 [5] .
High impact information on Re
Unlike secondary oocytes , fertilized eggs denuded of their zona pellucida no longer contained the enzyme, suggesting that tissue-type PA production stops at or around fertilization, and that the bulk of the enzyme is secreted at this time [6] .
The locus at which the denuded blastocysts attached to the culture dish was usually a random section of their mural trophoblasts , in which case single egg cylinders developed unilaterally [7] .
By electron microscopy both strains showed a similar attachment of PMN to the denuded GBM together with swelling and necrosis of endothelial cells [8] .
Furthermore, markers of leukocyte activation - in particular, increased expression of the beta2-integrin Mac-1 (alphaMbeta2, or CD11b/CD18), which is responsible for firm leukocyte adhesion to platelets and fibrinogen on denuded vessels - predict restenosis after PTCA [9] .
The injury destroyed all medial smooth muscle cells, denuded the injured segment of intact endothelium , and induced transient platelet-rich mural thrombosis [10] .
Chemical compound and disease context of Re
In these studies we utilized intrinsically labeled 14C-labeled LPS from Salmonella minnesota or the 14C-labeled glycolipid derived from the Re mutant of S. minnesota (R595) [11] .
Monophosphoryl lipid A (MPL) from Salmonella typhimurium Re mutant strain was used as a potential immune response modifier in some vaccines [12] .
Treatment with nontoxic monophosphoryl lipid A (MPL) derived from a polysaccharide -deficient, heptoseless Re mutant of either Salmonella typhimurium or Salmonella minnesota R595 enhanced the immunoglobulin M (IgM) anti-type III pneumococcal polysaccharide (SSS-III) antibody response of C3H/HeSnJ mice [13] .
Lipopolysaccharide (LPS) extracted from three strains of Salmonella typhimurium, i.e., the rough Re mutant SL1102, the rough Ra mutant TV119, and the smooth strain SH4809, was first electrodialyzed (eLPS) and then divalent cation deprived by EDTA treatment and finally made monomeric by deoxycholate solubilization [14] .
Immunotherapeutic agents studied included live Bacillus Calmette-Guerin ( BCG ) preparations in varying doses and strains (Tice, Pasteur, and Glaxo), Re mutant glycolipid (ReG) from Salmonella typhimurium, BCG cell wall skeletons (CWS), CWS plus B4 glycolipid fraction of ReG, and Keyhole-Limpet Hemocyanin (KLH) [15] .
Biological context of Re
The dominant alopecia phenotypes Bareskin, Rex- denuded , and Reduced Coat 2 are caused by mutations in gasdermin 3 [16] .
The Hox-2 homeo box gene complex on mouse chromosome 11 is closely linked to Re [17] .
A single copy fragment was isolated from the 3' flanking region of the U1a1 gene and used as a hybridization probe for Southern blotted DNAs from recombinant inbred strains of mice , mouse-hamster hybrid cells , and the offspring from backcrosses between BALB/c mice and mice which were heterozygous for the Rex (Re) marker [18] .
Characterization and mapping of DNA sequence homologous to mouse U1a1 snRNA: localization on chromosome 11 near the Dlb-1 and Re loci [18] .
Redesign of the metal binding site resulted in a second-generation Re-peptide complex (ReCCMSH) that displayed a receptor-binding affinity of 2.9 nM, 25-fold higher than the initial Re- alpha-MSH analog [4] .
Anatomical context of Re
Therefore, the endogenous C1q of macrophages also appears to be involved in attachment of the S. minnesota Re mutant [19] .
In contrast to the S-form of Salmonella minnesota, its Re mutant binds to mouse peritoneal macrophages [19] .
Macrophages preincubated with immunoglobulin G-sensitized erythrocytes had a low chemiluminescent signal, and after treatment of the cells with the Re mutant, there was an additional, higher signal [19] .
In vitro stimulation of spleen cells from animals classically immunized with Salmonella Re mutant enhanced the number of lipid A-specific IgG-producing hybridomas from six after direct fusion to 17 after stimulation [20] .
Salmonella Re mutants are non-invasive for cell monolayers but still can enter and replicate in L-929 murine fibroblast cells [21] .
Associations of Re with chemical compounds
IgM antibody to the Re mutant was protective against bacterial challenge with both test strains of bacteria and S. typhi LPS [22] .
Spermidine concentration in the livers of both male and female PRO/Re mice was approx. 130% that of the controls [23] .
Male PRO/Re mice excreted putrescine at 175% and spermidine at 300% the amount of male C57BL/6J controls [23] .
The increased polyamine biosynthesis and excretion in the PRO/Re mutant mice may be a mechanism to decrease the extent of proline accumulation [23] .
When the concentrations of the polyamines in the tissues of the PRO/Re mice were determined, spermidine and spermine concentrations in the kidneys of the male PRO/Re mice were twice those of the controls [23] .
Regulatory relationships of Re
There was no significant difference between PRO/Re and C57BL/6J male mice for either putrescine - or spermidine -stimulated S-adenosylmethionine decarboxylase activity [23] .
SMC forming a pseudoendothelium in chronically denuded vessels continued to express high levels of VCAM-1 and MCP-1 , thus perpetuating the inflammatory response [24] .
Müllerian inhibiting substance (MIS) inhibited the resumption of meiosis in both denuded and cumulus cell-enclosed rat oocytes in vitro [25] .
Other interactions of Re
A family of type I keratin genes and the homeobox-2 gene complex are closely linked to the rex locus on mouse chromosome 11 [26] .
Examination of the enzymes involved in polyamine biosynthesis revealed that ornithine decarboxylase , the initial enzyme in the polyamine-biosynthetic pathway, was increased by 150% in the kidneys and by 100% in the liver of male PRO/Re mice [23] .
Preincubation of macrophages with the Re mutant abolishes immunoglobulin G-sensitized erythrocyte -induced chemiluminescence [19] .
Mouse protection induced by Pseudomonas aeruginosa PAC1R and its defective mutants, Salmonella minnesota Re-mutant and Escherichia coli O14 [27] .
The animals challenged with WT LPS showed a decrease in uterine cAMP when the mice were starting to expel the fetuses while the Re LPS treated group maintained control levels of cAMP [28] .
Analytical, diagnostic and therapeutic context of Re
Active and passive immunization with Re chemotype mutants of Salmonella minnesota afforded significant protection against heterologous gram-negative bacilli and were considerably more effective than immunization with smooth S. minnesota or its Ra, Rb, Rc, Rd1 and Rd2 mutants [29] .
Mouse monoclonal antibodies were raised against heat-killed bacteria of the Re mutant R595 of Salmonella minnesota and characterized by the passive hemolysis and passive hemolysis inhibition tests and by double immunodiffusion experiments using lipopolysaccharide (LPS) from different rough mutants of S. minnesota and synthetic antigens [30] .
Active immunization experiments were also performed with the Re mutant of Salmonella minnesota 595 which carries a lipopolysaccharide composed of lipid A and three residues of ketodeoxyoctonic acid [31] .
Membrane proteins of the murine-pre-B-cell line 70Z/3 were separated by SDS-PAGE , transferred electrophoretically onto nitrocellulose, and the blot was incubated with LPS of the Salmonella minnesota Re-mutant R595 (mRe-LPS) [32] .
Transmission electron microscopy , light microscopy, and immunohistochemistry revealed that electric injury destroyed all medial smooth muscle cells, denuded the injured segment of intact endothelium , and transiently induced platelet-rich mural thrombosis [33] .
References
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The Hox-2 homeo box gene complex on mouse chromosome 11 is closely linked to Re. Hart, C.P., Dalton, D.K., Nichols, L., Hunihan, L., Roderick, T.H., Langley, S.H., Taylor, B.A., Ruddle, F.H. Genetics (1988) [ Pubmed ]
Characterization and mapping of DNA sequence homologous to mouse U1a1 snRNA: localization on chromosome 11 near the Dlb-1 and Re loci. Michael, S.K., Hilgers, J., Kozak, C., Whitney, J.B., Howard, E.F. Somat. Cell Mol. Genet. (1986) [ Pubmed ]
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Monoclonal antibody of IgG isotype against a cross-reactive lipopolysaccharide epitope of Chlamydia and Salmonella Re chemotype enhances infectivity in L-929 fibroblast cells. Haralambieva, I.H., Iankov, I.D., Petrov, D.P., Mladenov, I.V., Mitov, I.G. FEMS Immunol. Med. Microbiol. (2002) [ Pubmed ]
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Altered polyamine metabolism in the PRO/Re strain of inbred mice. Manen, C.A., Blake, R.L., Russell, D.H. Biochem. J. (1976) [ Pubmed ]
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Effect of active and passive immunizations with lipid A and salmonella minnesota Re 595 on gram-negative infections in mice. Hodgin, L.A., Drews, J. Infection (1976) [ Pubmed ]
Detection of lipopolysaccharide-binding proteins on membranes of murine lymphocyte and macrophage-like cell lines. Kirikae, T., Kirikae, F., Schade, F.U., Yoshida, M., Kondo, S., Hisatsune, K., Nishikawa, S., Rietschel, E.T. FEMS microbiology immunology. (1991) [ Pubmed ]
Vascular wound healing and neointima formation induced by perivascular electric injury in mice. Carmeliet, P., Moons, L., Stassen, J.M., De Mol, M., Bouché, A., van den Oord, J.J., Kockx, M., Collen, D. Am. J. Pathol. (1997) [ Pubmed ]
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Collection Description
A collection of approximately 5,000 original letters sent by San Diego State students on active duty in the armed forces during World War II, or their families, to Professor Lauren Post who compiled and distributed the Aztec News Letter.
Immediately after Pearl Harbor and as the War progressed, Aztec students were soon scattered all over the globe, disconnected and separated from their college, their friends, their loved ones, and their former lives. In the spring of 1942, Dr. Post, professor of geography from 1937-69 and a veteran of World War I, decided to try a "news service experiment" intended to provide information about the locations of current and former Aztecs dispersed around the world. The Aztec News Letter thus became a crucial lifeline throughout the War for Aztec servicemen and women facing difficulty and danger wherever they were stationed. Lauded as one of the first of its kind in the nation, the Aztec News Letter premiered in May of 1942 and was released monthly until its 48th issue in March of 1946. By then, The Aztec News Letter circulated to more than 3,000 service and home front readers. The project and the letters that made it possible would forever characterize the Aztec spirit during wartime. Not only are the letters historically significant; they also offer a unique perspective about San Diego State during a global crisis.
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Swift & Co. v. Wickham, 382 U.S. 111, 86 S. Ct. 258, 15 L. Ed. 2d 194, 1965 U.S. LEXIS 2252 – CourtListener.com
Opinion for Swift & Co. v. Wickham, 382 U.S. 111, 86 S. Ct. 258, 15 L. Ed. 2d 194, 1965 U.S. LEXIS 2252 — Brought to you by Free Law Project, a non-profit dedicated to creating high quality open legal information.
Summaries (8)
Judge-written summaries of this case:
Overruling Kesler v. Department of Public Safety of Utah, 369 U. S. 153 (1962), to reaffirm "pre- Kesler precedent" and restore the law to the "view . . . which this Court has traditionally taken" in older cases
(from 1 case)
"The 'unconstitutionality' clause of Sec. 2281 can hardly be thought to encompass the voiding of a state statute for inconsistency with the state constitution."
(from 1 case)
“[T]he Judiciary of the several States shall be bound thereby in their decisions, any thing in the respective laws of the Individual States . . . notwithstanding”
(from 1 case)
Cited By (289)
Authorities (29)
This opinion cites:
Kesler v. Department of Public Safety of Utah, 369 U.S. … (9 times)
Ex Parte Bransford, 310 U.S. 354 (4 times)
Ex Parte Buder, 271 U.S. 461 (4 times)
Florida Lime & Avocado Growers, Inc. v. Jacobsen, 362 U.S. … (3 times)
Cloverleaf Butter Co. v. Patterson, 315 U.S. 148 (3 times)
Swift & Co. v. Wickham, 382 U.S. 111
Supreme Court of the United States
Filed: November 22nd, 1965
Precedential Status: Precedential
Citations: 382 U.S. 111, 86 S. Ct. 258, 15 L. Ed. 2d 194, 1965 U.S. LEXIS 2252
Docket Number: 9
Supreme Court Database ID: 1965-013
Author: John Marshall Harlan II
382 U.S. 111 (1965)
SWIFT & CO., INC., ET AL. v. WICKHAM, COMMISSIONER OF AGRICULTURE & MARKETS OF NEW YORK.
Supreme Court of United States.
Argued October 13, 1965.
Decided November 22, 1965.
APPEAL FROM THE UNITED STATES DISTRICT COURT FOR THE SOUTHERN DISTRICT OF NEW YORK.
*112 William J. Condonargued the cause for appellants. With him on the brief were William J. Colavito, William P. Woods, Arthur C. O'Meara, Earl G. Spikerand Edmund L. Jones.
Samuel A. Hirshowitz,First Assistant Attorney General of New York, argued the cause for appellee. With him on the brief were Louis J. Lefkowitz,Attorney General, and Philip Kahaner, Lester Estermanand Joel Lewittes,Assistant Attorneys General.
Joseph O. Parkerand L. Alton Denslowfiled a brief for the Institute of American Poultry Industries, as amicus curiae,urging reversal.
Solicitor General Marshall, Assistant Attorney General Douglas, Jack S. Levin, Sherman L. Cohnand Richard S. Salzmanfiled a brief for the United States, as amicus curiae,urging affirmance.
MR. JUSTICE HARLAN delivered the opinion of the Court.
Appellants, the Swift and Armour Companies, stuff, freeze, and package turkeys which they ship to retailers throughout the country for ultimate sale to consumers. Each package is labeled with the net weight of the particular bird (including stuffing) in conformity with a governing federal statute, the Poultry Products Inspection Act of 1957, 71 Stat. 441, 21 U.S. C. §§ 451-469 (1964 ed.), and the regulations issued under its authority by the Secretary of Agriculture. [1]Many of these turkeys are *113sold in New York. Section 193 of New York's Agriculture and Markets Law [2]has been interpreted through regulations and rulings to require that these packaged turkeys be sold with labels informing the public of the weight of the unstuffed bird as well as of the entire package. Because the amount of stuffing varies with each bird, the State thus seeks to help purchasers ascertain just how much fowl is included in each ready-for-the-oven turkey.
Swift and Armour requested permission of the Poultry Products Section of the Department of Agriculture to change their labels in order to conform with New York's requirements, but such permission was refused at the initial administrative level and no administrative review of that refusal was sought. Swift and Armour *114then brought this federal action to enjoin the Commissioner of Agriculture and Markets of New York from enforcing the State's labeling provisions, asserting that enforcement would violate the Commerce Clause and the Fourteenth Amendment of the Federal Constitution and overriding requirements of the federal poultry enactment.
Pursuant to appellants' request, a three-judge district court was constituted under 28 U.S. C. § 2281 (1958 ed.), which provides for such a tribunal whenever the enforcement of a state statute is sought to be enjoined "upon the ground of the unconstitutionality of such statute." The District Court, unsure of its jurisdiction for reasons appearing below, dismissed the suit on the merits [3]acting both in a three-judge and single-judge capacity. [4]Appeals were lodged in the Court of Appeals for the Second Circuit from the single-judge determination, and in this Court from the three-judge decision in accordance with the direct appeal statute, 28 U.S. C. § 1253 (1964 ed.). The threshold question before us, the consideration of which we postponed to the merits ( 379 U.S. 997), is whether this Court, rather than the Court of Appeals, has jurisdiction to review the District Court determination, and this in turn depends on whether a three-judge court was required. We hold that it was not.
At the outset, we agree with the District Court that the Commerce Clause and Fourteenth Amendment *115claims alleged in the complaint are too insubstantial to support the jurisdiction of a three-judge court. It has long been held that no such court is called for when the alleged constitutional claim is insubstantial, Ex parte Poresky, 290 U.S. 30; California Water Service Co.v. City of Redding, 304 U.S. 252. Since the only remaining basis put forth for enjoining enforcement of the state enactment was its asserted repugnancy to the federal statute, the District Court was quite right in concluding that the question of a three-judge court turned on the proper application of our 1962 decision in Keslerv. Department of Public Safety, 369 U.S. 153. There we decided that in suits to restrain the enforcement of a state statute allegedly in conflict with or in a field pre-empted by a federal statute, § 2281 comes into play only when the Supremacy Clause of the Federal Constitution is immediately drawn in question, but not when issues of federal or state statutory construction must first be decided even though the Supremacy Clause may ultimately be implicated. Finding itself unable to say with assurance whether its resolution of the merits of this case involved lessstatutory construction than had taken place in Kesler,the District Court was left with the puzzling question how much morestatutory construction than occurred in Kesleris necessary to deprive three judges of their jurisdiction.
It might suffice to dispose of the three-judge court issue for us to hold, in agreement with what the District Court indicated, 230 F. Supp. , at 410, that this case involves so much more statutory construction than did Keslerthat a three-judge court was inappropriate. (We would indeed find it difficult to say that lessor no more statutory construction was involved here than in Keslerand that therefore under that decision a three-judge court was necessary.) We think, however, that such a disposition of this important jurisdictional question would be *116less than satisfactory, that candor compels us to say that we find the application of the Keslerrule as elusive as did the District Court, and that we would fall short in our responsibilities if we did not accept this opportunity to take a fresh look at the problem. We believe that considerations of stare decisisshould not deter us from this course. Unless inexorably commanded by statute, a procedural principle of this importance should not be kept on the books in the name of stare decisisonce it is proved to be unworkable in practice; the mischievous consequences to litigants and courts alike from the perpetuation of an unworkable rule are too great. For reasons given in this opinion, we have concluded that the Keslerdoctrine in this area of § 2281 is unsatisfactory, and that Keslershould be pro tantooverruled. The overruling of a six-to-two decision [5]of such recent vintage, which was concurred in by two members of the majority in the present case, [6]and the opinion in support of which was written by an acknowledged expert in the field of federal jurisdiction, demands full explication of our reasons.
I.
The three-judge district court is a unique feature of our jurisprudence, created to alleviate a specific discontent within the federal system. The antecedent of § 2281 was a 1910 Act [7]passed to assuage growing popular displeasure with the frequent grants of injunctions by federal courts against the operation of state legislation regulating railroads and utilities in particular. [8]The *117federal courts of the early nineteenth century had occasionally issued injunctions at the behest of private litigants against state officials to prevent the enforcement of state statutes, [9]but such cases were rare and generally of a character that did not offend important state policies. The advent of the Granger and labor movements in the late nineteenth century, [10]and the acceleration of state social legislation especially through the creation of regulatory bodies met with opposition in the federal judiciary. In Chicago, M. & St. P. R. Co.v. Minnesota, 134 U.S. 418, this Court held that the setting of rates not permitting a fair return violated the Due Process Clause of the Fourteenth Amendment. Ex parte Young, 209 U.S. 123, established firmly the corollary that inferior federal courts could enjoin state officials from enforcing such unconstitutional state laws.
This confrontation between the uncertain contours of the Due Process Clause and developing state regulatory *118legislation, arising in district courts that were generally considered unsympathetic to the policies of the States, had severe repercussions. Efforts were made in Congress to limit in various ways the jurisdiction of federal courts in these sensitive areas. [11]State officials spoke out against the obstruction and delay occasioned by these federal injunction suits. [12]The sponsor of the bill establishing the three-judge procedure for these cases, Senator Overman of North Carolina, noted:
"[T]here are 150 cases of this kind now where one federal judge has tied the hands of the state officers, the governor, and the attorney-general . . . .
.....
Whenever one judge stands up in a State and enjoins the governor and the attorney-general, the people resent it, and public sentiment is stirred, as it was in my State, when there was almost a rebellion, whereas if three judges declare that a state statute is unconstitutional the people would rest easy under it." 45 Cong. Rec. 7256.
[13]
Section 2281 was designed to provide a more responsible forum for the litigation of suits which, if successful, would render void state statutes embodying important state policies. The statute provides for notification to the State of a pending suit, 28 U.S. C. § 2284 (2) (1964 ed.), thus preventing ex parteinjunctions common previously. [15]It provides for three judges, one of whom must be a circuit judge, 28 U.S. C. § 2284 (1) (1964 ed.), to allow a more authoritative determination and less opportunity for individual predilection in sensitive and politically emotional areas. It authorizes direct review by this Court, 28 U.S. C. § 1253, as a means of accelerating a final determination on the merits; an important criticism of the pre-1910 procedure was directed at the *120length of time required to appeal through the circuit courts to the Supreme Court, and the consequent disruption of state tax and regulatory programs caused by the outstanding injunction. [16]
That this procedure must be used in any suit for an injunction against state officials on the ground that a state enactment is unconstitutional has been clear from the start. What yet remains unclear, in spite of decisions by this and other courts, is the scope of the phrase "upon the ground of the unconstitutionality of such statute" when the complaint alleges not the traditional Due Process Clause, Equal Protection Clause, Commerce Clause, or Contract Clause arguments, but rather that the state statute or regulation in question is pre-empted by or in conflict with some federal statute or regulation thereunder. Any such pre-emption or conflict claim is of course grounded in the Supremacy Clause of the Constitution: if a state measure conflicts with a federal requirement, the state provision must give way. Gibbonsv. Ogden, 9 Wheat. 1. The basic question involved in these cases, however, is never one of interpretation of the Federal Constitution but inevitably one of comparing two statutes. Whether one district judge or three must carry out this function is the question at hand.
The first decision of this Court casting light on the problem was Ex parte Buder, 271 U.S. 461, in which the question presented was, as here, whether an appeal was properly taken directly from the District Court to the Supreme Court. At issue was whether a Missouri statute authorizing taxation of bank shares remained valid after the enactment of a federal statute which enlarged the scope of the States' power to tax national banks by permitting taxation of shares, or dividends, or *121income. Under the federal scheme, States were apparently expected to choose one of the three methods. Although the Missouri law applied the first basis of assessment, the District Court held that because the State did not explicitly choose among the three types of taxation, but instead relied on a prior statute, the assessment was void. Mr. Justice Brandeis, writing for a unanimous Court, held that this was not properly a three-judge court case ". . . because no state statute was assailed as being repugnant to the Federal Constitution." 271 U.S. , at 465. Although the complaint in Buderdid not explicitly invoke the Supremacy Clause, it should be noted that the defendants' answer asserted that if the federal statute was constitutional under the Tenth Amendment, then it would indeed be the " `supreme law of the land' within the meaning and provisions of Article VI of the Constitution of the United States," and thus controlling over the particular state statute unless that statute could be construed as consistent with the federal law. The District Court in Buderwas thus clearly presented with the Supremacy Clause basis of the statutory conflict.
Ex parte Bransford, 310 U.S. 354, raised a similar problem, also in the context of the validity of a state tax. The Court again held this type of federal-state confrontation outside the purview of the predecessor of § 2281:
"If such assessments are invalid, it is because they levy taxes upon property withdrawn from taxation by federal law or in a manner forbidden by the National Banking Act. The declaration of the supremacy clause gives superiority to valid federal acts over conflicting state statutes but this superiority for present purposes involves merely the construction of an act of Congress, not the constitutionality of the state
enactment." 310 U.S. , at 358-359
.
*122In a third case, Casev. Bowles, 327 U.S. 92, the question involved the proposed sale by the State of Washington of timber on state-owned land at a price violating the Federal Emergency Price Control Act of 1942. A federal district court enjoined the sale, and on appeal the State argued that the single judge lacked jurisdiction. This Court held otherwise: "the complaint did not challenge the constitutionality of the state statute but alleged merely that its enforcement would violate the Emergency Price Control Act. Consequently a three-judge court is not required." 327 U.S. , at 97. [17]
The upshot of these decisions seems abundantly clear: Supremacy Clause cases are not within the purview of § 2281. [18]This distinction between cases involving claims *123that state statutes are unconstitutional within the scope of § 2281 and cases involving statutory pre-emption or conflict remained firm until Keslerv. Department of Public Safety, 369 U.S. 153, in which the plaintiff alleged a conflict between the federal bankruptcy laws and a state statute suspending the driving licenses of persons who are judgment debtors as a result of an adverse decision in an action involving the negligent operation of an automobile. It was argued that federal policy underlying the bankruptcy law overrode the State's otherwise legitimate exercise of its police power. Mr. Justice Frankfurter, for a majority, declared first that § 2281 made no distinction between the Supremacy Clause and other provisions of the Constitution as a ground for denying enforcement of a state statute, and second that Buder, Bransford,and Casecould be distinguished on the ground that they presented no claims of unconstitutionality as such: "If in immediate controversy is not the unconstitutionality of a state law but merely the construction of a state law or the federal law, the three-judge requirement does not become operative." 369 U.S. , at 157. In the Keslercase itself, Mr. Justice Frankfurter said, there was no problem of statutory construction but only a "constitutional question" whether the state enactment was pre-empted. After what can only be characterized as extensive statutory analysis (369 U. S., at 158-174) the majority concluded that there had in fact been no pre-emption. [19]
*124 III.
In re-examining the Keslerrule the admonition that § 2281 is to be viewed "not as a measure of broad social policy to be construed with great liberality, but as an enactment technical in the strict sense of the term and to be applied as such," Phillipsv. United States, 312 U.S. 246, 251, should be kept in mind. The Kesleropinion itself reflects this admonition, for its rationalization of Buder, Bransford,and Caseas being consistent with the view that Supremacy Clause cases are not excluded from "the comprehensive language of § 2281," 369 U.S. , at 156, is otherwise most difficult to explain.
As a procedural rule governing the distribution of judicial responsibility the test for applying § 2281 must be clearly formulated. The purpose of the three-judge scheme was in major part to expedite important litigation: it should not be interpreted in such a way that litigation, like the present one, is delayed while the proper composition of the tribunal is litigated. We are now convinced that the Keslerrule, distinguishing between cases in which substantial statutory construction is required and those in which the constitutional issue is "immediately" apparent, is in practice unworkable. Not only has it been uniformly criticized by commentators, [20]but lower courts have quite evidently sought to avoid dealing with its application [21]or have interpreted it with uncertainty. [22]As Judge Friendly's opinion for the court below demonstrates, in order to ascertain the *125correct forum, the merits must first be adjudicated in order to discover whether the court has "engaged in so much more construction than in Kesler as to make that ruling inapplicable." 230 F. Supp. , at 410. Such a formulation, whatever its abstract justification, cannot stand as an every-day test for allocating litigation between district courts of one and three judges.
Two possible interpretations of § 2281 would provide a more practicable rule for three-judge court jurisdiction. The first is that Keslermight be extended to hold, as some of its language might be thought to indicate, [23]that allsuits to enjoin the enforcement of a state statute, whatever the federal ground, must be channeled through three-judge courts. The second is that nosuch suits resting solely on "supremacy" grounds fall within the statute.
The first alternative holds some attraction. First, it is relatively straightforward: a court need not distinguish among different constitutional grounds for the requested injunction; it need look only at the relief sought. Moreover, in those cases, as in that before us, in which an injunction is sought on several grounds, the proper forum would not depend on whether certain alleged constitutional grounds turn out to be insubstantial. Second, § 2281 speaks of "unconstitutionality," and, to be sure, any determination that a state statute is void for obstructing a federal statute does rest on the Supremacy Clause of the Federal Constitution. And, third, there is some policy justification for a wider rule. In a broad sense, what concerned the legislators who passed the progenitor of § 2281 was the voiding of state legislation by inferior federal courts. The sensibilities of the citizens, and *126perhaps more particularly of the state officials, were less likely to be offended, the Congress thought, by a judgment considered and handed down by three judges rather than by one judge. This rationale can be thought to be as applicable to a suit voiding state legislation on grounds of conflict with a federal statute as it is to an identical suit alleging a conflict with the Federal Constitution directly.
Persuasive as these considerations may be, we believe that the reasons supporting the second interpretation, that is, returning to the traditional Buder-Bransford-Caserule, should carry the day. This restrictive view of the application of § 2281 is more consistent with a discriminating reading of the statute itself than is the first and more embracing interpretation. The statute requires a three-judge court in order to restrain the enforcement of a state statute "upon the ground of the unconstitutionality of such statute." Since all federal actions to enjoin a state enactment rest ultimately on the Supremacy Clause, [24]the words "upon the ground of the unconstitutionality of such statute" would appear to be superfluous unless they are read to exclude some types of such injunctive suits. [25]For a simple provision prohibiting the restraint of the enforcement of any state statute except by a three-judge court would manifestly have sufficed to embrace every such suit whatever its particular constitutional ground. It is thus quite permissible to read *127the phrase in question as one of limitation, signifying a congressional purpose to confine the three-judge court requirement to injunction suits depending directly upon a substantive provision of the Constitution, leaving cases of conflict with a federal statute (or treaty) to follow their normal course in a single-judge court. We do not suggest that this reading of § 2281 is compelled. We do say, however, that it is an entirely appropriate reading, and one that is supported by all the precedents in this Court until Keslerand by sound policy considerations.
An examination of the origins of the three-judge procedure does not suggest what the legislators would have thought about this particular problem, but it does show quite clearly what sort of cases wereof concern to them. Their ire was aroused by the frequent grants of injunctions against the enforcement of progressive state regulatory legislation, usually on substantive due process grounds. (See pp. 116-119, supra.) Requiring the collective judgment of three judges and accelerating appeals to this Court were designed to safeguard important state interests. In contrast, a case involving an alleged incompatibility between state and federal statutes, such as the litigation before us, involves more confining legal analysis and can hardly be thought to raise the worrisome possibilities that economic or political predilections will find their way into a judgment. Moreover, those who enacted the three-judge court statute should not be deemed to have been insensitive to the circumstance that single-judge decisions in conflict and pre-emption cases were always subject to the corrective power of Congress, whereas a "constitutional" decision by such a judge would be beyond that ready means of correction and could be dealt with only by constitutional amendment. The purpose of § 2281 to provide greater restraint and dignity at the district court level cannot well be thought generally applicable to cases that involve conflicts *128between state and federal statutes, in this instance determining whether the Department of Agriculture's regulations as applied to the labeling of total net weight on frozen stuffed turkeys necessarily renders invalid a New York statute requiring a supplemental net weight figure which excludes the stuffing.
Our decision that three-judge courts are not required in Supremacy Clause cases involving only federal-state statutory conflicts, in addition to being most consistent with the statute's structure, with pre- Keslerprecedent, and with the section's historical purpose, is buttressed by important considerations of judicial administration. As Mr. Justice Frankfurter observed in Florida Lime & Avocado Growers, Inc.v. Jacobsen, 362 U.S. 73, 92-93 (dissenting opinion):
"[T]he convening of a three-judge trial court makes for dislocation of the normal structure and functioning of the lower federal courts, particularly in the vast non-metropolitan regions; and direct review of District Court judgments by this Court not only expands this Court's obligatory jurisdiction but contradicts the dominant principle of having this Court review decisions only after they have gone through two judicial sieves . . . ."
Although the number of three-judge determinations each year should not be exaggerated, [26]this Court's concern for efficient operation of the lower federal courts persuades us to return to the Buder-Bransford-Caserule, *129thereby conforming with the constrictive view of the three-judge jurisdiction which this Court has traditionally taken. Ex parte Collins, 277 U.S. 565; Oklahoma Gas & Elec. Co.v. Oklahoma Packing Co., 292 U.S. 386; Rorickv. Board of Commissioners, 307 U.S. 208; Phillipsv. United States, 312 U.S. 246.
We hold therefore that this appeal is not properly before us under 28 U.S. C. § 1253 and that appellate review lies in the Court of Appeals, where appellants' alternative appeal is now pending. The appeal is dismissed for lack of jurisdiction.
It is so ordered.
MR. JUSTICE DOUGLAS, with whom MR. JUSTICE BLACK and MR. JUSTICE CLARK concur, dissenting.
Less than four years ago, this Court decided that a three-judge district court was required in suits brought under 28 U.S. C. § 2281, even though the alleged "ground of the unconstitutionality" of the challenged statute was based upon a conflict between state and federal statutes. Keslerv. Department of Public Safety, 369 U.S. 153.
A state statute may violate the Equal Protection Clause of the Fourteenth Amendment or the Due Process Clause or some other express provision of the Constitution. If so a three-judge court is plainly required by 28 U.S. C. § 2281. But the issue of the "unconstitutionality" of a state statute can be raised as clearly by a conflict between it and an Act of Congress as by a conflict between it and a provision of the Constitution. The Supremacy Clause, contained in Art. VI, cl. 2, of the Constitution, states as much in clear language:
"This Constitution, and the Laws of the United States which shall be made in Pursuance thereof . . . shall be the supreme Law of the Land; and the
*130
Judges in every State shall be bound thereby, any Thing in the Constitution or Laws of any State to the Contrary notwithstanding."
An issue of the "unconstitutionality" of a state statute is therefore presented whether the conflict is between a provision of the Constitution and a state enactment or between the latter and an Act of Congress. What Senator Overman, author of the three-judge provision, said of it in 1910 is as relevant to enjoining a state law on the ground of federal pre-emption as it is to enjoining it because it violates the Fourteenth Amendment:
"The point is, this amendment is for peace and good order in the State. Whenever one judge stands up in a State and enjoins the governor and the attorney-general, the people resent it, and public sentiment is stirred, as it was in my State, when there was almost a rebellion, whereas if three judges declare that a state statute is unconstitutional the people would rest easy under it. But let one little judge stand up against the whole State, and you find the people of the State rising up in rebellion. The whole purpose of the proposed statute is for peace and good order among the people of the States." 45 Cong. Rec. 7256.
Some of the most heated controversies between State and Nation which this Court has supervised have involved questions whether there was a conflict between a state statute and a federal one or whether a federal Act was so inclusive as to pre-empt state action in the particular area. One of the earliest and most tumultuous was Cohensv. Virginia, 6 Wheat. 264, 440, where the alleged unconstitutionality of a Virginia law was based on the argument that an Act of Congress, authorizing a lottery in the District of Columbia, barred Virginia from making it a criminal offense to sell lottery *131tickets within that State. The protest from the States was vociferous [1]even though the Court in the end construed the federal Act to keep it from operating in Virginia. Id.,at 447. I therefore see no difference between a charge of "unconstitutionality" of a state statute whether the conflict be between it and the Constitution or between it and a federal law. Neither the language of the Supremacy Clause nor reason nor history makes any difference plain.
Pre-emption or conflict of a state law with a federal one is a recurring theme [2]arising in various contexts. The storm against Cohensv. Virginiawas a protest against this Court's acting as referee in a federal-state contest involving pre-emption or a conflict between the *132laws of the two regimes. Congress has recently been concerned with the problem in another aspect of the matter, [3]when efforts were made to curb the doctrine of pre-emption by establishing standards for an interpretation of an Act of Congress. [4]The three-judge court is only another facet of the self-same problem.
The history of 28 U.S. C. § 2281, as related by the Court, speaks of the concern of Congress over the power *133of one judge to bring a halt to an entire state regulatory scheme. That canand will hereafterhappen in all cases of pre-emption or conflict where the Supremacy Clause is thought to require state policy to give way. A fairly recent example is Cloverleaf Co.v. Patterson, 315 U.S. 148, where a federal court injunction in a pre-emption case suspended Alabama's program for control of renovated buttera demonstrably important health measure. The Court in Florida Lime Growersv. Jacobsen, 362 U.S. 73, where one of the issues was pre-emption or conflict between two statutory systems, emphasized that the interest of the States in being free from such injunctive interference at the instance of a single judgeoutweighed the additional burdens that such a rule imposed on the federal court system. On reflection I think that result better reflects congressional policy even though, as in Cohensv. Virginia ,the end result is only a matter of statutory construction.
On the basis of virtually no experience in applying that interpretation of the statute, a majority has now decided that the rule of Kesleris "unworkable" and, therefore, that our previous interpretation of the statute must have been incorrect. I regret that I am unable to join in that decision. My objection is not that the Court has not given Kesler"a more respectful burial," Gideonv. Wainwright, 372 U.S. 335, 349 (concurring opinion), but that the Court has engaged in unwarranted infanticide.
Stare decisisis no immutable principle. [5]There are many occasions when this Court has overturned a prior decision, especially in matters involving an interpretation of the Constitution or where the problem of statutory construction had constitutional overtones.
An error in interpreting a federal statute may be easily remedied. If this Court has failed to perceive the intention *134of Congress, or has interpreted a statute in such a manner as to thwart the legislative purpose, Congress may change it. The lessons of experience are not learned by judges alone.
I am unable to find a justification for overturning a decision of this Court interpreting this Act of Congress, announced only on March 26, 1962.
If the Court were able to show that our decision in Keslerhad thrown the lower courts into chaos, a fair case for its demise might be made out. The Court calls the rule "unworkable." But it is not enough to attach that label. The Court broadly asserts that "lower courts have quite evidently sought to avoid dealing with its [ Kesler's] application or have interpreted it with uncertainty." For this proposition, only three cases (in addition to the instant case) are cited. The Court's failure to provide more compelling documentation for its indictment of Kesleris not the result of less than meticulous scholarship, for so far as I have been able to discover, the truth of the matter is that there are no cases (not even the three cited) even remotely warranting the conclusion that Kesleris "unworkable."
Keslerwas an attempt to harmonize our earlier cases. If the Keslertest is "unworkable" as the Court asserts, we should nonetheless accept its basic premise:
"Neither the language of § 2281 nor the purpose which gave rise to it affords the remotest reason for carving out an unfrivolous claim of unconstitutionality because of the Supremacy Clause from the comprehensive language of §
2281." 369 U.S. , at 156
.
If there is overruling to be done, we should overrule Ex parte Buder, 271 U.S. 461, and Ex parte Bransford, 310 U.S. 354.
That the ground of unconstitutionality in many so-called Supremacy Clause cases is found only in the asserted conflict between federal and state statutes is, *135as I have said, no basis for distinguishing that class of cases from others in which three-judge courts are plainly required. While courts are, strictly speaking, engaging in statutory construction in such cases, the task of adjudication is much the same as in what all would concede to be constitutional adjudication. Though the purpose of Congress is the final touchstone, the interests which must be taken into account in either case are much the same, as Cohensv. Virginiaeloquently demonstrates.
The Court has decided, on no more than the gloomy predictions contained in a handful of law review articles, that Keslerwould inevitably produce chaos in the federal courts, that the rule announced there is "unworkable." Those predictions have plainly not been borne out. If difficulties arise, Congress can cure them. Until Congress acts, I would let Keslerstand.
I therefore believe that a three-judge court was properly convened and that we should decide this appeal on the merits.
NOTES
[1] Section 457 (b) declares:
"The use of any written, printed or graphic matter upon or accompanying any poultry product inspected or required to be inspected pursuant to the provisions of this chapter or the container thereof which is false or misleading in any particular is prohibited."
Section 458 (d) prohibits "Using in commerce, or in a designated major consuming area, a false or misleading label on any poultry product."
The Secretary of Agriculture is authorized by § 463 to issue regulations. 7 CFR § 81.125 requires containers to bear "approved labels"; § 81.130 (a) (3) declares that labels must include the net weight of the contents and that "The net weight marked on containers of poultry products shall be the net weight of the poultry products and shall not include the weights of the wet or dry packaging materials and giblet wrapping materials."
[2] Section 193-3 provides:
"All food and food products offered for sale at retail and not in containers shall be sold or offered for sale by net weight, standard measure or numerical count under such regulations as may be prescribed by the commissioner."
Net weight was not defined in the regulation, 1 NYCRR § 221.40 (now § 221.9 (c)), but "[t]he Director of the Bureau of Weights and Measures of the Department testified that he interpreted the regulation, as applied to stuffed turkeys, to require statement of the net weight both of the unstuffed and of the stuffed bird, and that, when asked, he so advised local sealers of weights and measures." Swift & Co.v. Wickham, 230 F. Supp. 398, 401 (1964).
[3] The court below rejected appellants' Commerce Clause and Fourteenth Amendment arguments, held that there had been no federal pre-emption of this field of regulation, and, though implying strongly that the New York labeling requirements did not conflict with federal requirements, held that this question should first be passed upon at a higher federal administrative level.
[4] The three-judge court dismissed the complaint "certifying out of abundant caution" that the original district judge, also a member of the three-judge panel, "individually arrived at the same conclusion." 230 F. Supp. , at 410. This procedure for minimizing prejudice to litigants when the jurisdiction of a three-judge court is unclear has been used before, see Queryv. United States, 316 U.S. 486.
[5] Mr. Justice Whittaker took no part in the decision of the case.
[6] MR. JUSTICE BRENNAN and the present writer were included in the Keslermajority.
[7] Act of June 18, 1910, c. 309, § 17, 36 Stat. 557.
[8] See Currie, The Three-Judge District Court in Constitutional Litigation, 32 U. Chi. L. Rev. 1, 3-9 (1964); Hutcheson, A Case for Three Judges, 47 Harv. L. Rev. 795 (1934); Warren, Federal and State Court Interference, 43 Harv. L. Rev. 345 (1930). For more contemporary accounts see, e. g.,Baldwin, Presidential Address: The Progressive Unfolding of the Powers of the United States, VI Am. Pol. Sci. Rev. 1, 8-9 (1912); Scott, The Increased Control of State Activities by the Federal Courts, III Am. Pol. Sci. Rev. 347 (1909). Although various types of state legislation were being challenged in injunctive suits, see Lockwood, Maw, and Rosenberry, The Use of the Federal Injunction in Constitutional Litigation, 43 Harv. L. Rev. 426 (1930), most numerous and prominent were the railroad cases. Senator Overman noted that ". . . nine out of ten of the cases where application for an injunction has been made to test the constitutionality of state statutes have been railroad cases." 45 Cong. Rec. 7254 (1910).
[9] E. g., Spoonerv. McConnell,22 Fed. Cas. 939 (No. 13245) (1838).
[10] See S. J. Buck, The Granger Movement, esp. 194-214, 231-237 (1913); Jackson, The Struggle for Judicial Supremacy 48-68 (1949); 2 Warren, The Supreme Court in United States History 574-599 (1935). For the related story of the use of the equity power in the labor field, see Frankfurter and Greene, The Labor Injunction (1930).
[11] See Hutcheson, supra,at 803-804.
[12] See, e. g.,45 Cong. Rec. 7253 (1910) (remarks of Senator Crawford). Although some litigation of this sort dragged on for as much as five years, ibid.,it is not clear that most state courts were any more expeditious, see Lilienthal, The Federal Courts and State Regulation of Public Utilities, 43 Harv. L. Rev. 379, 417 and n. 176 (1930).
[13] Senator Overman was probably referring to Southern R. Co.v. McNeill, 155 F. 756(1907). There, after an injunction had been sustained by the Circuit Court, the Governor publicly urged state officials to ignore it. The railway complained to the Court that "these attacks on the part of the Governor and state officials against the company and its agents . . . had the effect of demoralizing the servants, agents, and employes of the company to such an extent as to render it well nigh impossible for complainant to properly discharge the duties which it owed the public . . . ." Id.,at 790-791.
[14] The procedure was extended to cover challenges to orders of state administrative commissions in 1913, 37 Stat. 1013, 28 U.S. C. § 2281, and in 1925 suits for permanent injunctions were brought within its purview, 43 Stat. 938, 28 U.S. C. § 2281. Three-judge district courts are also required in certain suits arising under federal law. See Note, The Three-Judge District Court: Scope and Procedure Under Section 2281, 77 Harv. L. Rev. 299, 300-301 and n. 19 (1963).
[15] See Hutcheson, supra,at 800-801. Senator Crawford of South Dakota told the Congress that when his State Legislature was debating a maximum rate law, the railway companies had already prepared motions for injunctions:
"The statute passed and was presented to the governor for his signature, and in less than an hour after he had signed the bill and it was filed in the office of the secretary of state a restraining order came by telegraph from a United States judge, enjoining the governor and the attorney-general and all the officers in the State from proceeding to enforce that statute." 45 Cong. Rec. 7252 (1910).
[16] See, id.,at 7256 (remarks of Senator Crawford); note 12, supra.
[17] This basic rule has been reiterated in other familiar cases where the facts did not require its application. See Queryv. United States, 316 U.S. 486, where, however, a three-judge court was found necessary because other not insubstantial constitutional claims had been clearly asserted. In Florida Lime & Avocado Growers, Inc.v. Jacobsen, 362 U.S. 73, the majority held that if a state statute is sought to be enjoined on constitutional grounds (Commerce Clause, Equal Protection) it did not matter that a "nonconstitutional" ground (pre-emption by the Federal Agricultural Marketing Agreement Act) was also asserted. Mr. Justice Frankfurter dissented, reasoning that the three-judge procedure should be read narrowly and that the mere availability of a "non-constitutional" basis for enjoining the state statute should give jurisdiction to a single judge. Both majority and dissent assumed that an attack upon a state enactment on the ground that it was inconsistent with a federal statute was such a "non-constitutional" ground.
[18] None of these cases can be read to suggest that the result depends on whether or not the complaint specifically invokes the Supremacy Clause, for that clause is the inevitable underpinning for the striking down of a state enactment which is inconsistent with federal law. See the quotation from Bransford, supra,p. 121, a case in which the Supremacy Clause was not invoked in the complaint. See also the discussion of Ex parte Buder, supra,pp. 120-121. Nor do any of these cases suggest that the issue turns on the amount of statutory construction involved, whether large, small, or simply of the character that entails laying the alleged conflicting statutes side by side.
[19] In dissent it was stated that the Kesleropinion "refutes the very test which it establishes." 369 U.S. , at 177(dissenting opinion of THE CHIEF JUSTICE). In addition, three Justices dissented in whole or in part from the conclusions derived from this statutory analysis.
[20] See Currie, supra,at 61-64 (1964); Note, 77 Harv. L. Rev. 299, 313-315 (1963); Note, 49 Va. L. Rev. 538, 553-555 (1963); 76 Harv. L. Rev. 168 (1962); 15 Stan. L. Rev. 565 (1963); 1962 U. Ill. L. F. 467; 111 U. Pa. L. Rev. 113 (1962).
[21] See Borden Co.v. Liddy, 309 F.2d 871; American Travelers Club, Inc.v. Hostetter, 219 F. Supp. 95, 102 n. 7.
[22] See, in addition to the case before us, Bartlett & Co.v. State Corp. Comm'n of Kansas, 223 F. Supp. 975.
[23] "Neither the language of § 2281 nor the purpose which gave rise to it affords the remotest reason for carving out an unfrivolous claim of unconstitutionality because of the Supremacy Clause from the comprehensive language of § 2281." 369 U.S. , at 156.
[24] Art. VI, cl. 2. "This Constitution, and the Laws of the United States which shall be made in Pursuance thereof; and all Treaties made, or which shall be made, under the Authority of the United States, shall be the supreme Law of the Land; and the Judges in every State shall be bound thereby, any Thing in the Constitution or Laws of any State to the Contrary notwithstanding."
[25] The "unconstitutionality" clause of § 2281 can hardly be thought to encompass the voiding of a state statute for inconsistency with the state constitution. Cf. Florida Lime & Avocado Growers, Inc.v. Jacobsen, 362 U.S. 73, 80.
[26] The statistics are summarized in Note, 77 Harv. L. Rev. 299, 303-305 (1963); Note, 72 Yale L. J. 1646, 1654-1659 (1963). The most recent figures show that out of the 11,485 trials completed in district courts in fiscal 1965, only 147 were heard by three-judge courts. Of these 60 dealt with I. C. C. regulations, 35 with civil rights, and only 52 with state or local law. 1965 Dir. Adm. Off. U. S. Courts Ann. Rep. II-25, II-28.
[1] See 1 Warren, The Supreme Court in United States History, p. 552 et seq.(1928).
"The Richmond Enquirerspoke of the opinion, `so important in its consequences and so obnoxious in its doctrines,' and said that `the very title of the case is enough to stir one's blood.' It feared that `the Judiciary power, with a foot as noiseless as time and a spirit as greedy as the grave, is sweeping to their destruction the rights of the States. . . . These encroachments have increased, are increasing and ought to be diminished'; and it advocated a repeal of the fatal Section of the Judiciary Act as `the most advisable and constitutional remedy for the evil.' A leading Ohio paper spoke of `the alarming progress of the Supreme Court in subverting the Federalist principles of the Constitution and introducing on their ruins a mighty consolidated empire fitted for the sceptre of a great monarch'; and it continued: `That the whole tenor of their decisions, when State-Rights have been involved, have had a direct tendency to reduce our governors to the condition of mere provincial satraps, and that a silent acquiescence in these decisions will bring us to this lamentable result, is to us as clear as mathematical demonstration.' " Id.,at 552-553.
[2] Thus the dissent in Cloverleaf Co.v. Patterson, 315 U.S. 148, 179, called that decision in favor of pre-emption "purely destructive legislation." And see Ricev. Santa Fe Elevator Corp., 331 U.S. 218; Campbellv. Hussey, 368 U.S. 297. Cf. Hostetterv. Idlewild Liquor Corp., 377 U.S. 324.
[3] H. R. 3, 88th Cong., 1st Sess., in material part provided:
"No Act of Congress shall be construed as indicating an intent on the part of Congress to occupy the field in which such Act operates, to the exclusion of all State laws on the same subject matter, unless such Act contains an express provision to that effect, or unless there is a direct and positive conflict between such Act and a State law so that the two cannot be reconciled or consistently stand together."
The first version of the bill was introduced in 1956. The House Committee on the Judiciary made numerous changes, limiting its application to the subject of subversion, and reported the bill out with a "do pass" recommendation. H. R. Rep. No. 2576, 84th Cong., 2d Sess. The Senate version, S. 3143, was not so narrowed in Committee. S. Rep. No. 2230, 84th Cong., 2d Sess. The bill was not passed in either the House or the Senate.
H. R. 3 was again introduced in the Eighty-fifth Congress. The Judiciary Committee again recommended that the bill "do pass," but this time did not narrow its scope to the subject of subversion. See H. R. Rep. No. 1878, 85th Cong., 2d Sess. It was passed by the House on July 17, 1958.
H. R. 3, having once again been approved by the Judiciary Committee, H. R. Rep. No. 422, 86th Cong., 1st Sess., was approved by the House on June 24, 1959.
In the Eighty-seventh Congress, H. R. 3 was favorably reported out by the Judiciary Committee. H. R. Rep. No. 1820, 87th Cong., 2d Sess., but was not acted upon by the full House.
[4] The concern of Congress in this chapter of federal-state relations did not concern the three-judge court problem but the broader aspects envisaged by such cases as Pennsylvaniav. Nelson, 350 U.S. 497, Phillips Petroleum Co.v. Wisconsin, 347 U.S. 672, Slochowerv. Board of Education, 350 U.S. 551, Railway Employesv. Hanson, 351 U.S. 225, and Cloverleaf Co.v. Patterson, 315 U.S. 148. See H. R. Rep. No. 1820, 87th Cong., 2d Sess., p. 3 et seq.
[5] See Radin, Case Law and Stare Decisis, 33 Colo. L. Rev. 199 (1933).
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Motion-Secondary: Joshua Rizack, et al Plaintiff vs. Signature Bank, NA, et al Defendant | Trellis.Law
Access the Motion-Secondary in the Joshua Rizack, et al Plaintiff vs. Signature Bank, NA, et al Defendant case on Trellis.Law. Review the document, case details, and relevant case updates to stay informed on this notable legal proceeding
Motion-Secondary: Joshua Rizack, et al Plaintiff vs. Signature Bank, NA, et al Defendant
On December 17, 2014 a
Motion-Secondary
was filed
involving a dispute between Ryan Family Trust, Jaquith Holdings, Inc. Profit Sharing Plan, Jaquith Holdings, Inc., The Peter F. Ryan Rollover Ira, Ryan, Peter F., Reed, Thomas, Raounas, Michael, Conte, Darren, Bey, Richard, Macritchie, Donald, Mahl Family Trust, The Gordon Fund, Mahl, Charles, Kirshner, Richard, Fogarty, Pat, Fogarty, Dennis, Rizack, Joshua,
and Gustafson, Sharon, Liggio, Charles, Landberg, William, Kreitman, Stanley, Florescue, Barry, Gould, Steven, Liggio, Chris, Efstratiou, Chris, Signature Bank, Na,
for 3
in the District Court of Broward County.
Preview
Filing# 173916033 E-Filed 05/24/2023 04:08:33 PM
IN THE CIRCUIT COURT OF THE
SEVENTEENTH JUDICIAL CIRCUIT,
IN AND FOR BROWARD, COUNTY, FLORIDA
JOSHUA RIZACK, AS PLAN ADMINISTRATOR
OF THE POST CONFIRMATION ESTATE OF
WEST END FINANCIAL ADVISORS LLC, et. al.
Plaintiffs,
V CASE NO- CACE 15-000367 (09)
SIGNATURE BANK, N.A., et. al.
Defendants.
SHARON GUSTAFSON, PERSONAL
REPRESENTATIVE OF THE ESTATE OF
BARRY FLORESCUE,
Counter-Plaintiff.
V
JOSHUA RIZACK, AS PLAN ADMINISTRATOR
OF THE POST-CONFIRMATION ESTATE OF
WEST END FINANCIAL ADVISORS, LLC,
Counter-Defendant.
SUPPLEMENTAL BRIEF IN OPPOSITION TO FDIC-RECEIVER'S STAY MOTION
Plaintiffs file this Supplemental Brief in opposition to the Motion to Stay all Judicial
Proceedings (the"Stay Motion") filed by Federal Deposit Insurance Corporationas Receiver for
SignatureBank ("FDIC-R") and state:
A 90-day stay would be appropriateunder 18 U.S.C. § 1821(d)(12)(A),but a longer stay
would not be appropriate.
Nation v. Resolution Trust Corp.,791 F. Supp. 1152 (N.D. Tex. 1992)
(holding that the statutory stay may not remain in effect more than 90 days after the date of the
receiver's appointment).In this case, the FDIC-R was appointedon March 12, 2023 (StayMotion,
p. in
3),so activity this case should resume on June 10, 2023.
70612759;1
*** FILED: BROWARD COUNTY, FL BRENDA D. FORMAN, CLERK 05/24/2023 04:08:33 PM.****
The FDIC-R argues that "under federal law, the court is without to proceed
jurisdiction
until exhaust their administrative remedies." But that is not true. Since this case was
plaintiffs filed
before the receiver was appointed,this Court has not lost See Praxis
subjectmatter jurisdiction.
Propertiesv. Colonial Sau Bank, 947 F. 2d 49, 64, n. Rosa
14 (3d Cir. 1991) (citing v. Resolution
Trust Corp.,938 F. 2d 383, 392, n. 12 (3d Cir 1991) and H/hatleyv. Resolution Trust Corp.,32
F.3d 905, 907 (5th Cir. 1994)).This is true because subjectmatter jurisdiction
is tested when the
action is commenced, not whenever a defendant bank happens to become insolvent. See id.
The Eleventh Circuit is clear about this. FDIC v. Lacentra Trucking Inc., 157 F. 3d 1292,
1300 (llth the existence of a pre-receivership
Cir. 1998) ("neither claim againstthe depository
-
nor the requirementof presentingclaims to the receiver,nor the actual presentation
institution,
none ofthese - stripsaway the existingjurisdiction claim. Nor
ofthe court over a pre-receivership
is the court requiredto dismiss the pre-receivership see also
case."); Damiano v. FDIC, 104 F .3d
328, 335 (llthCir. 1997).Other circuits have been justas clear. See Lacentra Trucking Inc., 157
F. 3d at 1300-1 (citingMarquis v. FDIC, 965 F.2d 1148, 1153 (lstCir. 1992) ("[W]e think that
subsections (d)(5)(F)(ii), and (d)(12)coalesce to
(d)(8)(E)(ii), show Congress' discernable intent
to preserve over
jurisdiction civil actions filed againstfailed institutions prior to the FDIC's
appointment as receiver.");
Carney v. Resolution Trust Corp., 19 F.3d 950,955 (5th Cir. 1994)
("[W]e agree with other circuits that have addressed this issue and conclude that when claims for
monetary damages are brought before the RTC is appointed receiver,a court continues to have
subjectmatter jurisdiction Praxis Properties,947 F.2d
over these issues."); at n. 14 ("[W]here a
claimant files its action againsta depositoryinstitution before the institution becomes insolvent
and is placed in receivership... the failure of the thrift and the appointment of RTC as receiver
would appear not to divest the Federal Court of Jurisdiction,
for "[i]tis a firmlyestablished rule
70612759;1
that is tested as the time ofthe filing
subjectmatterjurisdiction US
ofthe complaint."); v. Chorice,
857 F.Supp. 672, 674 (W.D. Mo. 1994) ("[T]heFDIC may stay a case that is pending at the time
the FDIC takes over a failed financial institution to allow the FDIC to analyze the case, but the
over the case the
If the court lost subjectmatter jurisdiction
court always retains jurisdiction....
moment the FDIC took over the Bank, then Congress would not have provided for a 90-stay for
the FDIC to analyze the case."))).
In some circumstances, the FDIC-R may have the option of proceeding with the pre-
or having
receivershiplitigation it stayed out of deference to the claims administration process,
see Lacentra Trucking Inc., 157 F. 3d at 1304; but this is not one of those circumstances. This
case is different because the property at issue in this case - approximately$30 million in insurance
proceeds
- is not an asset ofthe receiversh* estate and cannot be used for anything other than the
satisfaction of the claims at issue in this case. See, e.g., In re Purcell, 141 B.R. 480, 486 (Bankr.
D. Vt. 1992), qlrd, 150 B.R. 111 (D. Vt. 1993). Indeed, the policiesthemselves confirm that
SignatureBank's insolvency does not affect the insurers' obligationsunder the policies.
This situation has arisen many times in the bankruptcy context, and the analysisis the same.
In Re Downey Fin. Corp.,428 B.R. 595,607-08 (Bankr.D. Del. 2010) (holdingthat proceeds of
a debtor's insurance policywere not property of the bankruptcy estate, even though the insurance
policyitself was property of the estate);
In re CHS Electronics, Inc., 261 B.R. 538, 542 (Bankr.
In re Goodenow, 157 B.R. 724, 725 (Bankr. D.
S.D. Fla. 2001) (citing Me. 1993));In re Stevens,
130 F.3d 1027,1029-30 (llth Cir. 1997);In re Continental Airlines,103 F.3d 203, 216-17 (3rd
Cir. 2000); In re Spaulding Composites Co., 207 B.R. 899, 906-07 (9th Cir. BAP 1997); In re
Louisiana World Exposition, Inc. (In re LAW), %31 F.ld 1391, 1400-01 (5th Cir. 1987); In re
Equinox Oil Co., Inc., 300 F.3d 614,618 (5th Cir. 2002).
70612759;1
To put it simply,the claims at issue in this case are not "claims" accordingto 12 U.S.C. §
1821. See, e.g, Glover v. F.D.LC., 698 F.3d 139 (3d Cir. 2012) (FDCPA claim againstfailed
bank's attorney was not a "claim" subjectto § 1821 because it was not an attempt to obtain payment
F.DJC.
from bank assets or a determination of rightswith respect to bank assets); v. Source One
Mortg. Services Corp., 844 F. Supp. 40 (D. Mass. 1994) (holdingthat defendant bank's self-help
recoupment of contractual amount held for failed bank was not a "claim" under FIRREA, in part
because the funds were not available to the FDIC for any other purpose);RTC v. Western
Technologies,Inc., 179 Ariz. 195, 877 P. 2d 294 App. 1994) (holding that a successful litigant's
request for attorneys'fees arisingout of contract or a request for sanctions arisingfrom the RTC's
is not a 'claim' for purposes of FIRREA).
conduct duringlitigation And since the claims at issue
are not "claims" under the statute, they are not subjectto the statute's stay. See,
in this litigation
e.g., Resolution Trust Corp. v. Love, 36 F.3d 972, 978 (10th Cir. 1994) (holdingthat affirmative
defenses are defensive responses and neither "claims" nor "actions" within the provisionsof §
1821, therefore they are not subjectto the administrative claims procedures);National Union Fire
Ins. v. CitySau, 28 F.3d 376,393 (3d Cir. 1994)(holdingthe same).
ifthere
Finally, is a in this
deficiencyl case, the deficiencycan and will be pursued through
the administrative process because the deficiencywould be recoverable againstthe assets of the
estate; but that
receivership is another matter.
WHEREFORE, the Court should enter an order imposing a stay through June 10, 2023,
to resume after that date.
but allowing all case activity
Respectfullysubmitted,
/s/Steven R. Wirth
Steven R. Wirth
seeking approximately $198 million exclusive of interest,but there is, apparently,only $30 million in
1
Plaintiffs are
available insurance coverage.
70612759;1
Florida Bar No.. 170380
Primary Email: steven.wirth@akerman.com
Secondary Email: caren.deruiter@akerman.corn
John L. Dicks II
Florida Bar No.. 89012
Primary Email: john.dicks@akerman.com
Secondary Email. judy.mcarthur@akerman. com
AKERMAN LLP
401 E. Jackson Street,Suite 1700
Tampa, FL 33602
Phone: (813) 223-7333; Fax: (813) 223-2837
and
Jay Cohen
Florida Bar No. 292192
Email. jcohen@jaycohenlaw.corn
Cohen Blostein &
Ayala PA
100 SE 3rd Avenue, Ste. 1100
Fort Lauderdale, FL 33394
Phone: 954.449-8700; Fax: 954.763.6093
Counsel for Plaintiffs
CERTIFICATE OF SERVICE
I HEREBY CERTIFY that on May 24,2023 a true and correct copy of the foregoingwas
filed
electronically with the Clerk of Court by using the Florida Courts e-Filingportalwhich will
effect service on all partiesand/or their counsel of record.
/s/Steven R. Wirth
70612759;1
Case Info
Judge
Levenson, Jeffrey R. Track Judge’s New Case
Case No.
Document Filed Date
May 24, 2023
Case Filing Date
December 17, 2014
County
Category
3
Status
Pending
Parties
Gustafson, SharonDefendant
Liggio, CharlesDefendant
Wirth, Steven RAttorney for the Plaintiff
RYAN FAMILY TRUSTPlaintiff
Wirth, Steven RAttorney for the Plaintiff
JAQUITH HOLDINGS, INC. PROFIT SHARING PLANPlaintiff
Cohen, JayAttorney for the Plaintiff
JAQUITH HOLDINGS, INC.Plaintiff
Wirth, Steven RAttorney for the Plaintiff
| https://trellis.law/doc/162231114/coverage/pennsylvania/allegheny |
Vadial Branch Post Office, Mahabub Nagar 57, Telangana
Vadial Post Office, Mahabub Nagar
Vadial post office is located at Vadial, Mahabub Nagar of Telangana state. It is a branch office (B.O.). A Post Office (PO) / Dak Ghar is a facility in charge of sorting, processing, and delivering mail to recipients. POs are usually regulated and funded by the Government of India (GOI). Pin code of Vadial PO is509357. This Postoffice falls under Wanaparthy postal division of the Andhra Pradesh postal circle. The related head P.O. for this branch office is Stn. Jadcherla head post office and the related sub-post office (S.O.) for this branch office is Midjil post office.
Vadial dak ghar offers all the postal services like delivery of mails & parcels, money transfer, banking, insurance and retail services. It also provides other services including passport applications, P.O. Box distribution, and other delivery services in Vadial.
Types of Post Offices
Post offices are basically classified into 3 types, namely – Head Post Office, Sub-Post Office including E.D. Sub-Office and Branch Postoffice. Vadial P.O. is a Branch Post Office. So far as the public is concerned, there is basically no difference in the character of the service rendered by Sub-Post Offices and Head-Post Offices except in regard to a few Post Office Savings Bank (SB) transactions. Certain Sub Post Offices do not undertake all types of postal business. Facilities are generally provided at Branch Post Offices for the main items of postal work like delivery and dispatch of mails, booking of registered articles and parcels accepting SB deposits and effecting SB withdrawals, and issue and payment of money orders, though in a restricted manner.
Post Office Type Head Post Office Sub-Post Offices including E.D. Sub-Offices Branch Post Office
Vadial Post Office & Its Pin Code
Branch Office Information
Vadial Post Office Services
Mail Services
Parcels
Retail Services
Premium Services
Speed Post
India Post Speed Post Tracking
Tracking System
India Post Tracking Number Formats
Express Parcel Post
Media Post
Greetings Post
Logistics Post
ePost Office
Financial Services
Savings Bank (SB) Account
Recurring Deposit (RD) Account
Monthly Income Scheme (MIS)
Monthly Public Provident Fund (PPF)
Time Deposit (TD)
Senior Citizen Saving Scheme (SCSS)
National Savings Certificate (NSC)
Kisan Vikas Patra (KVP)
Sukanya Samriddhi Accounts (SSA)
Post Office Timings
India Post Tracking
Vadial Post Office Recruitment
Location Map
Contact Details
About India Post
Vadial Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Vadial Post Office has the Postal Index Number or Pin Code 509357. A Pincode is a 6 digit post code of postal numbering system used by India Post. The first digit indicates one of the regions. The first 2 digits together indicate the sub region or one of the postal circles. The first 3 digits together indicate a sorting / revenue district. The last 3 digits refer to the delivery post office type.
P.O. Name Vadial PO Pincode 509 357
The first digit of 509357 Pin Code '5' represents the region, to which this Post Office of Vadial belongs to. The first two digits of the Pin Code '50' represent the sub region, i.e, Andhra Pradesh. The first 3 digits '509' represent the post-office revenue district, i.e, Wanaparthy. The last 3 digits, i.e, '357' represent the Vadial Delivery Branch Office.
Branch Office Information
The Vadial Post Office is a branch office. The Delivery Status for this PO is that it has delivery facility. Postal division name for this Dak Ghar is Wanaparthy, which falls under Hyderabad region. The circle name for this PO is Andhra Pradesh and it falls under Mahabub Nagar Taluka and Mahabub Nagar District. The state in which this Dakghar is situated or located is Telangana. The related head postoffice is Stn. Jadcherla post office and the related sub post office is Midjil post-office. The phone number of Vadial post office is unavailable at present.
PO Type Branch Office Delivery Status Delivery Postal Division Wanaparthy Postal Region Hyderabad Postal Circle Andhra Pradesh Town / City / Tehsil / Taluka / Mandal Mahabub Nagar District Mahabub Nagar State Telangana Related Sub PO Midjil Sub Office Related Head PO Stn. Jadcherla Head Post Office
Vadial Post Office Services
Traditionally the primary function of Vadial post office was collection, processing, transmission and delivery of mails but as of today, a Post Office offers many other vital services in addition to its traditional services. The additional services provided by a Dak Ghar include – Mail Services, Financial Services, Retail Services and Premium Services.
Mail Services
Mail Services are the basic services provided by Vadial P.O. Mails and mail services include all or any postal articles whose contents are in the form of message which may include Letters, Postcards, Inland letter cards, packets or parcels, Ordinary mails etc.
Parcels
Mail Service also includes transmission and delivery of Parcels. A parcel can be anything ranging from a single written letter or anything addressed to an addressee. No parcel shall be by any chance be in a shape, way of packing or any other feature, such that it cannot be carried or transmitted by post or cause serious inconvenience or risk. Every parcel (including service parcels) that needs to be transmitted by post must be handed over at the window of the post office. Any parcel found in a letter box will be treated and charged as a registered parcel. Delivery services are provided by some selected delivery and branch post offices. This dakghar have the facility of delivery, thus the people of Vadial and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Vadial Post Office offer most of the retail services. They offer the facility to accept or collect constomer bills like telephone or mobile bills, electricity bills for Government and private organizations through Retail Post. Some of the aditional agency services that Post offices offers through retail services are as follows - Telephone revenue collection, e-Ticketing for Road Transport Corporations and Airlines, Sale of UPSC forms, university applications, Sale of Passport application forms, Sale of Gold Coins, Forex Services, Sale of SIM and recharge coupons, Sale of India Telephone cards, e-Ticketing of Railway tickets etc. The postal customers of Vadial can pay their bills and avail other retail services from this Dak Ghar.
Premium Services
Most of the premium services can be availed by the Vadial peoples and nearby living people. The premium services provided by Vadial Post Office are - Speed Post, Business Post, Express Parcel Post, Media Post, Greeting Post, and Logistics Post.
Speed Post
Speed Post is a time bound service in express delivery of letters and parcels. The max weight up to which an article or parcel be sent is 35 kgs between any two specified stations in India. Speed Post delivers 'Value for money' to everyone and everywhere, delivering Speed Post upto 50 grams @ INR 35 across the country and local Speed Post upto 50 grams @ INR 15, excluding applicable Service Tax. Kindly check official website for updated Speed Post service charges.
India Post Speed Post Tracking
Speed Post offers a facility of on-line tracking and tracing that guarantees reliability, speed and customer friendly service. Using a 13 digit barcode that makes a Speed Post consignment unique and identifiable. A web-based technology (www.indiapost.gov.in/speednettracking.aspx) helps the Vadial customers track Speed Post consignments from booking to delivery.
Tracking System
Except Speed Post, India Post also allows people to track their order information for certain products like Parcels, Insured letters, Speed Post, Registered Post, Electronic Money Orders (EMO) and Electronic value payable parcel (EVPPs) etc. The tracking number is available on the receipt given at Vadial Post Office. Using the tracking number postal customers can find out the date and time of dispatch of an article at various locations. The time of booking and the time of delivery of article.
India Post Tracking Number Formats
Different types of postal service have different kinds of tracking number formats. The tracking number for Express Parcel is a 13 digit alphanumeric format. The format for Express Parcel is XX000000000XX. The tracking number for a Registered Mail is a 13 digit alphanumeric number and its format is RX123456789IN. But a Electronic Money Order (EMO) has a 18 digit tracking number and its format is 000000000000000000. For domestic Speed Post (EMS) there is a 13 digit alphanumeric tracking number with the format EE123456789IN.
Bharatiya Dak Ghar Seva Tracking Number Format Number of Digits Electronic Money Order (eMO) 000000000000000000 18 Express Parcel XX000000000XX 13 International EMS Artilces to be delivered in India EE123456789XX 13 Registered Mail RX123456789IN 13 Speed Post (EMS) Domestic EE123456789IN 13
Express Parcel Post
In Express Parcel Post, the Vadial postal customer gets time bound delivery of parcels. These parcels will be transmitted through air or any other fastest mean available at that time. Minimum chargeable weight for which Express Parcel consignments will be booked is 0.5 Kg. Maximum weight of Express Parcel consignments which shall be booked across the Post Office counter by a retail customer shall be 20 Kg and maximum weight that can be booked by corporate customer is 35 kgs.
Media Post
India Post offers a unique way or concept to help the Indian corporate organisations and the Government organizations reach potential customers through media post. Through media post people can advertise on postcards, letters, aerogramme, postal stationary etc. Customers get to see the logo or message of the respective corporate or government organizations. The Aerogramme even gives the organizations the opportunity to make their product have a global impact.
Greetings Post
Greeting Post is yet another innovative or unique step by India Post. It consists of a card with an envelope with pre-printed and pre attached postage stamp on the envelope. The stamp on the envelope is a replica of the design that appears upon the card but in miniature form. Thus there is no need affix postage stamps on the envelope implicitly saving your time of going to post offices and standing in the queue. All the rules and that are applicable for the postage dues will also be applicable to the Greeting Post.
Logistics Post
Logistics Post manages the entire transmission and distribution side of the parcels. It deals with collection of goods, storage of goods, carriage and distribution of the various parcels or goods, from order preparation to order fulfilment. And that too at the minimum possible price. Logistics Post services provides the Vadial postal customer with cost-effective and efficient distribution across the entire country.
ePost Office
The advent of internet made communication very rapid through emails. But, the internet has not yet reached most of the rural parts of India. To change this division between rural & urban life, and to get the benefit of internet technology to Vadial people's lives, Indian Postal Department has introduced e-post. e-post is a service in which personalized handwritten messages of customers are scanned and sent as email through internet. And at the destination address office, these messages are again printed, enveloped and delivered through postmen at the postal addresses. E-post centres are established in the Post Offices, covering a large geographical area including major cities and districts. These e-post centres are well equipped with internet connection, scanners, printers and other necessary hardware equipment. However, this e-post service doesn’t particularly need a e-post centre, but can this facility can be availed at any normal Post Office or you can visit www.epostoffice.gov.in to access postal services on your desktop, laptop or even on mobile. If a message is booked at Vadial post office, the post is scanned and sent to an e-post centre by e-mail and a mail received at e-post centre is printed and sent to nearby Post Office for dispatch.
A Vadial customer can also avail these services of an e-post, at his/ her home. All he/ she has do is to register as a user at www.epostoffice.gov.in website. After registration, a user can use e-post by scanning and sending messages, printing and receive messages. The message to be scanned must not be written in a paper not more A4. There is no limit for sending number of sheets of messages in e-post.
E-Post Office offers certain services like – Philately, Postal Life Insurance, Electronic Indian Postal Order, Information Services, Track & Trace and Complaints & Guidelines services.
Philately
Philately service deals with collection, sale and study of postage stamps. Philately includes lot of services Philately Information, Stamp issue Program, Stamps List and Buy Stamps service.
Postal Life Insurance (PLI)
A service offered by the Government to pay a given amount of money on the death of an individual to his prescribed nominee. The amount may also be paid to the person himself, in case he survives that maturity period. The two services offered under Postal Life Insurance are – Pay Premium service and PLI information.
Electronic Indian Postal Order
eIPO or Electronic Indian Postal Order is a facility to purchase an Indian Postal Order electronically by paying a fee on-line through e-Post Office. This service is launched by the Department of Posts, Ministry of Communications & IT, Government of India.
eIPO can now be used by Indian Citizens living in India for paying online fee, whoever seeks information under the RTI Act, 2005. eIPO offers 2 types of services – eIPO information and payment of online fees.
Information Services
This helps Vadial customers to get information regarding certain products like – Pin Code search, Speed post, Banking, Insurance, Business Post, Logistics Post, IMTS and many more other services.
Track & Trace
The track & trace service is very helpful as it aids in getting information of our valuables. Track & Trace service offers 5 different services – Pin Code search, EMO tracking, Speed Post tracking, WNX tracking and International mail service.
Complaints & Guidelines
Using e-post office service Vadial postal costumer can access services based on – complaint registration, complaint status and guidelines on complaints.
ePost Office Website www.epostoffice.gov.in
Financial Services
The customers of Vadial can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Vadial area. The Financial service offered by PO includes Savings and Postal Life Insurance (PLI). There are various options available to save and invest with post-offices. The commonly used ones include - Savings account, Recurring Deposit, Monthly Income Scheme, Monthly Public Provident Fund, Time Deposit, Senior Citizen Saving Scheme, National Savings Certificate, Kisan Vikas Patra and Sukanya Samriddhi Yojana. Post Office also offers Insurance product through Postal Life Insurance (PLI) and Rural Postal Life Insurance (RPLI) schemes that offer low premium and high bonus.
Post Office Financial Services Kisan Vikas Patra (KVP) Monthly Income Scheme (MIS) Monthly Public Provident Fund (PPF) National Savings Certificate (NSC) Recurring Deposit (RD) Account Savings Bank (SB) Account Senior Citizen Saving Scheme (SCSS) Sukanya Samriddhi Accounts (SSA) Time Deposit (TD)
Savings Bank (SB) Account
A Savings bank account serves the need of regular deposits for its customers as well as withdrawals. Cheque facility is also avail by Vadial postal consumers.
Recurring Deposit (RD) Account
A post office offers a monthly investment option with handsome return at the time period with an option to extend the investment period. Insurance facility is also available with certain conditions.
Monthly Income Scheme (MIS)
MIS offers a fixed investment technique for five or more years with monthly interest payment to the account holder. There is also a facility of automatic crediting of interest to SB account of the Vadial postal customer.
Monthly Public Provident Fund (PPF)
This service offers intermittent deposits subject to a particular limit for a time period of 15 years with income tax exemptions, on the investment. It also offers loan and withdrawal facilities for the postal customers.
Time Deposit (TD)
Fixed deposit option for periods ranging from one, two, three to five years with facility to draw yearly interest offered at compounded rates. Automatic credit facility of interest to SB account.
Senior Citizen Saving Scheme (SCSS)
Offers fixed investment option for senior citizens for a period of five years, which can be extended, at a higher rate of interest that are paid in quarterly instalments.
National Savings Certificate (NSC)
NSC is offered with a fixed investment for 5 or 10 years on certificates of various denominations. Pledging facility available for availing loan from Banks.
Kisan Vikas Patra (KVP)
Kisan Vikas Patra is a saving certificate scheme in which the amount Invested doubles in 110 months (i.e. 9 years & 2 months). It is available in denominations of Rs 1,000, 5000, 10,000 and Rs 50,000. Minimum deposit is Rs 1000/- and there is no maximum limit. The KVP certificate can be purchased by any adult for himself or on the behalf of a minor. This certificate can also be transferred from one account holder to another and from one post office to another. This certificate can be en-cashed only after 2 and 1/2 years from the date of issue.
Sukanya Samriddhi Accounts (SSA)
Sukanya Samriddhi Account Yojana offers a small deposit investment for the girl children as an initiative under 'Beti Bachao Beti Padhao' campaign. This yojana is to facilitate girl children proper education and carefree marriage expenses. One of the main benefits of this scheme is that it is very affordable and offers one of the highest interest rates. Currently its interest rate is set as 8.6% per annum that is again compounded yearly. The minimum deposit allowed in a financial year is INR. 1000/-and Maximum is INR. 1,50,000/-. Subsequent deposits can be made in multiples of INR 100/-. Deposits can be made all at a time. No limit is set on number of deposits either for a month or a financial year. A legal Guardian can open an account in the name of a Girl Child. Account can be closed only after completion of 21 years of the respective child. The normal Premature closure allowed is after completion of 18 years only if that girl is getting married.
Disclaimer: All the information in this website is published for general information purpose only. Some schemes and other postal services may not be available in Vadial Post Office. Kindly verify for all India post saving schemes and other postal services with official resources.
Post Office Timings
The official working hours of Post Offices vary from one another, but the general Post Office opening time starts from 09:00 AM or 10:00 AM and the closing time is 06:00 PM or 07:00 PM respectively. The working days are from Monday to Saturday, Sunday being a holiday. This doesn't include the public holidays or the extended working hours. You can verify the working hours of Vadial Branch Post Office from the official resources.
India Post Tracking
Online tracking of India Post allowed Vadial people to access their postal article tracking information and confirm the delivery of their postal article by using the tracking number assigned to them at the time of Booking. They can find the tracking number on the Postal acknowledgement handed over to them at the Vadial Branch Post Office counter at the time of postal article booking. Following items can track through the www.indiapost.gov.in/articleTracking.aspx official website.
Business Parcel
Business Parcel COD
Electronic Money Order (e-MO)
Electronic Value Payable Parcel (eVPP)
Express Parcel
Express Parcel COD
Insured Letter
Insured Parcel
Insured Value Payable Letter
Insured Value Payable Parcel
International EMS
Registered Letter
Registered Packets
Registered Parcel
Registered Periodicals
Speed Post
Value Payable Letter
Value Payable Parcel
The India Post tracking system is updated at regular intervals to give the Vadial postal customers with the most up to date information available about the location and status of their postal article. They'll be able to find out the following:
When their postal article was booked
When their postal article was dispatched at various locations during its Journey
When their postal article was received at various locations during its Journey
When their postal article was delivered, or
When a delivery intimation notice was issued to notify the recipient that the postal article is available for delivery
Vadial Post Office Recruitment
For latest Vadial post office recruitment kindly visit www.indiapost.gov.in/recruitment.aspx.
Location Map
Vadial Branch Post Office is located in Vadial, Mahabub Nagar.
Contact Details
All the queries or complaints regarding Bill Mail Service, Booking Packets, Business Post, Direct Post, Flat Rate Box, Indian Postal Orders, Inland Letters, Instant Money Orders, Insurance of Postal Articles, Insurance of Postal Parcels, Letters, Logistics Posts, MO Videsh, Money Orders, Parcels, Post Office Savings Bank, Postal Life Insurance, Postcards, Registration of Postal Articles, Registration of Postal Parcels, Rural Postal Life Insurance, Saving Certificates, Small Saving Schemes, Speed Post, Value Payable Post etc. services in Vadial Post Office, can be resolved at Vadial Branch Post Office. You can send letters to "Postmaster, Vadial Branch Post Office, Vadial, Mahabub Nagar, Telangana, India, Pincode: 509 357". The official website of the Berhampur University Sub Office is www.indiapost.gov.in.
Vadial Branch Office
Address: Vadial Branch Post Office, Vadial, Mahabub Nagar, Telangana, India
Pin Code: 509357
Website: www.indiapost.gov.in
About India Post
India Post is a government-operated postal system, which is part of the Ministry of Communications and Information Technology of the Government of India. It has the largest Postal Network in the India with over 154882 Post Offices. There are around 139182 Post Offices in the rural India and 15700 Post Offices in urban India. The individual post office serves an area of 21.22 Sq. Km. and a population of 8221 people. The slogan of India Post is Dak Seva Jan Seva. There are 25464 departmental post offices and 129418 extra-departmental branch post offices in India.
Vadial Post Office Summary
Dak Ghar Name Vadial Branch Post Office Pincode 509357 Dakghar Type Branch Office Post Office Delivery Status Delivery Branch Office Postal Division Wanaparthy Postal Region Hyderabad Postal Circle Andhra Pradesh Location Vadial District Mahabub Nagar State Telangana Country India Related Sub Office Midjil Sub Office Related Head Office Stn. Jadcherla Head Post Office Website www.indiapost.gov.in ePost-office Web Site Address www.epostoffice.gov.in Speed Post Tracking Website www.indiapost.gov.in/speednettracking.aspx Recruitment Web Site Address www.indiapost.gov.in/recruitment.aspx
Chndradana Post Office
| https://www.postoffices.co.in/telangana-tg-ts/vadial-mahabub-nagar-57/amp/ |
JCM | Free Full-Text | Bedside Renal Doppler Ultrasonography and Acute Kidney Injury after TAVR
Acute kidney injury (AKI) following transcatheter aortic valve replacement (TAVR) is associated with a dismal prognosis. Elevated renal resistive index (RRI), through renal Doppler ultrasound (RDU) evaluation, has been associated with AKI development and increased systemic arterial stiffness. Our pilot study aimed to investigate the performance of Doppler based RRI to predict AKI and outcomes in TAVR patients. From May 2018 to May 2019, 100 patients with severe aortic stenosis were prospectively enrolled for TAVR and concomitant RDU evaluation at our institution (Nouvel Hôpital Civil, Strasbourg University, France). AKI by serum Creatinine (sCr-AKI) was defined according to the VARC-2 definition and AKI by serum Cystatin C (sCyC-AKI) was defined as an sCyC increase of greater than 15% with baseline value. Concomitant RRI measurements as well as renal and systemic hemodynamic parameters were recorded before, one day, and three days after TAVR. It was found that 10% of patients presented with AKIsCr and AKIsCyC. The whole cohort showed higher baseline RRI values (0.76 ± 0.7) compared to normal known and accepted values. AKIsCyC had significant higher post-procedural RRI one day (Day 1) after TAVR (0.83 ± 0.1 vs. 0.77 ± 0.6, CI 95%, p = 0.005). AUC for AKIsCyC was 0.766 and a RRI cut-off value of ≥ 0.795 had the most optimal sensitivity/specificity (80/62%) combination. By univariate Cox analysis, Mehran Risk Score, higher baseline right atrial pressure at baseline >0.8 RRI values one day after TAVR (HR 6.5 (95% CI 1.3–32.9; p = 0.021) but not RRI at baseline were significant predictors of AKIsCyC. Importantly, no significant impact of baseline biological parameters, renal or systemic parameters could be demonstrated. Doppler-based RRI can be helpful for the non-invasive assessment of AKI development after TAVR.
Bedside Renal Doppler Ultrasonography and Acute Kidney Injury after TAVR
Laurence Jesel 1,4 ,
Patrick Ohlmann 1,4 and
Olivier Morel 1,4,*
1
Université de Strasbourg, Pôle d’Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, 67000 Strasbourg, France
2
Université de Strasbourg, Pôle de Biologie, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, 67000 Strasbourg, France
3
Université de Strasbourg, Département de néphrologie et dialyse, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, 67000 Strasbourg, France
4
UMR CNRS 7213 Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 67400 Illkirch, France
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020 , 9 (4), 905; https://doi.org/10.3390/jcm9040905
Received: 11 February 2020 / Revised: 20 March 2020 / Accepted: 21 March 2020 / Published: 25 March 2020
(This article belongs to the Section Cardiology )
Abstract
:
Acute kidney injury (AKI) following transcatheter aortic valve replacement (TAVR) is associated with a dismal prognosis. Elevated renal resistive index (RRI), through renal Doppler ultrasound (RDU) evaluation, has been associated with AKI development and increased systemic arterial stiffness. Our pilot study aimed to investigate the performance of Doppler based RRI to predict AKI and outcomes in TAVR patients. From May 2018 to May 2019, 100 patients with severe aortic stenosis were prospectively enrolled for TAVR and concomitant RDU evaluation at our institution (Nouvel Hôpital Civil, Strasbourg University, France). AKI by serum Creatinine (sCr-AKI) was defined according to the VARC-2 definition and AKI by serum Cystatin C (sCyC-AKI) was defined as an sCyC increase of greater than 15% with baseline value. Concomitant RRI measurements as well as renal and systemic hemodynamic parameters were recorded before, one day, and three days after TAVR. It was found that 10% of patients presented with AKI
sCr
and AKI
sCyC
. The whole cohort showed higher baseline RRI values (0.76 ± 0.7) compared to normal known and accepted values. AKI
sCyC
had significant higher post-procedural RRI one day (Day 1) after TAVR (0.83 ± 0.1 vs. 0.77 ± 0.6, CI 95%,
p
= 0.005). AUC for AKI
sCyC
was 0.766 and a RRI cut-off value of ≥ 0.795 had the most optimal sensitivity/specificity (80/62%) combination. By univariate Cox analysis, Mehran Risk Score, higher baseline right atrial pressure at baseline >0.8 RRI values one day after TAVR (HR 6.5 (95% CI 1.3–32.9;
p
= 0.021) but not RRI at baseline were significant predictors of AKI
sCyC
. Importantly, no significant impact of baseline biological parameters, renal or systemic parameters could be demonstrated. Doppler-based RRI can be helpful for the non-invasive assessment of AKI development after TAVR.
Keywords:
aortic stenosis
;
transcatheter aortic valve replacement
;
acute kidney injury
;
doppler based renal resistive index
New & Highlights
What is known about this topic?
Acute kidney injury (AKI) is a common complication following Transcatheter Aortic Valve Replacement (TAVR)
AKI occurs in a sizeable proportion of TAVR patients (22.1% ± 11.2 according to the VARC-2 definition) and carries poor prognosis
Intrarenal Doppler ultrasonography can assess intrarenal hemodynamic
Doppler based renal resistive index (RRI) measurements is a rapid and non-invasive method proposed for early AKI detection
What does the paper add?
24 h post-TAVR evaluation by Doppler-based resistive index is associated with AKI occurrence up to day 3
Doppler based renal resistive index is an easy, objective, reliable and low-cost tool that succeeded to identify an at-risk population for AKI and able to improve the post TAVR management
This study clarifies the characteristics of intrarenal Doppler RRI profiles and their interactions with systemic hemodynamic in TAVR patients
1. Introduction
Acute kidney injury (AKI) is a common complication following transcatheter aortic valve replacement (TAVR) and remains associated with a dismal prognosis. Based on the current Valve Academic Research Consortium (VARC)-2 definition [
1
], the reported incidence of post TAVR AKI is 22.1% ± 11.2 [
2
]. Depicting the scope of AKI in the field of TAVR relies on a variety of factors from impaired baseline renal function, hemodynamic instability during pacing, and use of contrast medium, to post procedural complications such as bleeding. Given that TAVR is expected to be increasingly performed, screening high-risk patients for AKI is of paramount importance since easy, accessible, and preventive measures, such as optimal periprocedural hydration and careful contrast use, are available. As AKI after TAVR is common and both transient and persistent AKI have been independently associated with higher mortality rates [
3
,
4
]. Thus, the prediction of AKI after TAVR and AKI prevention are key approaches in current practice.
Intrarenal Doppler ultrasonography is a well-recognized and non-invasive method aimed to better assess intrarenal hemodynamic. Renal Doppler ultrasound (RDU) can easily measure the renal resistive index (RRI), a sonographic index reflecting renal arterial blood flow profile, arterial stiffness, sensitivity to arterial resistance, and capacitance changes. Elevated RRI has been associated to adverse outcomes in hypertensive, diabetic, and elderly patients [ 5 , 6 , 7 , 8 ], increased mortality in chronic kidney disease [ 9 ], post procedural AKI development [ 10 , 11 , 12 ], and increased systemic arterial stiffness [ 13 ].
To date, there are few data regarding cardio-renal hemodynamics in the field of TAVR. Therefore, the aim of this pilot study was to (i) investigate the association of Doppler based RRI with acute kidney injury after the TAVR procedure and (ii) evaluate the dynamic change of various cardio-renal hemodynamic parameters according to AKI occurrence.
2. Methods
2.1. Patients
100 patients with severe aortic stenosis (AS) and high or intermediate surgical risk according to Logistic EuroSCORE were prospectively enrolled for TAVR and concomitant RDU evaluation at our institution (Nouvel Hôpital Civil, Strasbourg University, France) from May 2018 to May 2019. The study was approved by the local bioethics committee. All participants gave their informed written consent and agreed to the anonymous processing of their data. Commercially available valves, such as the balloon expandable Edwards SAPIEN XT or S3 prosthesis (Edwards Life sciences LLC, Irvine, CA, USA) and the self-expandable CoreValve or Evolute-R (Medtronic CV, Irvine, CA, USA), were used. Anesthesiological management included a local anaesthesia plus sedation. It consisted of lidocaine injected subcutaneously at the arterial and venous access sites (maximum dose 4 mg/kg), with sedation accomplished with remifentanil infusion adjusted according to the patient’s response (target level: score 2–3 with modified Wilson sedation scale; starting dose 0.025 µg/kg/min, maximum dose 0.2 µg/kg/min).
2.2. Definition of AKI
Acute kidney injury by serum Creatinine (AKI
sCr
) was defined according to the VARC-2 definition (1) as an absolute increase in serum creatinine of ≥ 0.3 mg/dL (≥ 26.4 µmol/L) OR ≥ 50% increase in serum creatinine 72 h after TAVR. The AKIN Classification classified biochemical severity of AKI as follow: (i) Stage 1: Increase in serum creatinine to 150–199% (1.5–1.99× increase compared with baseline) (ii) Stage 2: Increase in serum creatinine to 200–299% (2.0–2.99× increase compared with baseline) (iii) Stage 3: Increase in serum creatinine to ≥ 300% (> 3× increase compared with baseline).
AKI as determined by Serum cystatin C was identified as AKI sCyC and defined as an sCyC increase of greater than 15% with baseline value [ 14 ].
We sought to evaluate the incremental value of a new definition of AKI: AKI
sCr
OR
sCyC
detected by a single marker (sCr increase ≥ 0.3 mg/dL or 50% from baseline OR sCyC increase ≥ 15% from baseline) and AKI
sCr
AND
sCyC
where AKI is detected using by both markers: sCr increase ≥ 0.3 mg/dL or 50% from baseline and sCyC increase ≥ 15% from baseline. Patients were excluded if they were receiving dialysis at baseline.
2.3. Intrarenal Hemodynamic Evaluation by Doppler Ultrasonography
Patients with previous known renal artery disease (renal artery stenosis, occlusion or renal artery/vein thrombosis) were excluded from further analysis. RDU measurements were performed 12 h prior, 24 h and 72 h after TAVR procedures. According to previous work and validated methodology, renal resistive index (RRI) was measured with an ultrasound-Doppler pulsed-wave Doppler probe (5S ultrasound transducer, General Electric Medical Systems) on a Vivid S7 ultrasound system by two independent trained physicians. After locating the kidneys, intrarenal renal vessels were identified using color Doppler and sampling for RRI screened at the level of interlobar arteries. Measurements using pulse-wave Doppler were repeated in different parts (superior, median, and lower) of the kidney and at least three reproducible and consecutive waveforms were obtained to measure RRI parameters (
Figure 1
). The RRI index was calculated according to the following formula: ((peak systolic velocity − end diastolic velocity)/peak systolic velocity). The mean value of three different measurements was recorded. The mean reference value for normal RRI in adults is 0.60 ± 0.10 and 0.70 considered as the upper limit of normal [
15
,
16
,
17
].
2.4. Echocardiography Protocol and Hemodynamic Parameters
Concomitant echocardiography was performed after RDU measurements 12 h prior, 24 h and 72 h after TAVR procedure. The following echocardiographic and clinical variables were collected from each patient: heart rate; systolic, diastolic, and mean blood pressures; left ventricular ejection fraction (LVEF); aortic flow time-velocity integral; Aortic velocity time integral and diastolic left ventricular function parameters. Systemic and local renal hemodynamic parameters were calculated according to current definitions ( Supplementary Files ) and included valvulo-arterial impedance, total arterial load, pulse pressure, systemic arterial compliance, resistive arterial load, renal arterial load, renal pulse pressure, and renal arterial compliance.
2.5. Collection of Data and Outcomes
All baseline and follow-up variables were recorded and entered into a secure, ethics-approved database. Clinical endpoint including acute kidney injury, mortality, stroke, bleeding, access-related complications and conduction disturbances were assessed according to the definitions provided by the Valve Academic Research Consortium-2 (VARC-2). All clinical events were adjudicated by an events validation committee.
The primary endpoint of the study was the AKI incidence 72 h after TAVR. The secondary endpoint was a composite endpoint defined by mortality, stroke, and hospitalization for heart failure. All patients were contacted by phone and questioned by a standardized questionnaire about their health status, symptoms, medications and the occurrence of adverse events.
2.6. Statistical analysis
Quantitative variables were described according to AKI occurrence and expressed as means ± standard deviation. Categorical variables were expressed as counts and percentages. Categorical variables were compared with chi-square tests or Fisher’s exact tests. Continuous variables were compared with the use of parametric (ANOVA) or non-parametric Mann–Whitney tests as appropriate. Normality of the distribution was tested using Kolmogorov—Smirnov Test. To determine predictors of AKI, regression analysis was performed. A p value < 0.05 was considered significant. Receiver-operating characteristic (ROC) curve analysis was performed to establish the threshold values most predictive of AKI. Calculations were performed using SPSS 17.0 for Windows (SPSS Inc., Chicago, IL, USA).
3. Results
3.1. Baseline Characteristics
Baseline, procedural, and biological characteristics are summarized in
Table 1
,
Table 2
and
Table 3
. Of the 100 TAVR patients recruited, AKI was documented respectively for 10%; 10%, 16%, and 4% of the global cohort according to the AKI
sCr
, AKI
sCyC
, AKI
sCr,
OR
sCyC
and AKI
sCr
AND
sCyC
definitions respectively (
Table 4
). Regarding AKI as determined by serum creatinine (AKI
sCr
), stage 1 AKI according to the AKIN system occurred in eight patients, stage 2 in two patients, and none in stage 3. No difference regarding traditional cardiovascular risk factors according to previous medical history apart from coronary artery disease could be evidenced between groups. Of note, AKI
sCyC
patients showed a higher Mehran contrast-induced nephropathy risk score (
p
= 0.016) while no difference regarding contrast media volume administration or length of procedure. No pre-operative complications could be evidence such as cardiac arrest, tamponade, immediate red blood cell transfusion nor vasopressor/inotropic support requirement. Likewise, no patients required dialysis therapy nor the short-term use of mechanical circulatory support devices.
3.2. Renal Resistive Index (RRI)
The whole cohort of AS patients eligible for TAVR showed higher baseline RRI values (0.76 ± 0.7) compared to normal known and accepted values. While RRI at baseline and Day 3 were similar between groups, patients with AKI sCyC had significant higher post-procedural RRI one day (Day 1) after TAVR ( Table 5 ). Receiver-operating characteristic curve was applied for the identification of an optimal RRI value ( Figure 2 ). AUC for AKI sCyC was 0.766 and a RRI cut-off value of ≥ 0.795 had the most optimal sensitivity/specificity (80/62%) combination. Similarly, higher post-procedural RRI one day after TAVR could be evidenced according to the AKI sCr OR sCyC and AKI sCr AND sCyC definition ( Table 6 ).
3.3. Hemodynamic Parameters
Likewise, AKI sCyC patients showed transient higher valvulo-arterial impedance and total arterial load one day after TAVR ( Table 7 ). Conversely and interestingly, no difference regarding inotropy (cardiac performance assessed by stroke volume and cardiac index), left ventricular filling pressure (E/A, E/e′) or renal hemodynamic parameter could be established. A higher preload at baseline evidenced by higher right atrial pressure (echocardiographic assessment of estimated right atrial pressure) was associated with AKI sCyC patients.
3.4. Predictors of AKI Following TAVR
By univariate Cox analysis, Mehran Risk Score, higher baseline right atrial pressure at baseline, > 0.8 RRI values one day after TAVR (HR 6.5 (95% CI 1.3–32.9; p = 0.021) but not RRI at baseline were significant predictors of AKI sCyC ( Table 8 ).
Importantly, no significant impact of baseline biological parameters, renal or systemic parameters could be demonstrated.
4. Discussion
AKI is a common complication in patients with TAVR and associated with adverse clinical outcomes [ 2 ]. Although prevalence and preventive measures for AKI in TAVR have been investigated in multiple clinical trials [ 18 , 19 ], methods designed to accurately detect early AKI are still lacking. Therefore, new diagnostic tools that could predict AKI and be commonly adopted by cardiologists are desperately needed. To the best of our knowledge, this is the first study evaluating the use and role of intrarenal Doppler ultrasonography in diagnosing AKI in an unselected TAVR population.
The results of our study show that, in AS patients undergoing TAVR, AKI patients exhibited (i) higher RRI values compared to normal known and accepted values; (ii) higher transient and residual afterload assessed by valvulo-arterial impedance and total arterial load one day after TAVR and finally (iii) no difference regarding renal hemodynamic parameter.
4.1. Impact of AKI Definitions
The main purposes of this study were to assess (i) the optimal RRI cutoff point to detect AKI and (ii) test whether Serum cystatin C and combined serum cystatin C and Serum cystatin C definition for AKI diagnosis provides extra benefit. sCyC has been validated as an alternative to sCr for diagnosing AKI [ 20 ]. Likewise, sCyC has been proposed as a more sensitive AKI marker [ 21 , 22 , 23 ]. Of importance, Cystatin C is not affected by muscle mass or diet and is less strongly associated with age, sex, and race than creatinine [ 24 ] and makes this biomarker of particular interest in AS patients and particularly among the TAVR population.
4.2. Impact of Renal Resistive Index (RRI)
The study’s findings highlight that higher immediate post-procedural RRI is strongly associated with AKI. The present observation is of clinical importance as RRI is a rapid, non-invasive and repeatable strategy that may help in assessing renal preclinical dysfunction and in evaluating subsequent risk of acute kidney injury. Additionally, as RRI can be performed in most patients by inexperienced operators following a half-day course [
25
] our data clearly challenge the routine and widespread use of bedside renal Doppler ultrasonography in the post TAVR management. Though, specific technical and clinical nuances must be raised in the field of TAVR patients.
First, due to arterial stiffness, TAVR patients exhibited higher baseline RRI values (0.76 ± 0.7) compared to normal known and accepted values: 0.60 ± 0.10 in adults and 0.70 considered as the upper limit of normal [ 15 , 16 , 17 ]. Indeed, RRI has been reported to increase in the healthy elderly population [ 26 , 27 , 28 , 29 ] and age-related changes in vascular compliance: two intrinsic features defining the TAVR population. Common RRI cut-off values are presently beyond the field of elderly AS patient’s eligible for TAVR, but RRI > 0.795 (Se 80%; 1-Sp 0.378) provided interesting diagnostic performance. The clinical significance of the extended proposed threshold and its diagnostic performance remains to be validated in adequately powered studies.
Second, RRI is the result of a complex interaction between intrarenal circulation and systemic hemodynamics. Not only is RRI a specific marker of kidney damage, but it shares strong relationships with the systemic circulation and some cardiovascular parameters such as cardiac function, aortic stiffness, vascular compliance, renal capillary wedge pressure, and clinical settings such as heart failure progression and regression [
30
]. We might have just performed a futile exercise in the field of RRI and cardio-renal interactions after TAVR in resuming RRI to either renal, systemic hemodynamics, heart failure or cardiorenal syndrome relief. We sought to specifically explore the hemodynamic factors in play that should be considered to understand RRI clinical meaning and to explain how systemic and renal parameters both can affect the RRI analysis as TAVR represents a unique therapeutic modality in acute hemodynamic changes. All this without forgetting that RRI goes beyond considering only one specific feature (renal, hemodynamics, renal capillary wedge pressure etc.) of its complex and dynamic definition.
4.3. Impact of Systemic and Renal Hemodynamics Parameters
The mechanistic model of acute relief of the valvular load provided by TAVR procedures enables the measurement and investigation of rapid systemic and renal hemodynamic changes. Albeit limited to a small sample size, we provided data suggesting that higher RRI is linked to transient higher valvulo-arterial impedance (Zva) and total arterial load (TAL) one day after TAVR.
In patients with AS, high Zva and TAL are accurate markers of advanced disease and have been previously associated with adverse outcomes both in AS [ 31 , 32 ] and post TAVR patients [ 33 , 34 ]. Our report stands out as the first insight demonstrating that transient residual high post TAVR afterload impacts AKI development through higher RRI, a surrogate marker of renal arterial resistance.
We believe the results of our findings suggest that systemic arterial afterload and RRI evaluation should be incorporated to optimize patient periprocedural TAVR management. Long-term prospective studies are needed to establish the prognostic value of measuring such indices before and after valve interventions and how such indices may aid selecting the best management strategy for patients after TAVR.
Our findings reinforce the understanding of the complex nature of RRI changeability and renal function in the field of TAVR with higher RRI depending on (i) fixed systemic and renal vascular resistance despite acute relief from AS provided by TAVR; (ii) absence of compensatory mechanism maintaining or improving GFR such as relief from heart failure and inherent cardiorenal syndrome and (iii) on the other hand true renal damage induced by contrast media, hypovolemia etc.
Our experimental data suggest therefore that Doppler-based RRI could be an integrative parameter that may help in detecting early renal dysfunction, portray the post procedural systemic vascular load and become a surrogate maker of cardiorenal interaction after TAVR.
Finally, RRI at 24 h after TAVR was not influenced by preoperative renal function but hemodynamic change, and it was thus considered as a surrogated marker. These results are important to assess the mechanism of AKI after TAVR. Indeed, due to the small number of subjects included and the complex pathophysiological factors as displayed in this paper, we could not establish that RRI evaluated preoperatively could predict AKI.
4.4. Study Limitations
Several limitations should be taken into account in the interpretation of the data. First, the observational design of the study, though prospective inclusions, did not allow us to establish a cause-effect relationship between the observed associations. Additionally, the inclusion of overwhelming elderly patients with preserved LVEF and moderately altered GFR (the mean LVEF of patients in our study was > 55% and mean sCr-GRF 54.5 µmol/L) limited the generalizability of the results to other populations. Indeed, further data supporting the link between altered cardiac output, renal function, and RRI evaluation (e.g., low-flow low-gradient AS or reduced LVEF patients) may represent a population of choice to study due to prominent hemodynamic changes and cardiorenal interactions after TAVR. While AKI is widely known to be associated with red blood cell transfusions, such association was not observed given the limited size of the cohort. Second, international standardization of the Cystatin C assay is not finalized. Third intra and Inter-observer RRI variability were not analysed but assumed to be very low in the literature. Fourth, concomitant therapeutic modalities after TAVR known to affect RRI (e.g., diuretic therapy with the consequent reduction in renal venous pressure) were not recorded. Finally, we conducted a pilot study, with a consequently small sample size (100 patients) and only 10 events, making any analysis, especially a logistic regression, tentative and for the purpose of hypothesis generation. The AUC of 0.766 should be considered with caution and interpreted in the light of a low number of events.
5. Conclusions
Doppler-based renal resistive index can be helpful for the non-invasive assessment of acute kidney injury development after transcatheter aortic valve replacement.
Supplementary Materials
The following are available online at https://www.mdpi.com/2077-0383/9/4/905/s1 , Figure S1: Circulatory system as an electric circuit, Table S1: Systemic and renal hemodynamic parameters.
Author Contributions
All authors contributed significantly to the submitted work as follows: M.P.: study conception and design, drafting of the manuscript, data collection and interpretation; B.M.: data collection and interpretation, drafting of the manuscript and critical revision for important intellectual content; S.B.: data interpretation and critical revision for important intellectual content; E.P.: data interpretation and critical revision for important intellectual content; K.M.: data collection and interpretation; A.C.: data collection and interpretation; J.H.: data collection and interpretation; A.T.: data collection and interpretation; H.P.-E.: data collection and interpretation; L.J.: interpretation of data and critical revision for important intellectual content; P.O.: interpretation of data and critical revision for important intellectual content; O.M.: study conception and design, data collection and interpretation, drafting of the manuscript, and critical revision for important intellectual content. All the authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by GERCA (Groupe pour l’Enseignement, la Recherche cardiologique en Alsace).
Conflicts of Interest
Matsushita has received scholarship from Uehara Memorial Foundation. Other authors have reported that they have no relationship to disclose.
RRI Doppler based renal resistive index
sCr serum Creatinine
sCyC Serum cystatin C
TAVR transcatheter aortic valve replacement.
TTE transthoracic echocardiography
VARC-2 valve academic research consortium-2 consensus
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Figure 1. Intrarenal Doppler Ultrasonography: Renal Resistive index measurement technique. A sample volume is placed within an interlobar artery using Colour Doppler guidance. Spectral analysis of vascular signals is then obtained, and measurement callipers are set as follow: (i) systolic peak (green arrow); (ii) end diastole peak (blue arrow). Renal Resistive index is then calculated according to the formula (Vs − Vs)/Vs.
Figure 1. Intrarenal Doppler Ultrasonography: Renal Resistive index measurement technique. A sample volume is placed within an interlobar artery using Colour Doppler guidance. Spectral analysis of vascular signals is then obtained, and measurement callipers are set as follow: (i) systolic peak (green arrow); (ii) end diastole peak (blue arrow). Renal Resistive index is then calculated according to the formula (Vs − Vs)/Vs.
Figure 2. Receiver-Operating Characteristic (ROC) Curve Displaying the Optimal Threshold and Goodness of Renal Resistive Index one day after TAVR for sCyC AKI. Renal Resistive Index one day after TAVR provides a good prediction of sCyC AKI with an optimal cutoff value of 0.795 and an area under the curve of 0.766. AUC = 0.766; Confidence interval (0.618; 0.913, p = 0.006); Optimal RRI threshold = 0.795 (Se 80%; 1-Sp 0.378).
Figure 2. Receiver-Operating Characteristic (ROC) Curve Displaying the Optimal Threshold and Goodness of Renal Resistive Index one day after TAVR for sCyC AKI. Renal Resistive Index one day after TAVR provides a good prediction of sCyC AKI with an optimal cutoff value of 0.795 and an area under the curve of 0.766. AUC = 0.766; Confidence interval (0.618; 0.913, p = 0.006); Optimal RRI threshold = 0.795 (Se 80%; 1-Sp 0.378).
Table 1. Baseline characteristics.
Table 1. Baseline characteristics.
Global Cohort AKI sCyC No AKI sCyC p -Value n = 100 n = 10 n = 90 Clinical parameters Age—years ± SD 83.7 ± 6.3 83.4 ± 6.7 83.7 ± 6.3 0.88 Male sex—no/total no. (%) 48 (48%) 5 (50%) 43 (48%) 0.58 Euroscore * (%) 5.5 ± 5 8 ± 8 5.3 ± 4.6 0.1 STS mortality (%) 5.2 ± 3.7 6.7 ± 4.4 5 ± 3.6 0.16 STS renal failure (%) 6.5 ± 8.5 10.2 ± 10.9 6.1 ± 8.2 0.16 Mehran Contrast nephropathy risk score (points) 7.75 ± 3 9.4 ± 4 7.6 ± 2.8 0.067 Mehran Risk Score (%) 13.9 ± 7.6 19.4 ± 14.7 13.3 ± 6.3 0.016 Coronary artery disease—no./total no. (%) 53 (53%) 2 (20%) 51 (56.7%) 0.03 Pacemaker—no./total no. (%) 12 (12%) 1 (10%) 11 (12.2%) 0.66 Cardiovascular Risk Factors Hypertension—no./total no. (%) 90 (90%) 9 (90%) 81 (90%) 0.67 Past or current smoker—no./total no. (%) 26 (26%) 4 (40%) 22 (24.4%) 0.24 Dyslipidaemia—no./total no. (%) 53 (53%) 5 (10%) 48 (52%) 0.55 Diabetes mellitus—no./total no. (%) 40 (40%) 5 (10%) 35 (38.9%) 0.36 BMI—kg/m 2 ± SD 32 ± 13 29 ± 9 32 ± 13 0.47 Prehospital management VKA—no./total no. (%) 18 (18%) 1 (10%) 17 (18.9%) 0.42 DOAC—no./total no. (%) 22 (22%) 3 (30%) 19 (21.1%) 0.38 ASA—no./total no. (%) 56 (56%) 4 (5.6%) 52 (57.8%) 0.23 Clopidogrel—no./total no. (%) 23 (23%) 0 23 (25.6%) 0.06 ACE inhibitors/ARBs—no./total no. (%) 56 (56%) 5 (50%) 51 (56.7%) 0.47 Beta blockers—no./total no. (%) 48 (48%) 5 (50%) 43 (47.8%) 0.58 Calcium channel blockers—no./total no. (%) 31 (31%) 2 (20%) 29 (32.2%) 0.35 Thiazide diuretics—no./total no. (%) 16 (16%) 3 (30%) 13 (14.4%) 0.19 Aldosterone-receptor antagonists (ARAs)—no./total no. (%) 12 (12%) 0 12 (13.5%) 0.26 Furosemide—mg ± SD 71 ± 147 84 ± 155 70 ± 147 0.77 Statin—no./total no. (%) 46 (46%) 3 (30%) 43 (47.8%) 0.23 Echocardiography LEVF—% ± median IQR 60 (51–67) 54.6 ± 12 59 ± 12.4 0.19 LV mass—g/m 2 ± SD 137 ± 77.8 112.7 ± 19.9 138.8 ± 80.8 0.43 LVendDV—mm ± SD 49 ± 8.5 46.2 ± 9 49 ± 8.4 0.33 Mean Aortic Gradient—mmHg ± SD 44.5 ± 11.9 43.5 ± 9.8 44.6 ± 12.2 0.72 E/A 0.9 ± 0.6 0.6 ± 0.2 1 ± 0.6 0.95 E/e′ 11.9 ± 4.6 12.9 ± 3.9 11.7 ± 4.6 0.48 Mean Pulmonary Artery Pressure (MPAP)—mmHg ± SD 40.5 ± 13.2 42 ± 11.1 40.3 ± 13.4 0.77 Right Atrial Pressure (RAP)—mmHg ± SD 7 ± 4 10 ± 6 6 ± 4 0.02 Stroke volume (SV)—mL ± median (IQR) 81.5 (65.3–99.5) 88.1 ± 22.2 80 (65.7–98.5) 0.34 Cardiac index—mL/min/m 2 ± SD 2.9 ± 0.9 3.3 ± 1.3 2.8 ± 0.9 0.17 Baseline biological parameters Creatinine (Cr) level—µmol/L ± SD 113.6 ± 77.9 135.9 ± 89.9 111.2 ± 76.6 0.34 Cr eGFR—mL/min/1.73 m 2 ± SD 54.5 ± 19.9 49 ± 23.5 55 ± 19.6 0.37 Cystatin (CysC)—mg/L ± SD 1.7 ± 0.9 1.9 ± 1 1.7 ± 0.9 0.59 CysC eGFR—ml/min/1.73m 2 ± SD 43.9 ± 18.3 38.5 ± 18.7 44.5 ± 18.3 0.32 Haemoglobin—g/dL median (IQR) 12 (11–13.1) 11.1 ± 2.1 12 ± 2 0.17 BNP—ng/L ± SD 471 ± 856 561 ± 848 461 ± 862 0.73
Data are presented as mean ± or n (%) or median (25th–75th percentile). ACE inhibitor = Angiotensin-converting enzyme inhibitor; AKI = Acute Kidney Injury; ARBs = Angiotensin II receptor blockers; ASA = Aspirin; BMI = body mass index; BNP = B-type natriuretic peptide; Cr = creatinine; CysC = Cystatin C; DOAC = direct oral anticoagulant; EuroSCORE = logistic EuroSCORE predicted risk of mortality at 30 days; GFR = glomerular filtration rate; LV = left ventricle; LVEF = left ventricular ejection fraction; sCr = serum creatinine; sCyC = serum Cystatin C; STS score = Society of Thoracic Surgeon; VKA = Vitamin K antagonists. * The logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) is calculated by means of a logistic-regression equation; online and downloadable versions of the EuroSCORE calculator are available on the EuroSCORE Web site.
Table 2. Procedural characteristics.
Table 2. Procedural characteristics.
Global Cohort AKI sCyC No AKI sCyC p -Value n = 100 n = 10 n = 90 Approach Transfemoral—no./total no. (%) 93 (93%) 9 (90%) 84 (93%) 0.48 Transcarotid—no./total no. (%) 5 (5%) 0 5 (5.6%) 0.58 Transaortic—no./total no. (%) 1 (1%) 1 (10%) 0 0.1 Valve Sapien—no./total no. (%) 64 (64%) 7 (70%) 57 (63.3%) 0.48 Corevalve—no./total no. (%) 34 (34%) 3 (30%) 31 (34.4%) 0.54 Boston Accurate—no./total no. (%) 2 (2%) 0 2 (2.2%) 0.81 Sizing—no./total no. (%) 23 mm 18 (18%) 2 (20%) 16 (17.8%) 0.57 25 mm 1 (1%) 0 1 (1.1%) 0.9 26 mm 40 (40%) 4 (40%) 36 (40%) 0.64 27 mm 1 (1%) 0 1 (1.1%) 0.9 29 mm 1 (1%) 0 1 (1.1%) 0.9 31 mm 33 (33%) 4 (40%) 29 (32.2%) 0.43 34 mm 6 (6%) 0 6 (6.7%) 0.52 Post Dilatation—no./total no. (%) 6 (6%) 0 6 (6.7%) 0.52 Procedure Length of the procedure—min ± DS 69 ± 21 78 ± 30 68 ± 20 0.16 Contrast media volume—mL ± DS 140 ± 50 138 ± 47 141 ± 50 0.88 Procedural and Post-procedural Complications Major vascular complications— n (%) 9 (9%) 0 9 (10%) 0.37 Minor vascular complications— n (%) 23 (23%) 2 (20%) 21 (23.3%) 0.58 Red blood cell transfusion— n (%) 0.5 ± 1 1 ± 1.7 0.4 ± 0.9 0.08 Length of Stay (days) 8.4 ± 4.6 8.4 ± 3.7 8.4 ± 4.7 0.98
Data are presented as mean ± or n (%). AKI = Acute Kidney Injury; BNP = B-type natriuretic peptide; ScyC = serum Cystatin C.
Table 3. Biological parameters.
Table 3. Biological parameters.
Global Cohort AKI SCyC No AKI SCyC p -Value n = 100 n = 10 n = 90 Serum Creatinine level—µmol/L Baseline 113.6 ± 77.9 135.9 ± 89.9 111.2 ± 76.6 0.34 Post TAVR—H 0 103.2 ± 98.8 141.7 ± 150.5 98.8 ± 91.4 0.2 Post TAVR—Day 1 108.6 ± 115.7 172.6 ± 193.5 101.5 ± 103 0.065 Post TAVR—Day 3 108.5 ± 95.5 177.1 ± 174.4 100.9 ± 80.4 0.016 Serum Cystatin—mg/L Baseline 1.7 ± 0.9 1.9 ± 1 1.7 ± 0.9 0.59 Post TAVR—Day 1 1.6 ± 1 2.2 ± 1.6 1.5 ± 0.8 0.025 Post TAVR—Day 3 1.6 ± 1 2.3 ± 1.7 1.6 ± 0.8 0.029 Haemoglobin—g/dL Baseline 12 (11–13.1) 10.2 (9.3–10.9) 11.2 (10.2–12.2) 0.17 Post TAVR—Day 1 10.2 (9.6–10.7) 10.2 (9.6–10.7) 10.6 (9.5–11.6) 0.25 Post TAVR—Day 3 9.6 (8.5–9.95) 9.6 (8.5–9.9) 10 (9.2–11) 0.08 BNP—ng/L ± SD Baseline 471 ± 856 561 ± 848 461 ± 862 0.73 Post TAVR—H 0 515 ± 920 690 ± 1140 495 ± 898 0.53 Post TAVR—Day 1 426 ± 747 686 ± 1185 397 ± 684 0.24 Post TAVR—Day 3 283 ± 402 511 ± 674 257 ± 356 0.058 Post TAVR—Day 3 60.8 ± 47 66.2 ± 86.7 60.2 ± 41 0.7
Data are presented as mean ± or n (%) or median (25th–75th percentile). AKI = Acute Kidney Injury; TAVR = Transcatheter aortic valve replacement.
Table 4. Acute Kidney injury (AKI) definitions and incidence.
Table 4. Acute Kidney injury (AKI) definitions and incidence.
Group Definition no./Total no. (%) Group 1: No AKI No AKI: No AKIsCr AND No AKI sCyC (84/100)—84% Group 2: AKIsCr AKI sCr: according to VARC2 definition. Absolute increase in sCr of ≥ 0.3 mg/dL (≥ 26.4 mmol/L) OR ≥ 50% increase in sCr (10/100)—10% Group 3: AKIsCyC AKI sCyC: sCyC increase ≥ 15% from baseline. (10/100)—10% Group 4: AKI sCr OR sCyC AKI sCr OR sCyC AKI detected by a single marker: fulfill only 1 of criteria as below: (1) sCr increase ≥ 0.3 mg/dL or 50% from baseline OR (2) sCyC increase ≥ 15% from baseline. (16/100)—16% Group 5: AKI sCr AND sCyC AKI sCr AND sCyC: AKI detected by both markers: sCr increase ≥ 0.3 mg/dL or 50% from baseline; and sCyC increase ≥ 15% from baseline. (4/100)—4%
Data are presented as mean ± or n (%). AKI = Acute Kidney Injury; sCr = serum creatinine; sCyC = serum Cystatin C; VARC2 = valve academic research consortium-2 consensus.
Table 5. Doppler based resistive index and hemodynamic parameters.
Table 5. Doppler based resistive index and hemodynamic parameters.
Global Cohort AKI SCyC No AKI SCyC p -Value n = 100 n = 10 n = 90 Renal Doppler based parameters Peak systolic velocity—cm/s ± SD Baseline 29.2 ± 9.5 28.9 ± 7.7 29.3 ± 9.7 0.91 Post TAVR—Day 1 32.5 ± 11 33.7 ± 6.9 32.4 ± 11.4 0.72 Post TAVR—Day 3 31.2 ± 8.7 26.7 ± 8.6 31.7 ± 8.6 0.083 End diastolic velocity—cm/s ± SD Baseline 6.8 ± 2.1 6.3 ± 1.4 6.8 ± 2.2 0.47 Post TAVR—Day 1 7 ± 3.3 5.7 ± 1.5 7.2 ± 3.4 0.17 Post TAVR—Day 3 6.9 ± 2.8 6.9 ± 4 6.9 ± 2.6 0.98 Renal doppler resistive index (RRI) Baseline 0.76 ± 0.7 0.78 ± 0.4 0.75 ± 0.7 0.34 Post TAVR—Day 1 0.78 ± 0.6 0.83 ± 0.1 0.77 ± 0.6 0.005 Post TAVR—Day 3 0.77 ± 0.6 0.75 ± 0.1 0.78 ± 0.5 0.11 RRI Day 1 > 0.7 (no./total no. (%)) 90 (90%) 10 (100%) 80 (80%) 0.37 RRI Day 1 > 0.8 (no./total no. (%)) 42 (42%) 8 (80%) 34 (37.8%) 0.013 RRI Day 3 > 0.7 (no./total no. (%)) 93 (93%) 8 (80%) 85 (94.4%) 0.14 RRI Day 3 > 0.8 (no./total no. (%)) 40 (40%) 4 (40%) 36 (40%) 0.64 Echocardiography Mean Aortic Gradient—mmHg ± SD Baseline 44.5 ± 11.9 43.5 ± 9.8 44.6 ± 12.2 0.72 Post TAVR—Day 1 8.4 ± 2.6 7.9 ± 3.5 8.5 ± 3.6 0.64 Post TAVR—Day 3 9.4 ± 4.2 9.9 ± 5 9.4 ± 4.1 0.71 Stroke volume—mL ± median IQR Baseline 81.5 (65.2–99.5) 92.5 (63–106.2) 80 (65.7–98.5) 0.34 Post TAVR—Day 1 75 (64.5–89.7) 78 (55–97) 75 (65.5–89) 0.87 Post TAVR—Day 3 78.5 (64.2–90.7) 84.5 (64.5–104.7) 77.5 (64–90.3) 0.5 Cardiac index—mL/min/m 2 Baseline 2.9 ± 0.9 3.3 ± 1.3 2.8 ± 0.9 0.17 Post TAVR—Day 1 2.9 ± 0.9 3 ± 0.8 2.9 ± 0.9 0.86 Post TAVR—Day 3 2.9 ± 0.98 3 ± 1.2 2.9 ± 0.96 0.59 E/A Baseline 0.9 ± 0.6 0.6 ± 0.2 1 ± 0.6 0.95 Post TAVR—Day 1 0.9 ± 0.5 0.95 ± 0.6 0.9 ± 0.5 0.85 Post TAVR—Day 3 1.4 ± 2.6 0.7 ± 0.1 1.5 ± 2.8 0.53 E/e′ Baseline 11.9 ± 4.6 12.9 ± 3.9 11.7 ± 4.6 0.48 Post TAVR—Day 3 10.4 ± 3.8 11.9 ± 3.6 10.2 ± 3.8 0.21 Post TAVR—Day 3 11.2 ± 4.3 11.7 ± 1.8 11.1 ± 4.6 0.69 Right Atrial Pressure—mmHg ± SD Baseline 7 ± 4 10 ± 6 6 ± 4 0.02 Post TAVR—Day 1 6.5 ± 3 8 ± 4 6 ± 3 0.09 Post TAVR—Day 3 7 ± 4 9 ± 6 7 ± 4 0.31
Data are presented as mean ± or n (%) or median (25th–75th percentile). AKI = acute kidney injury; RAP = right atrial pressure; RRI = renal resistive index; SV = stroke volume; sCyC = serum Cystatin C; TAVR = Transcatheter aortic valve replacement.
Table 6. Renal Resistive index (RRI) values one-day after TAVR according to AKI definitions.
Table 6. Renal Resistive index (RRI) values one-day after TAVR according to AKI definitions.
AKI Definition RRI J1 p Group 1: No AKI 0.78 ± 0.6 x Group 2: AKI sCr 0.8 ± 0.05 0.149 Group 3: AKI sCyC 0.83 ± 0.04 0.05 Group 4: AKI sCr OR sCyC 0.81 ± 0.05 0.033 Group 5: AKI sCr AND sCyC 0.85 ± 0.05 0.013
Data are presented as mean ± or n (%). AKI = Acute kidney injury; RRI = renal resistive index; sCr: serum creatinine; sCyC = serum Cystatin C.
Table 7. Systemic and renal hemodynamic parameters.
Table 7. Systemic and renal hemodynamic parameters.
Global Cohort AKI sCyC NO AKI sCyC p -Value n = 100 n = 10 n = 90 Renal parameters Renal pulse pressure—mmHg ± SD Baseline 84 ± 14 87 ± 18 83 ± 14 0.38 Post TAVR—Day 1 82 ± 14 78 ± 14 82 ± 14 0.39 Post TAVR—Day 3 78 ± 14 82 ± 19 78 ± 13 0.36 Renal arterial load Baseline 10 ± 3.5 10.1 ± 4.4 10 ± 3.5 0.87 Post TAVR—Day 1 10 ± 3.3 9.8 ± 3.4 10 ± 3.3 0.76 Post TAVR—Day 3 9.2 ± 2.5 9.5 ± 3.7 9.2 ± 2.3 0.72 Renal arterial compliance Baseline 0.11 ± 0.4 0.1 ± 0.6 0.11 ± 0.4 0.27 Post TAVR—Day 1 0.11 ± 0.4 0.12 ± 0.5 0.11 ± 0.4 0.39 Post TAVR—Day 3 0.12 ± 0.4 0.12 ± 0.4 0.12 ± 0.4 0.77 Systemic parameters Valvuloarterial impedance—mmHg/mL/m 2 Baseline 4.3 ± 1.3 4.2 ± 1.5 4.3 ± 1.3 0.77 Post TAVR—Day 1 3.7 ± 1.6 4.9 ± 4 3.6 ± 1.1 0.016 Post TAVR—Day 3 3.2 ± 0.9 3.3 ± 1 3.2 ± 0.9 0.9 Total arterial load Baseline 2.9 ± 1 3 ± 1.2 2.9 ± 1 0.95 Post TAVR—Day 1 1.7 ± 0.9 2.4 ± 2.3 1.7 ± 0.5 0.008 Post TAVR—Day 3 1.5 ± 0.41 1.5 ± 0.5 1.5 ± 0.4 0.967 Systemic arterial compliance Baseline 0.9 ± 0.1 0.7 ± 0.3 1 ± 0.3 0.71 Post TAVR—Day 1 1.2 ± 4.3 1 ± 0.5 1.2 ± 0.4 0.23 Post TAVR—Day 3 0.7 ± 0.3 0.69 ± 0.2 0.7 ± 0.3 0.78 Pulse Pressure mmHg ± SD Baseline 65 ± 20 72 ± 12 64 ± 20 0.26 Post TAVR—Day 1 63 ± 20 70 ± 11 62.4 ± 21 0.3 Post TAVR—Day 3 63 ± 20 69 ± 10 62 ± 21 0.3 Resistive arterial load—dynes/s/cm—5 ± SD Baseline 2905 ± 1217 2743 ± 1272 2923 ± 1217 0.66 Post TAVR—Day 1 2755 ± 1506 3500 ± 3454 2672±1117 0.09 Post TAVR—Day 3 2631 ± 1069 2512 ± 888 2644±1091 0.71 Systolic Blood Pressure—mmHg ± SD Baseline 135 ± 22 143 ± 22 134 ± 22 0.21 Post TAVR—Day 1 132 ± 22 129 ± 22 132 ± 22 0.66 Post TAVR—Day 3 127 ± 25 133 ± 18 126 ± 25 0.42 Diastolic Blood Pressure—mmHg ± SD Baseline 70 ± 12 71 ± 17 70 ± 12 0.7 Post TAVR—Day 1 65 ± 13 63 ± 9 65 ± 13 0.69 Post TAVR—Day 3 64 ± 9 64 ± 10 64 ± 10 0.93 Mean Arterial Pressure—mmHg ± SD Baseline 91 ± 13 97 ± 16 90 ± 13 0.97 Post TAVR—Day 1 88 ± 13 86 ± 12 88 ± 13 0.59 Post TAVR—Day 3 86 ± 13 91 ± 17 85 ± 13 0.19
Data are presented as mean ± or n (%). AKI = acute kidney injury; TAVR = Transcatheter aortic valve replacement.
Table 8. Univariate COX regression for the development of AKI assessed by serum cystatine up to 3 days after TAVR.
Table 8. Univariate COX regression for the development of AKI assessed by serum cystatine up to 3 days after TAVR.
Univariate HR CI 95% p -Value Baseline characteristics Age 0.99 0.89–1.1 0.88 Male Sex 1 0.3–4 0.89 EuroScore 1 0.98–1.2 0.12 Mehran contrast nephropathy risk score (points) 1.2 0.98–1.5 0.074 Mehran Risk Score (%) 1.1 1–1.2 0.04 Hypertension 1 0.1–8.8 1 Current or past Smoking 2 0.5–8 0.29 Dyslipidaemia 0.88 0.24–3.2 0.84 Diabetes melitus 1.6 0.4–5.8 0.5 BMI 1 0.94–1.1 0.47 Coronary Artery Disease (CAD) 0.19 0.04–0.95 0.04 ACE inhibitors/ARBs 0.77 0.21–2.8 0.69 Furosemide 1 0.99–1 0.77 Procedural characteristics Length of procedure 1 0.99–1.1 0.16 Contrast media volume 0.99 0.99–1 0.88 Transfemoral approach 0.53 0.06–5.1 0.59 Sapien 1.3 0.33–5.6 0.68 Corevalve 0.82 0.2–3.4 0.78 Baseline and Day 1 biological parameters BNP Baseline 1 0.99–1 0.73 Day 1 1 1–1.1 0.28 Serum Creatinine Baseline 1 0.99–1 0.36 Day 1 1 0.99–1 0.1 Serum Cystatin Baseline 1.2 0.6–2.2 0.59 Day 1 1.6 1–2.5 0.05 Baseline and Day 1 Echocardiography parameters Baseline LVEF 0.97 0.93–1 0.29 Baseline Mean Aortic Gradient 0.99 0.94–1.1 0.72 Right Atrial Pressure (RAP) Baseline 1.1 1–1.3 0.035 Day 1 1.1 0.97–1.7 0.11 Stroke Volume Baseline 1 0.98–1.1 0.28 Day 1 1 0.95–1.1 0.77 Cardiac index Baseline 1.6 0.82–3.1 0.17 Day 1 1.1 0.51–2.3 0.86 Renal doppler parameters High Renal Resistive Index (RRI > 0.8) Baseline 0.9 0.18–4.8 0.935 Day 1 6.5 1.3–32.9 0.021 Renal hemodynamic parameters Renal pulse pressure Baseline 1 0.98–1.1 0.38 Day 1 0.98 0.93–1 0.38 Renal Arterial Load Baseline 1 0.85–1.2 0.87 Day 1 0.97 0.78–1.2 0.76 High Renal Arterial Compliance (> 0.12) Baseline 1.5 0.355–6.337 0.581 Day 1 1.325 0.315–5.565 0.701 Systemic hemodynamic parameters Valvulo-arterial impedance Baseline 0.93 0.56–1.5 0.77 Day 1 1.3 0.96–1.9 0.083 Total arterial load Baseline 1 0.53–1.9 0.95 Day 1 1.8 0.89–3.6 0.099 Pulse Pressure Baseline 1 0.99–1.1 0.26 Day 1 1 0.95–1 0.85 Systemic arterial compliance Baseline 0.67 0.51–8.7 0.76 Day 1 0.33 0.53–2 0.23 Resistive arterial load Baseline 1 0.99–1 0.67 Day 1 1 0.98–1.01 0.14
| https://www.mdpi.com/2077-0383/9/4/905 |
MR-guided laser focal therapy in Prostate Cancer - Clinical Trials Registry - ICH GCP
Target recruitment: 1000 subjects. The purpose of this research study is to continue to investigate the safety and effectiveness of using MR (magnetic resonance...
Phase II Laser Focal Therapy of Prostate Cancer (LITT or FLA)
A Phase II Study to Evaluate Outpatient Magnetic Resonance Image-guided Laser Focal Therapy for Prostate Cancer, a 20-year Survival Study
Target recruitment: 1000 subjects.
The purpose of this research study is to continue to investigate the safety and effectiveness of using MR (magnetic resonance) guided laser focal therapy for prostate cancer and to evaluate oncologic control over 20 years.
We hypothesize that laser focal therapy can be used to achieve oncologic control in carefully selected patients.
MR uses large magnets to produce pictures of areas/organs inside the body.
The laser uses light to heat a target area to try to destroy cancerous cells.
The laser system that will be used is called the Visualase® Thermal Therapy System.
This system has been used for the treatment of brain, bone (spine), thyroid, and liver cancers.
However; this study is the first time this system has been studied for use in the treatment of prostate cancer with a trans-rectal approach.
MR-guided biopsies and laser applicator placement will be performed using the Invivo DynaTRIM trans-rectal biopsy guidance system.
This system is cleared (approved) by the U.S. Food and Drug Administration (FDA) for such uses.
Study Overview
Status
Active, not recruiting
Conditions
Prostate Cancer
Intervention / Treatment
Device: MR-guided laser focal therapy
Detailed Description
Laser-induced interstitial thermal therapy (LITT) is a novel form of controlled, targeted thermal ablation that may offer measurable advantages over other ablative therapies for focal prostate therapy.
Because LITT is magnetic resonance (MR) compatible, it enables an imaging advantage over other surgical or ablation techniques that utilize transrectal ultrasound to target and monitor treatment.
MR imaging provides excellent soft-tissue contrast and three-dimensional (3D) anatomical imaging in any arbitrary plane, which can help to improve treatment planning and targeting.
Additionally, MR-based temperature monitoring allows real-time feedback during MRI-guided thermal therapy as both deposition of light energy and MR signal acquisition can be performed simultaneously without degradation in the MR signal.
Also, being in the MR diagnostic environment allows use of post- treatment imaging to verify tissue damage.
Because MR images clearly depict the prostate anatomy and the surrounding critical structures, MR imaging has been incorporated into planning for external- beam radiotherapy, brachytherapy, and other treatments of the prostate.
In addition to these basic features, Multiparametric prostate MRI (mpMRI) may be used to identify regions of disease in the prostate and better target therapy.
In this study, the investigators propose to evaluate the efficacy of a novel, FDA-approved thermal therapy and feedback system (Visualase® Thermal Therapy System) for the treatment of biopsy confirmed and MR-imageable prostate lesions.
This system has been used in humans for the treatment of brain, bone (spine), thyroid, and liver cancers.
Early feasibility studies for prostate cancer used a transperineal approach; however it is now being evaluated for the primary treatment of prostate cancer using a transrectal approach.
This system allows delivery of laser energy while the patient is simultaneously being imaged by an MRI unit.
The system's real-time MR thermal imaging (MRTI) provides information on the thermal dose delivered to the target, resulting in a more precise and controlled delivery which has previously not been possible with other ablative therapies.
The investigators hypothesize the system can be integrated into a practical and feasible outpatient treatment paradigm for focal treatment of localized prostate cancer and allow patients to avoid the complications associated with radical whole-gland therapy.
Study Type
Observational
Enrollment (Anticipated)
1000
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
United States
California
Indian Wells, California, United States, 92210
Desert Medical Imaging
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
45 years to 90 years (ADULT, OLDER_ADULT)
Accepts Healthy Volunteers
No
Genders Eligible for Study
Male
Sampling Method
Non-Probability Sample
Study Population
Men with prostate cancer
Description
Inclusion Criteria:
Treatment Naïve patients:
Male, 45 years of age or older.
Diagnosis of prostate adenocarcinoma.
Clinical stage T1c or T2a.
Gleason score of 7 (3+4 or 4+3) or less.
Three or fewer biopsy cores with prostate cancer.
PSA density not exceeding 0.375.
One, two, or three tumor suspicious regions identified on multiparametric MRI.
Negative radiographic indication of extra-capsular extent.
Karnofsky performance status of at least 70.
Estimated survival of 5 years or greater, as determined by treating physician.
Tolerance for anesthesia/sedation.
Ability to give informed consent.
At least 6 weeks since any previous prostate biopsy.
MR-guided biopsy confirmation of one or more MRI-visible prostate lesion(s) with Gleason score of 7 (3+4 or 4+3) or less.
Salvage candidates will be accepted upon physician referral.
Exclusion Criteria:
Presence of any condition (e.g., metal implant, shrapnel) not compatible with MRI.
Severe lower urinary tract symptoms as measured by an International Prostate Symptom Score (IPSS) of 20 or greater
History of other primary non-skin malignancy within previous three years.
Diabetes
Smoker
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
1
Cohorts and Interventions
<table><tr><th> Group / Cohort</th><th> Intervention / Treatment</th></tr><tbody><tr><td> Visualase MR-guided laser focal therapy</td><td> Device: MR-guided laser focal therapy Placement of laser applicator under MRI guidance and real-time MR thermal imaging of tissue necrosis. Other Names: Visualase Tranberg</td></tr></tbody></table>
What is the study measuring?
Primary Outcome Measures
<table><tr><th> Outcome Measure</th><th> Measure Description</th><th> Time Frame</th></tr><tbody><tr><td> Safety and adverse events Time Frame: 1 yr. post treatment</td><td> Number of subjects reporting serious adverse events.</td><td> 1 yr. post treatment</td></tr></tbody></table>
Secondary Outcome Measures
<table><tr><th> Outcome Measure</th><th> Measure Description</th><th> Time Frame</th></tr><tbody><tr><td> Efficacy of treatment Time Frame: 1 yr. post treatment</td><td> MR-guided biopsy results of treated area and PSA.</td><td> 1 yr. post treatment</td></tr></tbody></table>
Other Outcome Measures
<table><tr><th> Outcome Measure</th><th> Measure Description</th><th> Time Frame</th></tr><tbody><tr><td> Time to biochemical recurrence Time Frame: Up to 20 years</td><td> PSA measurement</td><td> Up to 20 years</td></tr><tr><td> Time to metastasis Time Frame: Up to 20 years</td><td> Imaging utilizing PET/CT or other modality</td><td> Up to 20 years</td></tr><tr><td> Cause of death Time Frame: Up to 20 years</td><td> Death certificate or report from partner/spouse/primary care physician</td><td> Up to 20 years</td></tr></tbody></table>
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
HALO Diagnostics
Investigators
Principal Investigator: John F. Feller, MD, Halo Diagnostics
Study Director: Bernadette M. Greenwood, MSc, Halo Diagnostics
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
Greenwood, B. et al.: Transrectal interventional MRI: initial prostate biopsy experience. SPIE Proceedings, 2010.
Hakimi AA, Feder M, Ghavamian R. Minimally invasive approaches to prostate cancer: a review of the current literature. Urol J. 2007 Summer;4(3):130-7.
Menon M, Tewari A, Peabody JO, Shrivastava A, Kaul S, Bhandari A, Hemal AK. Vattikuti Institute prostatectomy, a technique of robotic radical prostatectomy for management of localized carcinoma of the prostate: experience of over 1100 cases. Urol Clin North Am. 2004 Nov;31(4):701-17. doi: 10.1016/j.ucl.2004.06.011.
Valerio M, Emberton M, Ahmed HU. Focal therapy will become a standard option for selected men with localized prostate cancer. J Clin Oncol. 2014 Nov 10;32(32):3680-1. doi: 10.1200/JCO.2014.56.7792. Epub 2014 Aug 18. No abstract available.
Helpful Links
HALODx
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
May 1, 2016
Primary Completion (ANTICIPATED)
May 1, 2036
Study Completion (ANTICIPATED)
November 1, 2036
Study Registration Dates
First Submitted
September 9, 2014
First Submitted That Met QC Criteria
September 15, 2014
First Posted (ESTIMATE)
September 17, 2014
Study Record Updates
Last Update Posted (ACTUAL)
March 25, 2022
Last Update Submitted That Met QC Criteria
March 23, 2022
Last Verified
March 1, 2022
Keywords
Prostate cancer
Transrectal
Focal therapy
Laser therapy
MRI-guided
Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Genital Neoplasms, Male
Prostatic Diseases
Prostatic Neoplasms
Other Study ID Numbers
DMI-Laser-001
WIRB Pr. No.: 20140945 (OTHER: Western Institutional Review Board)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
YES
IPD Plan Description
Publication
IPD Sharing Time Frame
Bi-annaually at the meetings of the International Laser Network until study closure.
IPD Sharing Access Criteria
Scientists and physicians studying or performing laser focal therapy.
IPD Sharing Supporting Information Type
STUDY_PROTOCOL
SAP
ICF
Clinical Trials on Prostate Cancer
NCT05931419
| https://ichgcp.net/clinical-trials-registry/NCT02243033 |
PARDAZI v. CULLMAN MEDICA | 838 F.2d 1155 (1988) | 2d115511813 | Leagle.com
GOODWIN Circuit Judge Dr. S.B. Pardazi an Iran educated medical practitioner appeals a summary judgment for the defendant...2d115511813
PARDAZI v. CULLMAN MEDICAL CENTER
No. 87-7099.
View Case
Cited Cases
838 F.2d 1155 (1988)
Dr. S.B. PARDAZI, Plaintiff-Appellant,
v.
CULLMAN MEDICAL CENTER, Defendant-Appellee.
United States Court of Appeals, Eleventh Circuit. https://leagle.com/images/logo.png
February 29, 1988.
February 29, 1988.
Attorney(s) appearing for the Case
Horace V. O'Neal, Jr., Victor L. Miller, Jr., Birmingham, Ala., for plaintiff-appellant.
Stanley A. Cash, Huie, Fernambucq & Stewart, John Herndon, Birmingham, Ala., for defendant-appellee.
Before ANDERSON, EDMONDSON and GOODWIN, Circuit Judges.
United States Court of Appeals, Eleventh Circuit.
GOODWIN, Circuit Judge:
Dr. S.B. Pardazi, an Iran-educated medical practitioner, appeals a summary judgment for the defendant hospital. The trial court held that because Dr. Pardazi was not an employee of the hospital, it was unnecessary to reach other questions presented in this Title VII action for damages and other relief arising out of a claim of national origins discrimination. We reverse and remand.
Before he applied for staff privileges at the defendant hospital, Dr. Pardazi had entered into an employment contract with Terry D. Neumaster, M.D., P.C., an Alabama corporation. The contract was conditioned upon Dr. Pardazi becoming a member, with staff privileges, of the defendant hospital staff.
Cullman Medical Center denied Pardazi's application in November 1983. Pardazi requested and received a rehearing. He was appointed to the active staff in March, 1984. The appointment thus was delayed for four months. It was then made subject to a one-year observation period, a deviation from the medical staff by-laws limiting observation periods to no more than four months.
Pardazi first sought relief from the Equal Employment Opportunity Commission. After the EEOC denied his claim, Pardazi filed this action against the medical center, alleging violations of Title VII, 42 U.S.C. § 2000e-2(a)(1) (1982). In his complaint, he alleged that section 2000e-2(a)(1) was violated by three acts: (1) the initial denial of his application for medical staff privileges; (2) the denial of his right to be represented by an attorney at the rehearing; and (3) the extension of the observation period from four months to one year. Pardazi sought a permanent injunction prohibiting the medical center and those connected with it from discriminating on the
[838 F.2d 1156]
basis of national origin and an order reducing his observation period to four months. He also requested damages, any appropriate further relief, and costs and attorneys' fees.
In granting the medical center summary judgment, the district court found the relationship between Pardazi and the medical center was not one of employment for Title VII purposes. In so holding, the court relied expressly upon Beverley v. Douglas,591 F.Supp. 1321(S.D.N.Y.1984), and Cobb v. Sun Papers, Inc.,673 F.2d 337, 340-41 (11th Cir.) (en banc), cert. denied,459 U.S. 874, 103 S.Ct. 163, 74 L.Ed.2d 135 (1982).
We accept the district court's finding that Pardazi was not an employee of the hospital either under the common meaning of "employee" or under the 11-factor test set forth in Beverley,591 F.Supp. at 1326-27 (applying the test to find that there was no employment relationship between a hospital and its voluntary staff). The Beverleycourt's checklist was first stated by the D.C. Circuit in Spirides v. Reinhardt,613 F.2d 826, 832 (D.C.Cir.1979):
(1) the kind of occupation, with reference to whether the work usually is done under the direction of a supervisor or is done by a specialist without supervision; (2) the skill required in the particular occupation; (3) whether the `employer' or the individual in question furnishes the equipment used and the place of work; (4) the length of time during which the individual has worked; (5) the method of payment, whether by time or by the job; (6) the manner in which the work relationship is terminated, i.e., by one or both parties, with or without notice and explanation; (7) whether annual leave is afforded; (8) whether the work is an integral part of the business of the `employer'; (9) whether the worker accumulates retirement benefits; (10) whether the `employer' pays Social Security taxes; and (11) the intention of the parties.
Pardazi argues, however, that the district court reads section 2000e-2(a)(1) too narrowly. He argues that the hospital's denial of staff privileges interfered with his employment opportunities — i.e., his employment contract with Terry D. Neumaster, M.D., P.C., an Alabama corporation. Several courts have recognized that Title VII's protection does extend to a claim that a defendant has interfered with an individual's employment relationship with a third party. Lutcher v. Musicians Union Local 47,633 F.2d 880, 883 n. 3 (9th Cir.1980) (such interference "might occur where a defendant subject to Title VII interferes with an individual's employment opportunities with another employer"); Gomez v. Alexian Bros. Hosp. of San Jose,698 F.2d 1019, 1021 (9th Cir.1983) (following Lutcher); Sibley Memorial Hosp. v. Wilson,488 F.2d 1338, 1340-41 (D.C.Cir.1973) (Title VII may not be interpreted "[t]o permit a covered employer to exploit circumstances peculiarly affording it the capability of discriminatorily interfering with an individual's employment opportunities with another employer").
We find the reasoning of the foregoing cases to be persuasive. If Dr. Pardazi can prove his claim that the hospital's discrimination against him interfered with his employment opportunities with the professional corporation, we hold that Title VII would encompass such a claim. We note that such a claim fits squarely within the language of Title VII, making it unlawful "to discriminate against any individualwith respect to his compensation, terms, conditions, or privileges of employment." 42 U.S.C. § 2000e-2(a)(1) (emphasis added). In light of the remedial nature of Title VII, we decline to accept the Medical Center's unduly restrictive interpretation.
The Medical Center argues that this circuit in Cobb,673 F.2d 337, rejected the proposition that Title VII encompasses such a claim. As we read Cobb,however, it did not address this issue. The sole issue in Cobbwas whether the plaintiff was an employee or an independent contractor. Cobbdid not involve an alleged interference with plaintiff's employment opportunities with another employer. Nor is Cobb's analysis inconsistent with our holding today. 1
[838 F.2d 1157]
We reverse the summary judgment and remand. Upon further proceedings, the court, in deciding whether summary judgment is appropriate under Fed.R.Civ.P. 56, should determine whether Pardazi has demonstrated a "genuine issue of material fact" on the claim that the hospital's actions interfered with his opportunities and privileges under his contract.
REVERSED and REMANDED.
FootNotes
* Honorable Alfred T. Goodwin, U.S. Circuit Judge, for the Ninth Circuit, sitting by designation.
1. We note that some courts have gone further and held that a Title VII claimant need not demonstrate an employer-employee relationship at all.
Compare Doe v. St. Joseph's Hosp. of Fort Wayne,
788 F.2d 411
, 423 (7th Cir.1986) (finding a Title VII claim to be viable where the plaintiff agreed that the hospital's action discriminatorily interfered with her opportunities to provide services to her patients);
Sibley Memorial Hosp.,
488 F.2d at 1342 (finding a potential Title VII claim where a male nurse claimed that the hospital interfered with his access to female patients);
Pao v. Holy Redeemer Hosp.,
547 F.Supp. 484
, 494-95 (E.D.Pa.1982) (finding that a Title VII claim exists where a hospital's discriminatory conduct has deprived an ophthalmologist of prospective patients);
with Beverley,
591 F.Supp. at 1327-28 (finding that a doctor's "relationship to her patients is not one of employment").
See also Lutcher,
633 F.2d at 884 (finding that no cause of action was stated under Title VII where a union at most "interfered with an independent contractor relationship between" the plaintiff and a school district).
In light of our holding that Dr. Pardazi can state a Title VII claim against the hospital for interfering with his employment opportunities with the professional corporation, we need not address this further question.
| https://www.leagle.com/decision/19881993838f2d115511813 |
Employed Persons by Industry and Occupation - Page 33 | Toc | FRASER | St. Louis Fed
Employed Persons by Industry and Occupation from Employment and Earnings, November 1986
Title:
Employed Persons by Industry and Occupation
Employed Persons by Industry and Occupation
DATE: November 1986
PART OF:
Employment and Earnings : November 1986
AUTHOR:
United States. Bureau of Labor Statistics
Table of Contents
Employment and Unemployment Developments
Employment Status of the Noninstitutional Population 16 Years and Over
Employment Status of the Noninstitutional Population 16 Years and Over by Sex
Employment Status of the Noninstitutional Population by Sex, Age, and Race
Employment Status of Black Workers by Sex and Age
Employment Status of Noninstitutional Population by Race, Sex, and Age
Full and Part-Time Status of the Civilian Labor Force by Sex, Age, and Race
Employment Status of the Noninstitutional Population in Family Relationship
Unemployed Persons, by Marital Status, Sex, Age, and Race
Unemployed Persons by Occupation and Sex
Unemployed Persons by Industry and Sex
Unemployed Persons, by Reason for Unemployment, Sex, Age, and Race
Unemployed Persons by Reason for Unemployment, Sex, and Age, Duration of Unemployment
Unemployed Jobseekers by Sex, Age, Race, and Jobsearch Methods Used
Unemployed Jobseekers by Sex, Reason for Unemployment, and Jobsearch Methods Used
Unemployed Persons, by Sex, Age, Race, Marital Status, and Duration of Unemployment
Unemployed Persons by Occupation, Industry, and Duration of Unemployment
Employed Persons by Occupation Group, Sex, and Age
Employed Persons by Occupation, Sex, and Race
Employed Persons by Age, Sex, and Class of Worker
Employed Persons by Industry and Occupation
Employed Persons with a Job But Not at Work, by Reason, Pay Status, and Sex
Persons at Work, by Hours of Work and Industry
Persons at Work 1-34 Hours, by Reason for Working Less than 35 Hours and Usual Status
Nonagricultural Workers, by Industry and Full or Part-Time Status
Persons at Work in Nonagricultural Industries, by Sex, Age, Race, Marital Status, and Full or Part-Time Status
Persons at Work in Nonfarm Occupations, by Sex and Full or Part-Time Status
Employment Status of the Noninstitutional Population by Sex and Age, Seasonally Adjusted
Unemployed Persons by Duration of Unemployment, Seasonally Adjusted
Unemployment Rates, by Sex and Age, Seasonally Adjusted
Unemployed Persons by Reason for Unemployment, Seasonally Adjusted
Employed Persons by Sex and Age, Seasonally Adjusted
Unemployed, by Sex and Age, Seasonally Adjusted
Employed Persons by Selected Social and Economic Categories, Seasonally Adjusted
Employment Status of Male Vietnam Era Veterans and Nonveterans by Age
Employees on Nonagricultural Payrolls, by Industry
Women Employees on Nonagricultural Payrolls, by Industry
Employees on Nonagricultural Payrolls, by Industry, Seasonally Adjusted
Women Employees on Nonagricultural Payrolls, by Industry, Seasonally Adjusted
Production or Nonsupervisory Workers on Private Nonagricultural Payrolls, Seasonally Adjusted
Indexes of Diffusion: Percent of Industries in Which Employment Increased
Employees on Nonagricultural Payrolls for States and Selected Areas, by Industry Division
Gross Hours and Earnings of Production or Nonsupervisory Workers on Private Nonagricultural Payrolls
Gross Hours and Earnings of Production or Nonsupervisory Workers on Private Nonagricultural Payrolls, by Industry
Average Hourly Earnings Excluding Overtime of Production Workers on Manufacturing Payrolls, by Industry
Gross and Spendable Average Weekly Earnings of Production or Nonsupervisory Workers on Private Nonagricultural Payrolls in Current Dollars
Average Weekly Hours of Production or Nonsupervisory Workers on Private Nonagricultural Payrolls, by Industry Division and Manufacturing Group, Seasonally Adjusted
Indexes of Aggregate Weekly Hours of Production or Nonsupervisory Workers on Private Nonagricultural Payrolls, by Industry Division and Major Manufacturing Group, Seasonally Adjusted
Hourly Earnings Index and Average Hourly and Weekly Earnings of Production or Nonsupervisory Workers on Private Nonagricultural Payrolls, Seasonally Adjusted
Hours of Wage and Salary Workers in Nonagricultural Establishments, by Industry Division
Indexes of Output and Compensation Per Hour, Unit Costs and Prices, Private Business Sector, Seasonally Adjusted
Percent Changes from Preceding Quarter and Year in Productivity, Hourly Compensation, Unit Costs and Prices, Private Business Sector, Seasonally Adjusted at Annual Rate
Labor Force and Unemployment, by State and Selected Metropolitan Areas
Explanatory Notes
Diversity is critical to the Federal Reserve, and we are firmly committed to fostering a diverse and inclusive culture throughout the Federal Reserve System. Collections within FRASER contain historical language, content, and descriptions that reflect the time period within which they were created and the views of their creators. Certain collections contain objectionable content—for example, discriminatory or biased language used to refer to racial, ethnic, and cultural groups. These viewpoints and attitudes are inconsistent with our values, but the original descriptions are retained to ensure that they are not erased from the historical record.
United States. Bureau of Labor Statistics. "Employed Persons by Industry and Occupation,"
in
United States. Bureau of Labor Statistics. "November 1986," Employment and Earnings(November 1986)
: 33-33. https://fraser.stlouisfed.org/title/60/item/19803/toc/334648, accessed on May 22, 2023.
| https://fraser.stlouisfed.org/title/employment-earnings-60/november-1986-19803/employed-persons-industry-occupation-334648 |
Lipad - March 31, 1949 - Browse the Canadian House of Commons
March 31, 1949
PERMITS FOR NEXT OF KIN TO VISIT WAR GRAVES OVERSEAS
Mr. Diefenbaker:
Progressive Conservative
1. Are permits available to enable parents or widows of Canadian service men whose graves are in the British or American zone in Germany to visit such graves?
2. If so, what is the procedure?
3. If not, would the government give consideration to granting issue of such permits?
Topic: PERMITS FOR NEXT OF KIN TO VISIT WAR GRAVES OVERSEAS
LIB
Mr. Pearson:
(Secretary of State for External Affairs)
Liberal
1. Permits are not generally available for
the specific purpose of visiting war graves. Recommendations may, however, be made to the military permit offices of the occupying powers in especially compassionate circumstances. Application in such cases may be addressed to the Department of External Affairs, Ottawa.
2. Answered by No. 1.
3. It does not lie within the competence of the Canadian government to grant permits to enter the occupied zones of Germany. The government, however, has on a number of occasions brought to the attention of the competent authorities the desire of Canadian relatives to visit war graves. Advice is now awaited from the government of the United Kingdom as to whether it will be possible to develop arrangements by which visits may soon be made to graves in the United Kingdom zone. While it is understood that military permit offices will not generally grant permits to the United States zone for the specific purpose of visiting war graves, it may nevertheless be possible for visitors to enter the United States zone as tourists under certain prescribed conditions laid down by the United States zone authorities.
Topic: PERMITS FOR NEXT OF KIN TO VISIT WAR GRAVES OVERSEAS
FORESTVILLE, QUE., HARBOUR FACILITIES
Mr. Dorion:
Independent
1. Has the government acquired the harbour facilities at Forestville, Quebec?
2. If so (a) from whom; (b) at what price; (c) under what conditions?
3. Has the public free access to the wharf at Forestville?
Topic: FORESTVILLE, QUE., HARBOUR FACILITIES
LIB
Mr. Fournier (Hull):
(Minister of Public Works; Leader of the Government in the House of Commons; Liberal Party House Leader)
Liberal
1. Yes, except the breakwater at the west side of the harbour and the pulpwood flume and loading plant, located on the wharf.
2. (a) Anglo-Canadian Pulp and Paper Mills, Limited.
(b) $385,000.
(c) The department undertakes to maintain wharf, berths, channels and navigation aids. In the event of minor repairs not exceeding $50 in cost, the company may proceed forthwith with such repairs, but thereupon shall notify the district engineer.
The company's flume and loading plant is to remain on the wharf as long as required for its pulpwood operations. The company will maintain and operate them and assume legal liability for any damages resulting from their operation.
General wharf tariff, as applied by the Department of Transport, is to be applicable to vessels and cargoes of the company.
The company may carry on its pulpwood operations, provided that in so doing there is no interference with navigation in the harbour or public use of the wharf. The company is to have reasonable priority, during the shipping season, in the use of the berth alongside the flume.
3. Yes.
Topic: FORESTVILLE, QUE., HARBOUR FACILITIES
QUESTIONS PASSED AS ORDERS FOR RETURNS
VEGETABLE OIL
OLEOMARGARINE
PC
Mr. Hatfield:
Progressive Conservative
1. What quantity of vegetable oil was imported into Canada from 1945 to date?
2. From what countries was the vegetable oil imported?
3. What quantity of vegetable oil suitable for the manufacture of margarine was imported into Canada?
4. What was the value of same and from what countries was it imported?
Topic: VEGETABLE OIL Subtopic: OLEOMARGARINE
POST OFFICE LOCK BOXES
SC
Mr. Fair:
Social Credit
1. Did the government take over post office lock boxes on the 1st of October, 1947?
2. If so, has the government collected rentals as from that date?
3. Did the government pay postmasters for the boxes taken over? If so, when?
4. If not, by what right has the government collected the rentals?
5. When will payment for the boxes be made?
Topic: POST OFFICE LOCK BOXES
NATURALIZATION
Mr. Maclnnis:
1. To how many persons were naturalization certificates issued in the calendar year, 1948?
2. What were the countries of origin of such persons and how many from each country?
Topic: NATURALIZATION
LIB
James Joseph McCann
(Minister of National Revenue)
Liberal
Mr. McCann:
Return tabled.
Topic: NATURALIZATION
CONTRACTS FOR SUPPLY OF SPONGES
EXTERNAL AFFAIRS
On the orders of the day:
CCF
Alistair McLeod Stewart
Co-operative Commonwealth Federation (C.C.F.)
Mr. Alistair Stewart (Winnipeg North):
I should like to direct a question to the Secretary of State for External Affairs. Although I have no brief for the people concerned, has the minister any comment to make on the recent summary ejection of two Canadian citizens from the United States? Further, has the government, or any member of it, received a letter concerning this matter from a nonpolitical and certainly noncommunist group of Canadians attending Columbia university?
Topic:
CONTRACTS FOR SUPPLY OF SPONGES
Subtopic:
EXTERNAL AFFAIRS
Sub-subtopic:
DEPORTATION OF CANADIAN CITIZENS FROM UNITED STATES
LIB
Lester Bowles Pearson
(Secretary of State for External Affairs)
Liberal
Hon. L. B. Pearson (Secretary of State for External Affairs):
The hon. member was good enough to give me notice of this question, which I think concerns an incident in New York last week end affecting three Canadians who were removed by United States authorities from a banquet which they were attending in connection with the so-called cultural and scientific conference for world peace which was being held in that city. The United States authorities have of course every right to prevent Canadians and others from entering their country. They have every right to deport Canadians and other foreigners who are in their country. We claim that right ourselves. However, in view of the fact that the circumstances surrounding the exercise of this right in the case of the three Canadians in question seem to have been, to say the least, unusual, and in view of the fact that only Canadians appear to have been interfered with at the banquet in question, I thought it desirable, when I noticed a reference to this matter in the press, to request at once a full report on the situation from our embassy in Washington and from our consulate general in New York. That report has been received, and I am examining it to see if any further action seems to be required.
Our interest in these persons was solely in the fact of their being Canadian citizens, and must not be interpreted as indicating approval of any political views they may
Inquiries of the Ministry hold, or endorsing in any way the conference they were attending.
As to the second part of the question, a letter was received this morning from Canadian students at Columbia university protesting against what they called "the highly arbitrary treatment of Canadian citizens on the occasion in question".
Topic:
CONTRACTS FOR SUPPLY OF SPONGES
Subtopic:
EXTERNAL AFFAIRS
Sub-subtopic:
DEPORTATION OF CANADIAN CITIZENS FROM UNITED STATES
| https://www.lipad.ca/full/1949/03/31/2/ |
POM Wonderful, LLC v. Federal Trade Commission | Legal Documents | H2O
United States Court of Appeals for the District of Columbia Circuit
414 U.S. App. D.C. 111, 777 F.3d 478
No. 13-1060
2015-01-30
777 F.3d 478
Argued May 2, 2014.
Rehearing En Banc Denied May 28, 2015.
*116Thomas C. Goldstein argued the cause for petitioners POM Wonderful, LLC, et al. With him on the briefs were John Graubert, Megan L. Rodgers, and Erik S. Jaffe.
Erik S. Jaffe was on the brief for petitioner Matthew Tupper.
Bilal K Sayyed was on the brief for amici curiae Consumer Healthcare Products Association and Council for Responsible Nutrition in support of petitioners.
Jonathan W. Emord was on the brief for amici curiae Alliance for Natural Health USA and TechFreedom in support of petitioners.
Jonathan E. Nuechterlein, General Counsel, Federal Trade Commission, argued the cause for respondent. With him on the brief were Joel Marcus, Assistant General Counsel, and Imad D. Abyad, Attorney. John F. Daly, Attorney, Federal Trade Commission, entered an appearance.
Julie A. Murray, Scott L. Nelson, Allison M. Zieve, and Stephen Gardner were on the brief for amici curiae Public Citizen, Inc. and Center for Science in the Public Interest in support of respondent.
Before: GARLAND, Chief Judge, SRINIVASAN, Circuit Judge, and GINSBURG, Senior Circuit Judge.
Opinion for the Court filed by Circuit Judge SRINIVASAN.
SRINIVASAN, Circuit Judge:
POM Wonderful, LLC produces, markets, and sells a number of pomegranate-based products. In a series of advertisements from 2003 to 2010, POM touted medical studies ostensibly showing that daily consumption of its products could treat, prevent, or reduce the risk of various ailments, including heart disease, prostate cancer, and erectile dysfunction. Many of those ads mischaracterized the scientific evidence concerning the health*117benefits of POM’s products with regard to those diseases.
In 2010, the Federal Trade Commission filed an administrative complaint charging that POM and related parties had made false, misleading, and unsubstantiated representations in violation of the Federal Trade Commission Act. After extensive administrative proceedings, the full Commission voted to hold POM and the associated parties liable for violating the FTC Act and ordered them to cease and desist from making misleading and inadequately supported claims about the health benefits of POM products. The Commission’s order also bars POM and the related parties from running future ads asserting that their products treat or prevent any disease unless armed with at least two randomized, controlled, human clinical trials demonstrating statistically significant results.
POM and the associated parties petition for review of the Commission’s order, arguing that the order runs afoul of the FTC Act, the Administrative Procedure Act, and the First Amendment. We deny the bulk of petitioners’ challenges. The FTC Act proscribes — and the First Amendment does not protect — deceptive and misleading advertisements. Here, we see no basis for setting aside the Commission’s conclusion that many of POM’s ads made misleading or false claims about POM products. Contrary to petitioners’ contentions, moreover, the Commission had no obligation to adhere to notice-and-comment rulemaking procedures before imposing liability in its adjudicatory proceeding. Additionally, we affirm the Commission’s remedial order insofar as it requires POM to gain the support of at least one randomized, controlled, human clinical trial study before claiming a causal relationship between consumption of POM products and the treatment or prevention of any disease. We find inadequate justification, however, for the Commission’s blanket requirement of at least twosuch studies as a precondition to any disease-related claim. In all other respects, we deny the petition for review.
I.
A.
Since 1987, entrepreneurs Stewart and Lynda Resnick have acquired and planted thousands of acres of pomegranate orchards in California. In 1998, they began to collaborate with doctors and scientists to investigate the potential health benefits of pomegranate consumption. They formed POM Wonderful, LLC to make, market, and sell pomegranate-based products. The products include POM Wonderful 100% Pomegranate Juice and two dietary supplements, POMx Pills and POMx Liquid, which contain pomegranate extract in concentrated form. The Resnicks are the sole owners of POM Wonderful and an affiliated company, Roll Global LLC, which provides advertising and other services to POM. Those entities have engaged in a broad array of advertising campaigns promoting POM products through various media including magazine ads, newspaper inserts, billboards, posters, brochures, press releases, and website materials.
POM’s promotional materials regularly referenced scientific support for the claimed health benefits of its pomegranate products. By 2010, the Resnicks, POM, and Roll had spent more than $85 million on pomegranate-related medical research, sponsoring more than one hundred studies at forty-four different institutions. This case involves studies examining the efficacy of POM’s products with regard to three particular ailments: heart disease, prostate cancer, and erectile dysfunction.
1. POM sponsored a number of studies examining the capacity of its products to*118improve cardiovascular health. One such study, led by Dr. Michael Aviram of the Technion-Israel Institute of Technology, examined the effect of pomegranate juice consumption by patients with carotid artery stenosis. Carotid artery stenosis is the narrowing of the arteries that supply oxygenated blood to the brain, usually caused by a buildup of plaque inside the arteries.
In Dr. Aviram’s study, ten patients with carotid artery stenosis consumed concentrated pomegranate juice daily for a year, while nine patients with carotid artery stenosis served as a control group and consumed no pomegranate juice. The investigators measured the change in the patients’ carotid intima-media thickness (CIMT), an indicator of plaque buildup. They found that patients who consumed pomegranate juice every day experienced a reduction in CIMT of “up to 30%” after one year, while CIMT for patients in the control group increased by 9% after one year. POM Wonderful LLC,No. 9344, Initial Decision of ALJ at 115 ¶ 791 (U.S. Fed. Trade Comm’n May 17, 2012) (ALJ Initial Decision). As one of POM’s experts would later testify, the Aviram study, while “suggesting] a benefit” from pomegranate juice consumption for patients with carotid artery stenosis, was “not at all conclusive,” in part because of the study’s small sample size. Id.at 118 ¶ 802 (quoting expert testimony). In 2004, the journal Clinical Nutritionpublished the study. SeeM. Aviram et al., Pomegranate Juice Consumption for 3 Years by Patients with Carotid Artery Stenosis Reduces Common Carotid Intima-Media Thickness, Blood Pressure and LDL Oxidation,23 Clinical Nutrition 423 (2004).
Subsequently, in 2005, a larger study, led by Dr. Dean Ornish of the University of California, San Francisco and the Preventative Medicine Research Institute, followed seventy-three patients with at least one cardiovascular risk factor for one year. The patients were randomly assigned either to drink one cup of pomegranate juice daily or to drink a placebo beverage. At the end of the study, Dr. Ornish and his co-investigators found no statistically significant difference between the treatment group and the placebo group in CIMT change or any other heart-related measure.
In 2006, a third, still larger study, led by Dr. Michael Davidson of the University of Chicago, followed 289 patients with one or more coronary heart disease risk factors. As in the Ornish study, the patients were randomly assigned to drink either pomegranate juice or a placebo beverage each day. At the end of eighteen months, Dr. Davidson and his co-investigators found no statistically significant difference in the rate of carotid intima-media thickening between patients in the treatment group and those in the placebo group. POM initially delayed publication of the adverse findings, but ultimately allowed publication of the study in 2009. SeeMichael H. Davidson et al., Effects of Consumption of Pomegranate Juice on Carotid Intimcu-Me-dia Thickness in Men and Women at Moderate Risk for Coronary Heart Disease,104 Am. J. Cardiology 936 (2009).
In them final report, Dr. Davidson and his co-investigators noted that they had found some evidence of an association between pomegranate juice consumption and decreased CIMT among subgroups of patients with high triglyceride levels and low levels of HDL (“good”) cholesterol. Dr. Davidson and his co-authors emphasized, however, that the findings for those subgroups were based on “post hoc exploratory analyses” unanticipated in the study protocol. As Dr. Davidson and his coauthors noted, “post hoc exploratory anal-yses ... should be interpreted with cau*119tion” because of an increased risk of “type I errors” (i.e., false positives). See id.at 941. Even for patients in the high-risk subgroups, moreover, the reduction in arterial thickness was between 4% and 9% (depending on the measurement), substantially below the 30% decrease reported by Dr. Aviram.
Although Drs. Ornish and Davidson completed their arterial thickness studies in 2005 and 2006, respectively, a consumer reading POM’s promotional materials after 2006 would not have known of those studies or that they cast doubt on Dr. Aviram’s prior findings. In June 2007, for example, POM distributed a brochure featuring a statement by Dr. Aviram that “POM Wonderful Pomegranate Juice has been proven to promote cardiovascular health,” along with a description of his arterial thickness study, but with no mention of Drs. Or-nish’s and Davidson’s contrary findings. POM Wonderful LLC,No. 9344, Opinion of the Commission, App. B fig.10, at 5 (U.S. Fed. Trade Comm’n Jan. 10, 2013) (FTC Op.). That same summer, POM published a newsletter in which it asserted that “NEW RESEARCH OFFERS FURTHER PROOF OF THE HEART-HEALTHY BENEFITS OF POM WONDERFUL JUICE.” Id.App. B fig.16, at 3. The newsletter claimed a “30% DECREASE IN ARTERIAL PLAQUE” on the basis of Dr. Aviram’s limited study but again omitted any mention of the Ornish and Davidson findings. Id.And in 2008 and 2009, POM conducted a $1 million promotional campaign, with seventy ads in newspapers and magazines across the country, in which it trumpeted Dr. Avi-ram’s findings — including the 30% figure— without any acknowledgement of the contrary Ornish and Davidson studies. Id.App. B fig.25; see also id.App. B fig. 19.
Dr. Ornish also conducted a separate study examining the relationship between pomegranate juice and blood flow. The study followed forty-five patients with coronary heart disease and myocardial ische-mia (insufficient blood flow to the heart due to narrowing of the arteries). The patients were randomly assigned to drink either pomegranate juice or a placebo beverage daily. Dr. Ornish later testified that, although his protocol called for a twelve-month study, he terminated the study abruptly after three months because the Resnicks did not follow through on their previous commitment to fund a twelve-month trial.
At the end of three months, patients in the treatment group outperformed patients in the placebo group on one measure of blood flow to the heart, known as the “summed difference score.” The study, however, found no statistically significant difference between the treatment and control groups on two other measures of blood flow (the “summed rest score” and the “summed stress score”), nor did it find any statistically significant differences in blood pressure, cholesterol, or triglycerides. Medical experts later noted a number of shortcomings of the study, including that patients in the placebo group began the study with significantly worse blood flow than patients in the treatment group, potentially skewing the outcomes.
POM touted the results of the second Ornish study in its ads and promotional materials without noting the study’s limitations or acknowledging that patients in the treatment group showed no statistically significant improvement in blood flow on two of three measures. In September 2005, for instance, POM issued a press release announcing the study in which it asserted that “blood flow to the heart improved approximately 17% in the pomegranate juice group” and that differences in blood flow between the two groups were “statistically significant.” Id.App. B flg.8.*120POM continued to make similar statements in its promotional materials through 2009. See id.App. B fig.10, at 5 (June 2007 brochure claiming that “[p]atients who consumed 8oz of POM Wonderful 100% Pomegranate Juice daily for three months experienced a 17% improvement in blood flow”); id.App. B fig.16, at 3 (summer 2007 newsletter claiming “17% IMPROVED BLOOD FLOW”); id.App. B figs.37, 38, 39 (similar claims on POM websites in 2009).
2. In addition to the cardiovascular studies, petitioners sponsored research on the effect of pomegranate juice consumption in prostate cancer patients. One study, led by Dr. Allan Pantuck of the University of California, Los Angeles Medical School, followed forty-six patients who had been diagnosed with prostate cancer. All of the patients had already been treated by radical prostatectomy, radiation therapy, or cryotherapy. The study called for them to drink eight ounces of pomegranate juice daily. There was no control group. The study concluded that the patients’ “PSA doubling time,” a measure of the rapidity of growth in prostate tumor cells, increased from fifteen months at the beginning of the study to fifty-four months at the end. But as Dr. Pantuck himself noted, patients who have undergone radical prostatectomy or radiation therapy for prostate cancer commonly experience a lengthening in PSA doubling time regardless of whether they consume pomegranate juice.
POM, however, made no mention of the limitations of the Pantuck study in its public statements. In a July 2006 press release, POM claimed that “drinking 8 ounces of POM Wonderful pomegranate juice daily prolonged post-prostate surgery PSA doubling time from 15 to 54 months,” without noting that some or all of the increase in the patients’ PSA doubling times may have resulted from the radical prostatectomies or radiation treatments undergone by the patients. Id.App. B flg.9, at 2. POM advanced similar claims in a June 2007 brochure and in a fall 2007 newsletter, again with no disclosure of the study’s limitations. See id.App. B flgs.10, 17. In 2008 and 2009, POM ads in the New York Times Magazine and TIME Magazine asserted that prostate cancer patients who drank eight ounces of POM Wonderful 100% Pomegranate Juice a day for at least two years experienced “significantly slower” PSA doubling times, once again without any acknowledgment that the patients’ PSA doubling times may have slowed regardless of whether they consumed pomegranate juice. Id.App. B flgs.21, 27; see also id.figs.36, 37, 38, 39 (similar claims on POM websites in 2009).
3. Petitioners additionally sponsored research of the effects of pomegranate juice consumption in men with mild to moderate erectile dysfunction. One study, led by Dr. Harm Padma-Nathan, a urologist in Beverly Hills, California, followed fifty-three patients over eight weeks. The study used a “crossover” design: one group of patients consumed pomegranate juice for the first four weeks and then consumed a placebo beverage for the next four, while a second group consumed the placebo beverage for the first four weeks and pomegranate juice for the next four. Dr. Padma-Nathan and co-investigators evaluated the results using two measures: the International Index of Erectile Function (IIEF), a fifteen-question instrument, and the Global Assessment Questionnaire (GAQ), a one-question test. The IIEF is a “validated” tool, which means that the measure has been shown to have statistical reliability, while the one-question GAQ is not a validated measure for assessing erectile function. See generallyR.C. Rosen et al., The International Index of Erectile Function (IIEF): A State-of-the-Science*121 Review,14 Int’l J. Impotence Res. 226, 226 (2002).
Dr. Padma-Nathan’s study showed some evidence that patients scored higher on the GAQ measure after drinking pomegranate juice. But the p-value — the probability of observing at least as strong an association between pomegranate juice consumption and GAQ scores due to random chance — was 0.058, falling just short of statistical significance at the conventional p<0.05 level. On the scientifically validated IIEF measure, however, the difference between patients’ scores after drinking pomegranate juice and after drinking the placebo beverage came nowhere near statistical significance: there was nearly a 3/4 likelihood of observing as strong an association due to random chance (p=0.72). SeeC.P. Forest, H. Padma-Nathan &H.R. Liker, Efficacy and Safety of Pomegranate Juice on Improvement of Erectile Dysfunction in Male Patients with Mild to Moderate Erectile Dysfunction: A Randomized, Placebo-Controlled, Double-Blind, Crossover Study,19 Int’l J. Impotence Res. 564, 566 (2007).
In its public statements about Dr. Pad-ma-Nathan’s study, POM made no mention of the negative results with respect to the validated IIEF measure. POM instead touted the study outcomes based exclusively on the non-validated GAQ measure. A 2007 POM press release thus described Dr. Padma-Nathan’s study as follows:
At the end of ... each four week period, efficacy was assessed using the International Index of Erectile Function (IIEF) and Global Assessment Questionnaire (GAQ). The IIEF is a validated questionnaire that has been demonstrated to correlate with ED intensity. The GAQ elicits the patient’s self-evaluation of the study beverages’ effect on erectile activity. Forty seven percent of the subjects reported that their erections improved with POM Wonderful Pomegranate Juice, while only 32% reported improved erections with the placebo (p=0.058).
FTC Op.App. B fig.15, at 2. That press release, while referencing IIEF and thus suggesting that its description of the findings would account for that measure, in fact promoted the results based solely on the GAQ measure with no acknowledgment of the adverse findings on IIEF scores. In 2009 and 2010, POM similarly touted the GAQ findings — again without any mention of the negative IIEF results — on websites and in print ads. See id.App. B figs.33, 36, 37, 38, 39.
B.
In September 2010, the Federal Trade Commission filed an administrative complaint alleging that POM, Roll, the Res-nicks, and POM’s then-President Matthew Tupper had made false, misleading, and unsubstantiated representations in violation of the FTC Act. SeeFTC Act § 5(a)(1),15 U.S.C. § 45(a)(1); FTC Act § 12(a),15 U.S.C. § 52(a). The complaint identified forty-three advertisements or promotional materials containing claims alleged to be false, misleading, or unsubstantiated.
In May 2012, following an administrative trial, the Commission’s chief administrative law judge found that nineteen of POM’s advertisements and promotional materials contained implied claims that POM products treat, prevent, or reduce the risk of heart disease, prostate cancer, or erectile dysfunction. He further concluded that POM and the related parties lacked sufficient evidence to substantiate those claims, and that the claims were material to consumers. He therefore held the POM parties liable under the FTC Act and ordered them to cease and desist from*122making further claims about the health benefits of any food, drug, or dietary supplement unless the claims are non-misleading and supported by competent and reliable scientific evidence.
Both sides appealed to the full Commission. POM and the related parties argued that they should not have been held liable at all, while the Commission’s complaint counsel argued that additional ads and promotional items (beyond the nineteen identified by the administrative law judge) made false or misleading claims. The complaint counsel also urged the Commission to impose an injunctive order barring POM from claiming that any of its products is effective in the treatment or prevention of any disease unless POM first gains pre-approval from the Food and Drag Administration.
In January 2013, the Commission unanimously affirmed the administrative law judge’s decision to impose liability on POM and the other parties. Four of the five commissioners found that thirty-six of POM’s ads and promotional items made false or misleading claims, but the Commission specified that injunctive relief would be justified even if based solely on the nineteen ads found by the administrative law judge (and affirmed by the Commission) to be false or misleading. Commissioner Ohlhausen filed a concurring statement saying that she, like the administrative law judge, would have found a smaller number of POM ads to be false or misleading. But she agreed that POM and the related parties should all be held liable for violating the FTC Act.
The Commission also broadened the scope of the injunctive order against POM and the other parties, although it declined complaint counsel’s request to require FDA pre-approval. Part I of the Commission’s final order prohibits POM, Roll, the Resnicks, and Tupper from representing that any food, drag, or dietary supplement “is effective in the diagnosis, cure, mitigation, treatment, or prevention of any disease” — including but not limited to heart disease, prostate cancer, and erectile dysfunction — unless the representation is non-misleading and supported by “competent and reliable scientific evidence that, when considered in light of the entire body of relevant and reliable scientific evidence, is sufficient to substantiate that the representation is true.” The order goes on to say:
For purposes of this Part I, competent and reliable scientific evidence shall consist of at least two randomized and controlled human clinical trials (RCTs) ... that are randomized, well controlled, based on valid end points, and conducted by persons qualified by training and experience to conduct such studies. Such studies shall also yield statistically significant results, and shall be double-blinded unless [POM, Roll, the Resnicks, or Tupper] can demonstrate that blinding cannot be effectively implemented given the nature of the intervention.
POM Wonderful LLC,No. 9344, Final Order at 2 (U.S. Fed. Trade Comm’n Jan. 10, 2013) (FTC Final Order).
Part II of the order prohibits POM and the related parties from misrepresenting the results of scientific studies in their ads. Part III bars them from making any claim about the “health benefits” of a food, drug, or dietary supplement unless the representation is non-misleading and supported by “competent and reliable scientific evidence.” But unlike Part I, which applies specifically and solely to disease-relatedclaims, Part III contains no requirement that randomized, controlled, human clinical trials support more general claims about health benefits.
POM, Roll, the Resnicks, and Tupper petitioned this court for review. We have*123jurisdiction under sections 5(c) and 5(d) of the FTC Act,15 U.S.C. § 45(c)-(d).
II.
Per our usual practice, we first address petitioners’ statutory challenges to the Commission’s order before turning to their constitutional claims. See In re Fashina,486 F.3d 1300, 1302-03 (D.C.Cir.2007). On review of an order under the FTC Act, “[t]he findings of the Commission as to the facts, if supported by evidence, shall be conclusive.” FTC Act § 5(c),15 U.S.C. § 45(c). That standard is “essentially identical” to the familiar “substantial evidence” test under the Administrative Procedure Act. FTC v. Ind. Fed’n of Dentists,476 U.S. 447, 454,106 S.Ct. 2009,90 L.Ed.2d 445(1986). The Commission “is often in a better position than are courts to determine when a practice is ‘deceptive’ within the meaning of the [FTC] Act,” and that “admonition is especially true with respect to allegedly deceptive advertising since the finding of a § 5 violation in this field rests so heavily on inference and pragmatic judgment.” FTC v. Colgate-Palmolive Co.,380 U.S. 374, 385,85 S.Ct. 1035,13 L.Ed.2d 904(1965).
A.
In determining whether an advertisement is deceptive in violation of section 5 of the FTC Act, the Commission engages in a three-step inquiry, considering: (i) what claims are conveyed in the ad, (ii) whether those claims are false, misleading, or unsubstantiated, and (iii) whether the claims are material to prospective consumers. See Kraft, Inc. v. FTC,970 F.2d 311, 314 (7th Cir.1992); see also Thompson Med. Co.,104 F.T.C. 648, 660-61 (1984), aff'd,791 F.2d 189, 197 (D.C.Cir.1986). At the first step, the Commission “will deem an advertisement to convey a claim if consumers acting reasonably under the circumstances would interpret the advertisement to contain that message.” Thompson Med. Co.,104 F.T.C. at 788. The Commission “examines the overall net impression” left by an ad, Kraft,970 F.2d at 314, and considers whether “at least a significant minority of reasonable consumers” would “likely” interpret the ad to assert the claim, Telebrands Corp.,140 F.T.C. 278, 291 (2005), aff'd,457 F.3d 354(4th Cir.2006).
In identifying the claims made by an ad, the Commission distinguishes between “efficacy claims” and “establishment claims.” See Thompson Med. Co. v. FTC,791 F.2d 189, 194 (D.C.Cir.1986). An efficacy claim suggests that a product successfully performs the advertised function or yields the advertised benefit, but includes no suggestion of scientific proof of the product’s effectiveness. See id.; Removatron Int'l Corp. v. FTC,884 F.2d 1489, 1492 n. 3 (1st Cir.1989). An establishment claim, by contrast, suggests that a product’s effectiveness or superiority has been scientifically established. See Thompson Med. Co.,791 F.2d at 194; Sterling Drug, Inc. v. FTC,741 F.2d 1146, 1150 (9th Cir.1984).
The distinction between efficacy claims and establishment claims gains salience at the second step of the Commission’s inquiry, which calls for determining whether the advertiser’s claim is false, misleading, or unsubstantiated. If an ad conveys an efficacy claim, the advertiser must possess a “reasonable basis” for the claim. See Pfizer Inc.,81 F.T.C. 23, 62 (1972). The FTC examines that question under the so-called “Pfizerfactors,” including “the type of product,” “the type of claim,” “the benefit of a truthful claim,” “the ease of developing substantiation for the claim,” “the consequences of a false claim,” and “the amount of substantiation*124experts in the field would consider reasonable.” Daniel Chapter One,No. 9329,2009 WL 5160000, at *25 (U.S.Fed.Trade Comm’n Dec. 24, 2009) (citing Pfizer,81 F.T.C. at 64), aff'd,405 Fed.Appx. 505(D.C.Cir.2010); see also Thompson Med. Co.,104 F.T.C. at 821.
For establishment claims, by contrast, the Commission generally does not apply the Pfizerfactors. See Removatron Int’l Corp.,111 F.T.C. 206, 297 (1988), aff'd,884 F.2d 1489(1st Cir.1989). Rather, the amount of substantiation needed for an establishment claim depends on whether the claim is “specific” or “nonspecific.” See Thompson Med. Co.,791 F.2d at 194. If an establishment claim “states a specific type of substantiation,” the “advertiser must possess the specific substantiation claimed.” Removatron,884 F.2d at1492 n. 3. If an ad instead conveys a non-specific establishment claim — e.g., an ad stating that a product’s efficacy is “medically proven” or making use of “visual aids” that “clearly suggest that the claim is based upon a foundation of scientific evidence” — the advertiser “must possess evidence sufficient to satisfy the relevant scientific community of the claim’s truth.” Bristol-Myers Co.,102 F.T.C. 21, 321 (1983), aff'd,738 F.2d 554(2d Cir.1984). The Commission therefore “determines what evidence would in fact establish such a claim in the relevant scientific community” and “then compares the advertisers’ substantiation evidence to that required by the scientific community.” Removatron,884 F.2d at 1498.
Even if the Commission concludes at the first step that an advertiser conveyed efficacy or establishment claims and determines at the second step that the claims qualify as false, misleading, or unsubstantiated, it can issue a finding of liability only “if the omitted information would be a material factor in the consumer’s decision to purchase the product.” Am. Home Prods. Corp.,98 F.T.C. 136, 368 (1981), enforced as modified,695 F.2d 681(3d Cir.1982); see also Colgate-Palmolive,380 U.S. at 386-88,85 S.Ct. 1035. Here, petitioners do not dispute the materiality of POM’s disease-related claims. We therefore confine our analysis to the first and second steps of the Commission’s determination: its findings that petitioners’ ads conveyed efficacy and establishment claims and that those claims were false, misleading, or unsubstantiated.
B.
At the first step of its inquiry, the Commission determined that thirty-six of petitioners’ advertisements and promotional materials conveyed efficacy claims asserting that POM products treat, prevent, or reduce the risk of heart disease, prostate cancer, or erectile dysfunction. The Commission further concluded that thirty-four of those ads also conveyed establishment claims representing that clinical studies substantiate the efficacy of POM products in treating, preventing, or reducing the risk of the same ailments. The Commission set forth the basis for those findings in considerable detail in an appendix to its opinion, with a separate explanation for each ad.
Those ads, as described earlier, see supraPart I.A, repeatedly claimed the benefits of POM’s products in the treatment or prevention of heart disease, prostate cancer, or erectile dysfunction, and consistently touted medical studies ostensibly supporting those claimed benefits. The question whether “a claim of establishment is in fact made is a question of fact the evaluation of which is within the FTC’s peculiar expertise.” Thompson Med. Co.,791 F.2d at 194; see also Removatron,884 F.2d at 1496. Here, we perceive no basis for setting aside the Com*125mission’s carefully considered findings of efficacy and establishment claims as unsupported by substantial evidence.
Petitioners argue that the Commission applied overly broad claim interpretation principles by “adopt[ing] a rule that if an advertisement correctlyreferences research connecting a food product to possible health benefits, it necessarily implies the vastly broader claim that there is ‘clinical proof that the product treats, cures, or prevents a disease.” Joint Reply Br. 6 (emphasis in original). We disagree with that characterization of the Commission’s approach. As the Commission made clear in its opinion, “[n]ot ‘every reference to a test or study necessarily gives rise to an establishment claim.’ ” FTC Op. at 488-89 (alteration omitted) (quoting Bristol-Myers,102 F.T.C. at321 n. 7). Here, however, the advertisements go beyond merely describing specific research in sufficient detail to allow a consumer to judge its validity. The study results are referenced in a way that suggests they are convincing evidence of efficacy.
As the Commission separately set forth for each ad, “these ads drew a logical connection between the study results and effectiveness for the particular diseases.” Id.at 13. Moreover, they invoked medical symbols, referenced publication in medical journals, and described the substantial funds spent on medical research, fortifying the overall sense that the referenced clinical studies establish the claimed benefits. Id.at 13-14. As the Commission explained, “[w]hen an ad represents that tens of millions of dollars have been spent on medical research, it tends to reinforce the impression that the research supporting product claims is established and not merely preliminary.” Id.at 14.
Petitioners accuse the Commission of “ ‘cherry-pick[ing]’ the record by focusing on a handful of the most aggressive advertisements — most of which have not been run in over six years.” Joint Reply Br. 5. There is no meaningful difference, however, between the more recent ads’ reliance on medical studies and that of the earlier ads. Consider, for instance, the advertisement for POMx Pills appearing in Playboy magazine in July 2010, less than three months before the Commission filed its complaint. SeeFTC Op.App. B fig.33. According to that ad, POMx is “backed by $34 million in medical research at the world’s leading universities” revealing “promising results for erectile, prostate and cardiovascular health.” Id.The ad goes on to discuss three specific studies: Dr. Padma-Nathan’s erectile dysfunction study, Dr. Pantuck’s PSA doubling time study, and Dr. Ornish’s blood flow study. Of the first, the ad says that, “[i]n a preliminary study on erectile function, men who consumed POM Juice reported a 50% greater likelihood of improved erections as compared to placebo.” The ad next asserts that “[a]n initial UCLA study on our juice found hopeful results for prostate health, reporting ‘statistically significant prolongation of PSA doubling times.’ ” Finally, the ad states that “[a] preliminary study on our juice showed promising results for heart health” — specifically, improved “blood flow to the heart.”
Materials appearing on POM websites in 2009-2010 convey substantially similar claims. Thepomwonderful.com site described POM juice as “backed by” $25 million in “medical research” and clinical testing. ALJ Initial Decision at 55 ¶ 370. The website pointed to “medical results” in the categories of “cardiovascular health,” “prostate health,” and “erectile function.” Id.For cardiovascular health, the webpage characterized Dr. Ornish’s blood flow study as showing “improved blood flow to the heart,” and Dr. Aviram’s CIMT study as showing a decrease in arterial plaque*126from daily consumption of POM juice. Id.at 56 ¶373. Further links contained descriptions of studies “demonstrat[ing] that pomegranate juice lowers blood pressure in patients with hypertension,” and “clearly demonstrat[ing] for the first time that pomegranate juice consumption by patients with carotid artery stenosis possesses anti-atherosclerotic properties.” Id.at 56-57 ¶¶ 375-76. In the category of prostate health, the webpage described Dr. Pantuck’s study as showing that men with prostate cancer who drank pomegranate juice daily “experienced significantly slower PSA doubling times,” id.at 56 ¶371, with PSA doubling time described as “an indicator of prostate cancer progression,” id.at 58 ¶ 381. And with regard to erectile function, the webpage described Dr. Padma-Nathan’s study as demonstrating that men who drank pomegranate juice “were 50% more likely to experience improved erections.” Id.at 56 ¶ 372.
The Commission reviewed the claims in POM’s ads “in light of any disclaimers or disclosures that [petitioners] actually made.” FTC Op. at 504-05. For the 2010 Playboy ad, for instance, the Commission concluded that “at least a significant minority of reasonable consumers” would construe the ad to claim that drinking eight ounces of POM juice or ingesting one POMx pill a day can treat, prevent, or reduce the risk of erectile dysfunction, prostate cancer, and heart disease. Id.App. A at A10-A11. The ad’s references to the described studies as “promising,” “initial” or “preliminary” did not detract from the Commission’s conclusion. The Commission considered the effect of such adjectives “in the context of each ad in its entirety,” explaining that those sorts of modifiers do “not neutralize the claims made when the specific results are otherwise described in unequivocally positive terms.” Id.App. A at A2. The Commission concluded that the “use of one or two adjectives does not alter the net impression,” especially “when the chosen adjectives” (such as “promising”) “provide a positive spin on the studies rather than a substantive disclaimer.” Id.at 13.
The Commission noted, though, that it might reach a different result if an ad were to incorporate an effective disclaimer, such as a statement that the “evidence in support of this claim is inconclusive.” Id.at 44 (quoting Pearson v. Shalala,164 F.3d 650, 659 (D.C.Cir.1999)). Because POM’s ads contained no such qualifier, the Commission held petitioners to the general substantiation standard for non-specific establishment claims — i.e., the requirement that petitioners possess evidence sufficient to satisfy the relevant scientific community of the truth of their claims. Petitioners advance no persuasive ground for rejecting that approach as beyond the Commission’s discretion.
C.
At the second stage of its analysis, the Commission found petitioners’ efficacy and establishment claims to be deceptive due to inadequate substantiation. “In reviewing whether there is appropriate scientific substantiation for the claims made, our task is only to determine if the Commission’s finding is supported by substantial evidence on the record as a whole.” Removatron,884 F.2d at 1497(internal quotation marks omitted). When conducting that inquiry, we are mindful of the Commission’s “special expertise in determining what sort of substantiation is necessary to assure that advertising is not deceptive.” Thompson Med. Co.,791 F.2d at 196.
1. For both petitioners’ efficacy claims and their non-specific establishment claims, the Commission found that “experts in the relevant fields” would require*127one or more “properly randomized and controlled human clinical trials”— “RCTs” — in order to “establish a causal relationship between a food and the treatment, prevention, or reduction of risk” of heart disease, prostate cancer, or erectile dysfunction. FTC Op. at 493. Without at least one such RCT, the Commission concluded, POM’s efficacy claims and its nonspecific establishment claims were inadequately substantiated.
In reaching that conclusion, the Commission emphasized a distinction between “generalized nutritional and health benefit claims” and “the specific disease treatment and prevention claims at issue in this case,” i.e., “that the Challenged POM Products treat, prevent or reduce the risk of heart disease, prostate cancer, and ED, and that such claims are scientifically established.” Id.at 20. The Commission declined to address the level of support required for general health or nutritional claims. See id.at 20-21. It instead confined its analysis to the specific disease prevention and treatment claims in question, concluding that the “expert evidence was clear that RCTs are necessary for adequate substantiation of these representations.” Id.
The Commission additionally explained that lesser substantiation might suffice for “claims that do not assert a causal relationship.” Id.at 23. POM’s ads, though, “convey the net impression that clinical studies or trials show that a causal relation has been established between the consumption of the Challenged POM Products and its efficacy to treat, prevent or reduce the risk of the serious diseases in question.” Id.at 22; see, e.g., id.App. B fig.2 (“Medical studies have shown that drinking 8oz. of POM Wonderful pomegranate juice daily minimizes factors that lead to atherosclerosis, a major cause of heart disease.”); id.App. B fig.7 (“POM Wonderful Pomegranate Juice ... can help prevent premature aging, heart disease, stroke, Alzheimer’s, even cancer.”); id.App. B fig. 20 (“Eight ounces a day is enough to keep your heart pumping.”). The Commission found that “experts in the relevant fields would require RCTs ... to establish” such a “causal relationship.” Id.at 22-23.
The Commission examined each of the studies invoked by petitioners in their ads, concluding that the referenced studies fail to qualify as RCTs of the kind that could afford adequate substantiation. Id.at 28-34. Petitioners’ claims therefore were deceptive. Id.at 34, 38. Moreover, in light of petitioners’ selective touting of ostensibly favorable study results and nondisclosure of contrary indications from the same or a later study, the Commission found that there were “many omissions of material facts in [the] ads that consumers cannot verify independently.” Id.at 43; seeFTC Act § 15(a)(1),15 U.S.C. § 55(a)(1) (“[I]n determining whether any advertisement is misleading, there shall be taken into account ... the extent to which the advertisement fails to reveal facts material in the light of such representations.”). Petitioners, the Commission observed, “made numerous deceptive representations and were aware that they were making such representations despite the inconsistency between the results of some of their later studies and the results of earlier studies to which [they] refer in their ads.” FTC Op. at 49.
With regard to heart disease, for instance, petitioners repeatedly touted the results of Dr. Aviram’s limited CIMT study without noting the contrary findings in Drs. Ornish’s and Davidson’s later and larger studies. See suprap. 7. For prostate cancer, petitioners consistently relied on Dr. Pantuck’s study of PSA doubling times but with no indication of the study’s*128limitations, including, for instance, that the study’s subjects all had undergone radical treatments associated with prolonged PSA doubling times regardless of consumption of pomegranate juice. See suprapp. 9-10. And in connection with erectile dysfunction, petitioners promoted the results of Dr. Padma-Nathan’s study based exclusively on the non-validated, one-question GAQ measure, without acknowledging that the study showed no improvement according to the only scientifically validated measure used to assess the results (the IIEF). See suprapp. 11-12.
2. Petitioners challenge the Commission’s factual finding that experts in the relevant fields require RCTs to support claims about the disease-related benefits of POM’s products. We conclude that the Commission’s finding is supported by substantial record evidence. That evidence includes written reports and testimony from medical researchers stating that experts in the fields of cardiology and urology require randomized, double-blinded, placebo-controlled clinical trials to substantiate any claim that a product treats, prevents, or reduces the risk of disease. SeeJ.A. 1018 (expert report of Dr. James Eastham of Memorial Sloan-Kettering Cancer Center); id,at 1048-49 (expert report of Dr. Frank Sacks of Harvard Medical School and Harvard School of Public Health); id.at 1081 (expert report of Dr. Arnold Melman of Albert Einstein College of Medicine); id.at 1104 (expert report of Dr. Meir Jonathan Stampfer of Harvard Medical School and Harvard School of Public Health).
The Commission drew on that expert testimony to explain why the attributes of well-designed RCTs are necessary to substantiate petitioners’ claims. FTC Op. at 494-95. A control group, for example, “‘allows investigators to distinguish between real effects from the intervention, and other changes, including those due to the mere act of being treated (‘placebo effect’) [and] the passage of time.’ ” Id.at 23 (quoting ALJ Initial Decision at 90 ¶ 611). Random assignment of a study’s subjects to treatment and control groups “increases the likelihood that the treatment and control groups are similar in relevant characteristics, so that any difference in the outcome between the two groups can be attributed to the treatment.” Id.(quoting ALJ Initial Decision at 90 ¶ 612). And when a study is “double-blinded” (i.e., when neither the study participants nor the investigators know which patients are in the treatment group and which patients are in the control group), it is less likely that participants or investigators will consciously or unconsciously take actions potentially biasing the results. Id.at 24.
Petitioners assert that certain of the Commission’s experts “admit[ted]” that RCTs are not always necessary to substantiate claims about the health benefits of foods and nutrients. Tupper Br. 41. Petitioners take the experts’ remarks out of context. For example, Dr. Meir Jonathan Stampfer acknowledged having made recommendations concerning diet and exercise “even when the data are not supported by randomized clinical trials,” but he also emphasized that a health recommendation based on the “best available evidence” is “not the same as stating that a causal link has been established.” J.A. 1218 (deposition testimony). Dr. Frank Sacks likewise acknowledged that “well-conducted, well-executed observational research is very important” for evaluating foods and nutrients, but he emphasized that a causal link between a food or nutrient and a reduction in disease risk “cannot be proven from an observational [i.e., non-RCT] study.” Id.at 1240 (deposition testimony). POM nonetheless claimed a scientifically established, causal link be*129tween its products and various disease-related benefits on the basis of studies that were not randomized or placebo-controlled. See, e.g.,FTC Op.App. B fig.2 (asserting, on basis of Dr. Aviram’s non-randomized and non-placebo-controlled CIMT study, that “[m]edical studies have shown that drinking 8oz. of POM Wonderful pomegranate juice daily minimizes factors that lead to atherosclerosis (plaque buildup in the arteries), a major cause of heart disease”); id.App. B fig.3 (stating, on basis of same study, that “a clinical pilot study shows that an 8 oz. glass of POM Wonderful 100% Pomegranate Juice, consumed daily, reduces plaque in the arteries up to 30%”); id.App. B fig.9 (claiming, on basis of Dr. Pantuck’s non-controlled study, that pomegranate juice consumption “prolonged post-prostate surgery PSA doubling time”).
Petitioners observe that some of their own experts offered divergent views about the need for RCTs to substantiate disease-related claims for food products. But section 5(c) of the FTC Act,15 U.S.C. § 45(c), which addresses judicial review, “forbids a court to ‘make its own appraisal of the testimony, picking and choosing for itself among uncertain and conflicting inferences.’” Ind. Fed’n of Dentists,476 U.S. at 454,106 S.Ct. 2009(quoting FTC v. Algoma Lumber Co.,291 U.S. 67, 73,54 S.Ct. 315,78 L.Ed. 655(1934)). The standard set forth in section 5(c) is “essentially identical” to the ‘“substantial evidence’ standard for review of agency factfinding,” id.,and “does not permit the reviewing court to weigh the evidence, but only to determine that there is in the record such relevant evidence as a reasonable mind might accept as adequate to support a conclusion.” Am. Home Prods. Corp. v. FTC,695 F.2d 681, 686 (3d Cir.1982) (quoting Steadman v. SEC,450 U.S. 91, 99,101 S.Ct. 999,67 L.Ed.2d 69(1981)). In asking us to substitute our own appraisal of the expert testimony for the Commission’s, petitioners ask us to do what section 5(c) forbids. See Thompson Med. Co.,791 F.2d at 196.
3. Petitioners contend that it is “too onerous” to require RCTs to substantiate disease-related claims about food products “because of practical, ethical, and economic constraints on RCT testing in that context.” Joint Reply Br. 32. The Commission was unpersuaded by that argument, seeFTC Op. at 494-95, and so are we.
As for the practical constraints on double-blinded, placebo-controlled, randomized trials, petitioners say that it is “difficult, if not impossible, to ‘blind’ a fruit.” POM Br. 13. But that argument does not apply to two of the three products at issue — POMx Liquid and POMx Pills — which are dietary supplements amenable to blinding. And as applied to POM juice, petitioners’ argument is called into question by the fact that several juice studies they sponsored were double-blinded and placebo-controlled, including studies led by Dr. Ornish, Dr. Davidson, and Dr. Padma-Nathan. See, e.g.,Davidson et al., supra,at 937 (explaining that beverage with “similar color and energy content” as pomegranate juice could be “labeled so that neither subjects nor staff members were aware” whether beverage was placebo). In any event, the Commission required double-blinding only “when feasible,” acknowledging that, “in some instances ... it may not be possible to conduct blinded clinical trials of food products.” FTC Op. at 494-95.
As for the ethical constraints on randomized controlled trials, petitioners say that it is “impossible to create a zero intake group for nutrients in an ethical manner — doctors cannot, for example, ethically deprive a control group of patients of all Vitamin C for a decade to determine whether Vitamin C helps prevent cancer.”*130POM Br. 15 (internal quotation marks omitted). Many of the challenged ads, however, made claims about the short-term benefits of consuming POM products. See, e.g.,FTC Op.App. B fig.l (asserting, on basis of ten-patient study with no control group, that “[p]omegranate juice inhibited [angiotensin converting enzyme (ACE) ] by 36% after two weeks of consumption” and that “[i]nhibition of ACE lessens the progression of atherosclerosis”). And whether or not it may be unethical to tell patients in a control group to stop consuming vitamin C, petitioners give us no reason to believe that it would be unethical to create a zero intake group for pomegranate juice.
We acknowledge that RCTs may be costly, although we note that the petitioners nonetheless have been able to sponsor dozens of studies, including several RCTs. Yet if the cost of an RCT proves prohibitive, petitioners can choose to specify a lower level of substantiation for their claims. As the Commission observed, “the need for RCTs is driven by the claims [petitioners] have chosen to make.” Id.at 25. An advertiser who makes “express representations about the level of support for a particular claim” must “possess the level of proof claimed in the ad” and must convey that information to consumers in a non-misleading way. Thompson Med. Co.,791 F.2d at 194. An advertiser thus still may assert a health-related claim backed by medical evidence falling short of an RCT if it includes an effective disclaimer disclosing the limitations of the supporting research. Petitioners did not do so.
D.
Petitioners argue that the substantiation standard applied by the Commission to POM’s establishment and efficacy claims amounts to a new legal rule adopted in violation of the Administrative Procedure Act’s notice-and-comment requirements for rulemaking. SeeAdministrative Procedure Act § 4,5 U.S.C. § 553; FTC Act § 18(a)-(b), 15 U.S.C. § 57a(a)-(b) (APA notice-and-comment requirements apply to FTC rules). We disagree. The Commission proceeded in this case via adjudication rather than rulemaking. And it “is well settled that an agency ‘is not precluded from announcing new principles in an adjudicative proceeding,’ ” and that “ ‘the choice between rulemaking and adjudication lies in the first instance within the agency’s discretion.’ ” Cassell v. FCC,154 F.3d 478, 486 (D.C.Cir.1998) (alteration omitted) (quoting NLRB v. Bell Aerospace Co. Div. of Textron Inc.,416 U.S. 267, 294,94 S.Ct. 1757,40 L.Ed.2d 134(1974)); see also Qwest Servs. Corp. v. FCC,509 F.3d 531, 536-37 (D.C.Cir.2007).
Petitioners point to Appalachian Power Co. v. EPA,208 F.3d 1015, 1024 (D.C.Cir.2000), where we said that “an agency may not escape the notice and comment requirements ... by labeling a major substantive legal addition to a rule a mere interpretation.” Appalachian Power,however, involved a guidance document that “in effect amended” a regulation, which the agency could not “legally do without complying with the rulemaking procedures.” Id.at 1028. Here, the Commission did not effectively amend a notice- and-comment regulation. It instead validly proceeded by adjudication. As we have explained, the “fact that an order rendered in an adjudication may affect agency policy and have general prospective application does not make it rulemaking subject to APA section 553 notice and comment.” Conference Grp., LLC v. FCC,720 F.3d 957, 966 (D.C.Cir.2013) (citation and internal quotation marks omitted).
The Commission’s decision, in any event, does not involve a “major substantive legal addition” to its substantiation standards.*131 Appalachian Power Co.,208 F.3d at 1024. With respect to POM’s establishment claims, the substantiation standard applied by the Commission is consistent with Commission precedent. When an advertiser represents that claims have been “scientifically established,” the FTC has long held the advertiser to “the level of evidence required to convince the relevant scientific community of the claim’s truthfulness.” Bristol-Meyers,102 F.T.C. at 317-18; accord Removatron,111 F.T.C. at 297-99; Thompson Med. Co.,104 F.T.C. at821-22 &n. 59. And the Commission has required RCTs to substantiate establishment claims in other contexts. See, e.g., Am. Home Prods. Corp.,98 F.T.C. at 200-06. With respect to POM’s efficacy claims, the Commission arrived at its RCT substantiation requirement by applying the traditional Pfizerfactors. That conclusion coheres with past Commission decisions applying Pfizer,including Pfizeritself. See Pfizer,81 F.T.C. at 66(finding that “for a test, standing alone, to provide a reasonable basis” for a claim that a nonprescription product is effective in treating minor burns and sunburns, “the test should be an adequate and well-controlled scientific test,” and noting “strong desirability” that the test be “double-blind”); Thompson Med. Co.,104 F.T.C. at 826(applying “six Pfizerfactors” and concluding that the “proper level of substantiation for ... efficacy claims” for topical analgesic marketed to treat minor arthritis is “two well-controlled clinical tests”).
E.
Matthew Tupper, for his part, challenges the Commission’s decision to hold him individually liable (along with the Resnicks) for POM’s deceptive acts and practices. Tupper, who became POM’s chief operating officer in 2003 and served as its president from 2005 to 2011, contends that he should not be held individually liable because Lynda Resnick, not he, had the “final say” on the ads. Tupper Br. 33.
Tupper cites no decisions supporting his assertion that individual liability under the FTC Act extends only to those with “final say” over deceptive acts or practices. The other circuits to address the issue have determined that “[i]ndividuals may be liable for FTC Act violations committed by a corporate entity if the individual ‘participated directly in the deceptive practices or acts or had authority to control them.’” FTC v. IAB Mktg. Assocs., LP,746 F.3d 1228, 1233 (11th Cir.2014) (alteration omitted) (quoting FTC v. Amy Travel Serv., Inc.,875 F.2d 564, 573 (7th Cir.1989)); accord FTC v. QT, Inc.,512 F.3d 858, 864 (7th Cir.2008); FTC v. Freecom Commc’ns, Inc.,401 F.3d 1192, 1204 (10th Cir.2005); FTC v. Publ’g Clearing House, Inc.,104 F.3d 1168, 1170 (9th Cir.1997). It is undisputed that Tupper participated directly in meetings about advertising concepts and content, reviewed and edited ad copy, managed the day-to-day affairs of POM’s marketing team, and possessed hiring and firing authority over the head of POM’s marketing department. Even assuming that “authority to control” is a prerequisite for individual liability under the FTC Act, we would still affirm based on the Commission’s unchallenged finding that Tupper “had the authority to determine which advertisements should run.” FTC Op. at 53.
Tupper next argues that the Commission failed to prove his knowledgethat POM’s ads conveyed misleading claims. But the FTC has been required to demonstrate an individual’s knowledge only when seeking equitable monetary relief. See FTC v. Network Servs. Depot, Inc.,617 F.3d 1127, 1138 (9th Cir.2010); Freecom Commc’ns,401 F.3d at 1197-203, 1207. In*132this case, the sole remedy imposed by the FTC was injunctive relief. And when the Commission does not seek restitution or monetary penalties, the FTC Act “imposes a strict liability standard” and “creates no exemption ... for unwitting disseminators of false advertising.” Porter & Dietsch, Inc. v. FTC,605 F.2d 294, 309 (7th Cir.1979); see Feil v. FTC,285 F.2d 879, 896 (9th Cir.1960); Koch v. FTC,206 F.2d 311, 317 (6th Cir.1953); Parke, Austin & Lipscomb, Inc. v. FTC,142 F.2d 437, 440 (2d Cir.1944).
Finally, Tupper contends that there is “no justification” for applying the Commission’s order to him because he has “voluntarily retired from his position at POM.” Tupper Br. 37. That argument occupied just two sentences of his opening brief, and he referenced no precedent supporting it until his reply brief. Joint Reply Br. 43-44 (citing FTC v. Accusearch Inc.,570 F.3d 1187, 1201 (10th Cir.2009); Borg-Warner Corp. v. FTC,746 F.2d 108, 110 (2d Cir.1984)). When a litigant’s opening brief presents an argument “in conclu-sory fashion and without visible support,” we have discretion to deem the argument forfeited. See Bd. of Regents of the Univ. of Wash. v. EPA,86 F.3d 1214, 1221 (D.C.Cir.1996). Tupper’s argument fails on the merits in any event. Injunctive relief may be inappropriate if the affected parties “have not shown a propensity toward violating” the statute and “nothing in the record ... suggests the likelihood or even the possibility” of further violations. Borg-Warner,746 F.2d at 110-11. But the Commission found that petitioners, including Tupper, “have a demonstrated propensity to misrepresent to their advantage the strength and outcomes of scientific research” and “engaged in a deliberate and consistent course of conduct — no mere isolated incident or mistake.” FTC Op. at 51. Additionally, there is no assurance that Tupper will not return to POM or join another company that markets food products or dietary supplements.
III.
Having rejected petitioners’ statutory claims, we now turn to their constitutional arguments. Petitioners challenge both the Commission’s liability determination and its remedy on First Amendment grounds. We reject both challenges except insofar as the Commission in its remedial order imposed an across-the-board, two-RCT substantiation requirement for any future disease-related claims by petitioners.
A.
“For commercial speech to come within [the First Amendment], it at least must concern lawful activity and not be misleading.” Cent. Hudson Gas & Elec. Corp. v. Pub. Serv. Comm’n,447 U.S. 557, 566,100 S.Ct. 2343,65 L.Ed.2d 341(1980). Consequently, “[mjisleading advertising may be prohibited entirely.” In re R.M.J.,455 U.S. 191, 203,102 S.Ct. 929,71 L.Ed.2d 64(1982).
In imposing liability against petitioners, the Commission found that POM’s ads are entitled to no First Amendment protection because they are “deceptive and misleading.” FTC Op. at 44. Petitioners ask us to review that finding de novo in light of the First Amendment context, see Bose Corp. v. Consumers Union of U.S.,466 U.S. 485, 505,104 S.Ct. 1949,80 L.Ed.2d 502(1984), and to overturn the Commission’s decision to impose liability. Our precedents, however, call for reviewing the Commission’s factual finding of a deceptive claim under the ordinary (and deferential) substantial-evidence standard, even in the First Amendment context. Novartis Corp. v. FTC,223 F.3d 783, 787 n. 4 (D.C.Cir.2000); FTC v. Brown & Wil*133 liamson Tobacco Corp.,778 F.2d 35, 41 n. 3 (D.C.Cir.1985); see also Kraft,970 F.2d at 316(cited in Novartis Corp.,223 F.3d at787 n. 4). We conclude that the Commission’s findings of deception are supported by substantial evidence in the record; and we would reach the same conclusion even if we were to exercise de novo review, at least with respect to the nineteen ads determined misleading by the administrative law judge and held by the Commission to form a sufficient basis for its liability determination and remedial order.
We have addressed eighteen of those nineteen ads in the course of our earlier discussion, and we affirm the Commission’s determination that those ads were deceptive for the reasons set forth above and in the FTC’s opinion. SeeFTC Op. App. A at A3-A7, A9-A14; id.App. B figs.l, 2, 3, 4, 6, 7, 8, 9, 10, 15, 16, 17, 21, 27, 33, 37, 38, 39. The sole remaining ad is one carried in two magazines in 2004 and 2005. It features an intravenous tube running through a bottle of POM juice alongside the headline “Life support.” Id.App. B fig.5. The ad says that POM juice “has more naturally occurring antioxidants than any other drink,” and that “[tjhese antioxidants fight hard against free radicals that can cause heart disease” and “even cancer.” Id.The ad then tells readers that, if they “[j]ust drink eight ounces a day,” they will “be on life support — in a good way.” Id.
The administrative law judge concluded that, “[biased on the overall, commonsense, net impression” of the ad, “a significant minority” of “reasonable” consumers “would interpret [the ad] to be claiming that drinking eight ounces of POM Juice daily prevents or reduces the risk of heart disease.” ALJ Initial Decision at 69 ¶ 455. The full Commission adopted the administrative law judge’s findings about the net impression conveyed by the ad, and we see no basis to overturn that conclusion. At the time, there was insufficient support for an unqualified efficacy claim of a link between daily consumption of pomegranate juice and prevention of heart disease. As a result, insofar as the FTC imposed liability on petitioners for the nineteen ads found to be deceptive by the administrative law judge, the Commission sanctioned petitioners for misleading speech unprotected by the First Amendment.
B.
Finally, we address petitioners’ First Amendment challenge to the Commission’s injunctive order. Part III of the order imposes a baseline requirement applicable to all of petitioners’ ads. It bars representations about a product’s general health benefits “unless the representation is non-misleading” and backed by “competent and reliable scientific evidence that is sufficient in quality and quantity” to “substantiate that the representation is true.” FTC Final Order at 3. For purposes of that baseline requirement, “competent and reliable evidence” means studies that are “generally accepted in the profession to yield accurate and reliable results.” Id.
Part I of the order, meanwhile, imposes heightened requirements in the specific context of claims about the treatment or prevention of “any disease” (including, but not limited to, heart disease, prostate cancer, and erectile dysfunction). Id.at 2. Such disease-related claims, like the broader category of health claims covered by Part III, must be “non-misleading” and supported by “competent and reliable scientific evidence.” Id.But “competent and reliable scientific evidence” is more narrowly defined for purposes of Part I to consist of “at least two randomized and controlled human clinical trials (RCTs)” that “yield statistically significant results” and are “double-blinded” whenever feasi*134ble. Id.In short, Part Ill’s baseline requirement for all health claims does not require RCT substantiation, whereas the specific requirements in Part I for disease-related claims not only contemplate RCT substantiation, but call for — as a categorical matter — two RCTs.
The Commission clarified in a footnote of its brief that Part I’s blanket, two-RCT-substantiation requirement for disease claims attaches only to unqualifiedrepresentations. FTC Br. 73 n. 33. But the evident leeway to make “effectively qualified”disease claims without two RCTs, id.,appears to be highly circumscribed. Representations characterizing a study’s results as “preliminary” or “initial” — even if describing a gold-standard RCT yielding results with an extremely high degree of statistical significance — would fail to count as adequately qualified and thus would be prohibited. SeeFTC Op.App. A at A2. Rather, an ad apparently would need to contain a disclaimer stating “unambiguously” that the evidence is “inconclusive” or that “additional research is necessary,” FTC Br. 10,19, even if the ad is substantiated by a well-designed RCT that experts uniformly consider to be conclusive, and regardless of the amount and quality of additional supporting evidence other than RCTs. Short of such a disclaimer, a disease-related claim faces a categorical bar unless substantiated by two RCTs.
Petitioners challenge the remedial order’s blanket, two-RCT-substantiation requirement under the First Amendment. They contend, and the Commission accepts, that their challenge should be examined under the general test for commercial speech restrictions set out in Central Hudson,447 U.S. at 566,100 S.Ct. 2343. SeeJoint Reply Br. 39-40; FTC Br. 74.
Central Hudsonfirst requires that the “asserted governmental interest [be] substantial.”447 U.S. at 566,100 S.Ct. 2343. The Supreme Court has made clear that the governmental “interest in ensuring the accuracy of commercial information in the marketplace is substantial.” Edenfield v. Fane,507 U.S. 761, 769,113 S.Ct. 1792,123 L.Ed.2d 543(1993). The Commission asserts that its remedial order aims to advance that concededly substantial interest, satisfying Central Hudson’sfirst prong.
With regard to the means by which the Commission seeks to further its asserted interest, Central Hudsonrequires that a challenged restriction “directly advance[] the governmental interest” and that it “is not more extensive than is necessary to serve that interest.”447 U.S. at 566,100 S.Ct. 2343. Here, insofar as the Commission’s order imposes a general RCT-substantiation requirement for disease claims — i.e., without regard to any particular number of RCTs — the order satisfies those tailoring components of Central Hudsonreview.
In finding petitioners liable for deceptive ads, the Commission determined that petitioners’ efficacy and establishment claims were misleading because they were unsubstantiated by RCTs. We have upheld that approach in this opinion. Requiring RCT substantiation as a forward-looking remedy is perfectly commensurate with the Commission’s assessment of liability for petitioners’ past conduct: if past claims were deceptive in the absence of RCT substantiation, requiring RCTs for future claims is tightly tethered to the goal of preventing deception. To be sure, the liability determination concerned claims about three specific diseases whereas the remedial order encompasses claims about any disease. But that broadened scope is justified by petitioners’ demonstrated propensity to make deceptive representations about the health benefits of their products, and also by the expert testimony support*135ing the necessity of RCTs to establish causation for disease-related claims generally. SeeFTC Op. at 22, 35-36. For purposes of Central Hudsonscrutiny, then, the injunctive order’s requirement of someRCT substantiation for disease claims directly advances, and is not more extensive than necessary to serve, the interest in preventing misleading commercial speech.
We reach the opposite conclusion insofar as the remedial order mandates twoRCTs as an across-the-board requirement for any disease claim. Central Hudson“requires something short of a least-restrictive-means standard,” Board of Trustees v. Fox,492 U.S. 469, 477,109 S.Ct. 3028,106 L.Ed.2d 388(1989), but the Commission still bears the burden to demonstrate a “reasonable fit” between the particular means chosen and the govern ment interest pursued, id.at 480,109 S.Ct. 3028. See Am. Meat Inst. v. U.S. Dep’t of Agric.,760 F.3d 18, 26-27 (D.C.Cir.2014) (en banc). Here, the Commission fails adequately to justify a categorical floor of two RCTs for any and all disease claims. It of course is true that, all else being equal, two RCTs would provide more reliable scientific evidence than one RCT, affording added assurance against misleading claims. It is equally true that three RCTs would provide more certainty than two, and four would yield more certainty still. But the Commission understandably does not claim a myopic interest in pursuing scientific certitude to the exclusion of all else, regardless of the consequences.
Here, the consequences of mandating more than one RCT bear emphasis. Requiring additional RCTs without adequate justification exacts considerable costs, and not just in terms of the substantial resources often necessary to design and conduct a properly randomized and controlled human clinical trial. If there is a categorical bar against claims about the disease-related benefits of a food product or dietary supplement in the absence of two RCTs, consumers may be denied useful, truthful information about products with a demonstrated capacity to treat or prevent serious disease. That would subvert rather than promote the objectives of the commercial speech doctrine. See Edenfield,507 U.S. at 766,113 S.Ct. 1792.
Consider, for instance, a situation in which the results of a large-scale, perfectly designed and conducted RCT show that a dietary supplement significantly reduces the risk of a particular disease, with the results demonstrated to a very high degree of statistical certainty (i.e., a very low p-value) — so much so that experts in the relevant field universally regard the study as conclusively establishing clinical proof of the supplement’s benefits for disease prevention. Perhaps, moreover, a wealth of medical research and evidence apart from RCTs — e.g., observational studies— reinforces the results of the blue-ribbon RCT. In that situation, there would be a substantial interest in assuring that consumers gain awareness of the dietary supplement’s benefits and the supporting medical research (and without any qualifiers stating, misleadingly, that the evidence is “inconclusive,” see suprap. 38). After all, as the Food and Drug Administration has explained in past guidance to the industry, “[a] single large, well conducted and controlled clinical trial could provide sufficient evidence to establish a substance/disease relationship, provided that there is a supporting body of evidence from observational or mechanistic studies.” U.S. Food & Drug Admin., Guidance for Industry: Significant Scientific Agreement in the Review of Claims for Conventional Foods and Dietary Supplements5 (Dec.1999),1999 WL 33935287(withdrawn 2009).
*136The two-RCT requirement in the Commission’s order brooks no exception for those circumstances. No matter how robust the results of a completed RCT, and no matter how compelling a battery of supporting research, the order would always bar any disease-related claims unless petitioners clear the magic line of two RCTs. The Commission has elsewhere explained to industry advertisers that, “[i]n most situations, the quality of studies will be moi-e important than quantity.” U.S. Fed. Trade Comm’n, Dietary Supplements: An Advertising Guide for Industry10 (Apr.2001), available athttp://www. business.ftc.gov/documents/bus09-dietary-supplements-advertising-guideindustry.
The blanket, two-RCT substantiation requirement at issue here is out of step with that understanding.
The Commission fails to demonstrate how such a rigid remedial rule bears the requisite “reasonable fit” with the interest in preventing deceptive speech. Fox,492 U.S. at 480,109 S.Ct. 3028; see also Am. Meat Inst.,760 F.3d at 26. In the liability portion of its opinion, the Commission went to great lengths to explain why RCTs, rather than less demanding studies, are required to substantiate the sorts of causal claims petitioners asserted in the past. But the Commission stressed that it “need not, and does not, reach the question of the number of RCTs needed to substantiate the claims made.” FTC Op. at 3. The Commission nonetheless imposed a categorical, two-RCT substantiation requirement in the remedial portion of its opinion. Id.at 61. As justification for that decision, the Commission tendered two grounds, in a brief, five-sentence explanation. Neither of the grounds (nor both together) adequately justifies the Commission’s blanket two-RCT requirement.
First, the Commission asserts that a two-RCT requirement is consistent with its precedent. The fact that the Commission may have imposed a remedy in the past, however, does not necessarily establish the closeness of its fit to a new set of facts. And here, we view the Commission’s history with a two-RCT remedy to cut against, not in favor of, its imposition of a two-RCT requirement for all disease claims. It is true that this Court observed, almost thirty years ago, that the “FTC has usually required two well-controlled clinical tests” before certain “nonspecific establishment claim[s] may be made.” Thompson Med. Co.,791 F.2d at 194. But all of the cases cited in support of that observation, like Thompsonitself, involved a highly specific type of representation: establishment claims about the comparative efficacy of over-the-counter analgesics. See Sterling Drug, Inc.,741 F.2d at 1152-53; Bristol-Myers Co. v. FTC,738 F.2d 554, 558-59 (2d Cir.1984); Am. Home Prods. Corp.,695 F.2d at 691-93. The decision to require two well-controlled clinical studies was confined to a particular type of claim about a particular product — the comparative ability of analgesics to afford pain relief. See, e.g., Thompson Med. Co.,791 F.2d at 192. And the decision came after extended analysis of considerations specific to that context. See Am. Home Prods. Corp.,98 F.T.C. at 201-06.
In particular, due to the subjective nature of pain sensitivity, the Commission concluded that “the elements of a well-controlled clinical trial” are especially important in the case of analgesics. Thompson Med. Co.,104 F.T.C. at 720. That is even more true in a “comparative drug trial,” in which the subjectivity of pain is compounded by the need to qualify the relative effect of two or more alternate treatments. See id.at 719-25. The Commission also found significant that FDA panels on analgesics (as well as the medical scientific community) “require[] repli*137cation of the results of a clinical test involving an analgesic drug.” Id.at 720-21. For all of those reasons, the Commission concluded that “[t]wo or more independently conducted, well-controlled clinical studies are required to establish the comparative efficacy of [over-the-counter] analgesics for the relief of mild to moderate pain.” Am. Home Prods. Corp.,98 F.T.C. at 201; see also Thompson Med. Co.,104 F.T.C. at 719. Rather than supporting the imposition of a two-RCT mandate as routinely necessary to prevent the misleading of consumers, Thompsonsuggests that the Commission has imposed two-RCT requirements only in narrow circumstances based on particularized concerns.
More recent Commission action does not demonstrate otherwise. After being asked at oral argument to identify two-RCT remedial orders other than those discussed in Thompson,the Commission produced a handful of examples in a post-argument submission. SeeFTC 28(j) Letter at 2 (May 5, 2014). Most of the examples are consent orders — entered without litigation or explanation of the Commission’s reasoning — providing little insight into why two RCTs would be required to prevent a claim from being misleading. See L’Occitane, Inc.,No. C-4445,2014 WL 1493613(U.S.Fed.Trade Comm’n Mar. 27, 2014); Dannon Co., Inc.,No. C4313,2011 WL 479884(U.S.Fed.Trade Comm’n Jan. 31, 2011); Nestle Healthcare Nutrition, Inc.,No. C-4312,2011 WL 188928(U.S.Fed. Trade Comm’n Jan. 12, 2011). The other examples impose two RCTs for only some subset of future claims, while requiring less support for other claims. See Schering Corp.,118 F.T.C. 1030, 1122-23 (1994) (requiring generally acceptable scientific evidence for some claims and two RCTs for others); Jerome Milton, Inc.,110 F.T.C. 104, 116 (1987) (requiring one RCT or generally acceptable scientific evidence for some claims and two RCTs for others).
Outside of those examples, several orders over the past decade require only “competent and reliable scientific evidence” — not necessarily RCTs, let alone two RCTs — to substantiate disease claims akin to those made by petitioners. See, e.g., Tropicana Prods., Inc.,140 F.T.C. 176, 184-85 (2005); Unither Pharma, Inc.,136 F.T.C. 145, 295-96 (2003). And in other recent orders, the Commission has imposed a one-RCT remedy. See, e.g., FTC v. Reebok Int’l Ltd.,No. 1:11-cv-02046-DCN, slip op. at 485-86 (N.D.Ohio Sept. 29, 2011). Indeed, in Removatronthe Commission itself modified an ALJ’s initial order to require one RCT rather than two.111 F.T.C. at 206. In short, the Commission’s precedents suggest that two-RCT remedial provisions are only selectively imposed in specific circumstances based on particular concerns.
The Commission observes that certain expert testimony in this case “recognized the need for consistent results in independently-replicated studies,” with one of its experts noting the possibility that the results of a single RCT “may be due to chance or may not be generalizable due to the uniqueness of the study sample.” FTC Op. at 51 (internal quotation marks omitted). But insofar as the results of any particular RCT may be suspect due to deficiencies in the sample or trial, the baseline requirement for health-related claims independently bars any representations unless supported by “competent and reliable scientific evidence that ... is sufficient to substantiate that the representation is true,” which in turn requires that a study be “generally accepted in the profession to yield accurate and rehable results.” FTC Final Order at 3. In any event, the Commission’s own expert testimony — as described by the Commission itself— weighs against imposing a categorical, two-RCT-substantiation requirement for all*138disease claims. As the Commission explained, expert testimony about the need for two RCTs was addressed to one particular disease, whereas one RCT could suffice for the other two examined diseases: “experts testified that two RCTs are necessary to substantiate the heart disease claims at issue, while the prostate cancer and ED claims can be substantiated with at least one RCT.” FTC Op. at 3. The Commission nonetheless imposed a categorical, two-RCT requirement for alldisease claims, regardless of the quality of any single RCT or the strength of other medical evidence.
Finally, the Commission justifies its two-RCT requirement on the ground that petitioners “have a demonstrated propensity to misrepresent to their advantage the strength and outcomes of scientific research” and “have engaged in a deliberate and consistent course of conduct.” Id.at 51. But by definition, every party subjected to a final FTC order has been found to have engaged in some unlawful advertising practice. The Commission does not explain how the two-RCT requirement is reasonably linked to the particular history of petitioners’ wrongdoing. The Commission does highlight petitioners’ history of selectively drawing on favorable studies while disregarding unfavorable results. Id.at 49. To the extent the two-RCT remedy aims to prevent petitioners from misleadingly highlighting favorable results alone, however, the order separately requires petitioners to base any representations on “competent and reliable scientific evidence that, when considered in light of the entire body of relevant and reliable scientific evidence,is sufficient to substantiate that the representation is true.” FTC Final Order at 2 (emphasis added). With that baseline already established by the order, the contribution of the two-RCT requirement to the order’s effectiveness in this regard is far from clear.
For those reasons, we hold that the Commission’s order is valid to the extent it requires disease claims to be substantiated by at least one RCT. But it fails Central Hudsonscrutiny insofar as it categorically requires two RCTs for all disease-related claims. That is not at all to say that the Commission would be barred from imposing a two-RCT-substantiation requirement in any circumstances. See Thompson Med. Co.,791 F.2d at 193-96. Rather, the Commission has failed in this case adequately to justify an across-the-board two-RCT requirement for all disease claims by petitioners.
* ❖ ❖ * * ❖
For the foregoing reasons, Part I of the Commission’s remedial order will be modified to require petitioners to possess at least one RCT before making disease claims covered by that provision and, as modified, enforced. We deny the petition for review in all other respects.
So ordered.
| https://opencasebook.org/documents/5576/ |
What’s for Dinner? – Week Starting 7 April 2018 - Paperblog
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What’s for Dinner? – Week Starting 7 April 2018
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What’s For Dinner Button
People are forever asking how I manage everything with such a busy schedule. I love to cook, but I don’t always have time to do so in the manner I would like. This weekly journal is a way to keep it real and show that while my intentions are good, sometimes life and all of its activities get in the way of serving a delicious, home-cooked meal and that it is perfectly okay.
Saturday:After getting up at 5:30 AM to prep for an all-day dance competition, the last thing either Holly or I wanted to do when we got home was to cook dinner. Jim was busy working on finishing the basement floors along with his brother, so Holly and I stuck with leftovers and sandwiches. It wasn’t the greatest meal but it did the trick.
Sunday:Because I was home, I wanted to make something a bit extra for dinner tonight. So I threw a pork roast in the oven with various spices that eventually turned into homemade carnitas. Holly spiced up some black beans, and we served everything with queso fresco, avocado, fresh lime wedges, and a choice of corn or flour tortillas. It seems like a simple meal, but it is so flavorful and simply delicious.
Monday:Tonight was my brother-in-law’s last night with us. As a thank you for laying all of the flooring in our basement, Jim and I took him out to dinner while Holly was at dance class. We took him to our favorite local spot, which is always a hit with guests. The floors are wonderful, and so was the meal.
Tuesday:Holly does not request recipes very often, so when she does I try to accommodate her requests. This week, she asked me to make aMushroom and Wild Rice Soup. Since Tuesdays tend to be our meatless day, this was a perfect fit. It was good but bland. I would definitely add more spices to the soup and maybe a shot or two of Worcestershire sauce to liven things up a bit. Everyone else had no problems with it, so it wasn’t all bad.
Wednesday:I have been craving fried rice lately, but I never remember to make it unless I have a formal recipe in front of me. I saw this recipe forTriple Pork Fried Riceon Pinterest and knew I had to make it. With Holly at dance, it was the best night to do so. I must say that this was an amazing recipe. I ran out of soy sauce and did not have any chili garlic sauce on hand, both of which would have put this in the outstanding category. Even without all of the sauce though, it was flavorful and filling. The flavors blended well together, and the little pieces of bacon made it extra. I do plan to make it again because it was so yummy but this time with that chili garlic sauce.
Thursday:Thursdays tend to be the best nights for leftovers, so that is what we had. Leftover fried rice, leftover black beans from Sunday turned into quesadillas – there was a little something for everyone without being bland with the added bonus of cleaning out my fridge.
Friday:Dinner was a quick bite out tonight, as we had to squeeze it in between Holly’s dance lessons and the beginning of a local high school production of Beauty and the Beast. Several of Holly’s fellow tap class students are in the musical, and it was important to Holly to support them. Plus, this high school’s theater program is AH-mazing; their productions of anything are can’t miss. So, Holly brought a friend, and all four of us watched the opening night after grabbing a quick bite of fast food before we hit the theater. Not necessarily what I wanted for dinner but needs must.
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What was for dinner at your house this week?
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| https://en.paperblog.com/what-s-for-dinner-week-starting-7-april-2018-1848749/ |
The Oxford Oratory
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A sanctuary in the midst of the city
The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman.
Saturday 24 June 2023
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Congratulations to Andrew and Nina, baptised this morning!
Today, the birthday of St John the Baptist, is a fitting day to baptise, and not just because he is famous for baptising people. His birth marks the end of the Old Testament and the beginning of the New. Today is about looking forward to the future. Baptism can sometimes feel like an ending after the period of preparation and catechesis, but it is of course only the beginning of the Christian life. The big work lies before us. As St Philip used to say, “The great thing is to become saints.”
#oxfordoratory
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Yesterday we welcomed Fr William Pearsall of the Society of Jesus to preach for the feast of St Aloysius.
“What Aloysius did is what many saints have done — many who are condemned for not being useful. They explored the frontiers of the spiritual life. They were heroic in the sense that those who went to the North Pole or the South Pole or climbed the highest mountains, they were heroic… They were heroic because they were living with the discovery of God and how the limits between nature and grace will always be an expanding horizon.”
St Aloysius, pray for us!
#oxfordoratory
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Happy feast of St Aloysius!
Two relics of his are displayed this month in our relic chapel, including a letter bearing his signature.
#oxfordoratory
Flos paradisi
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Today we celebrate the great solemnity of the patron of our church: St Aloysius Gonzaga of the Society of Jesus. St Aloysius is, together with St Gabriel Possenti, patron of young people, students, and seminarians and thus was a natural choice as patron for our church in this university city. He is also the patron of our parish school and we entrust to his loving intercession all our children who are able to learn the love of God from his example. We have his shrine in the chapel of Our Lady of Oxford, his statue is there on the reredos, and his initials guide our eyes towards his heavenly home as we look up at the sanctuary ceiling. Our patrons are important — St Aloysius has been given to us in this parish by God, through his Church, to watch over us in a particular manner, to intercede for all those who live and worship here, and to encourage us in our own quest for holiness.
Born the eldest son of the Marquis of Castiglione, St Aloysius seemed destined for a life of political intrigue and secular affairs, but, as with St Ignatius before him, it was the lives of the saints that really captivated him and placed in his heart the desire to strive for something better. This was not some childish caprice; he had seen the reality of life at court with its violence, frivolity, and degradation of human dignity, and desired not only to turn his back on it, but to embrace with all his heart a life given wholly to God. He began in earnest, adopting severe penances and teaching the local children their catechism. Hearing about the missions of St Francis Xavier, he set his heart on becoming a Jesuit — much to the horror of his family.
Eventually, having not overcome family opposition but at least its concrete obstacles, and having renounced his rights of inheritance, he entered the Jesuit novitiate in Rome in 1585. He had much to learn and much to which to adapt himself, but whatever he had to do he simply did it with all his heart — trusting in the sure knowledge that God was at work. Would he have met St Philip in Rome? Concrete evidence is hard to find, though these two saints of Rome are often depicted in art. We know they had mutual friends and these no doubt would have told them of Rome’s Third Apostle and of the holy Jesuit novice. One can imagine St Aloysius on a novitiate walk popping in to the Chiesa Nuovato see Mister Father Philip whom all Rome spoke of and revered or of St Philip blessing a crowd of passing Jesuit novices and knowing the heart of one of them that would see them both in glory.
St Aloysius’ real work in Rome was that which St Philip had embarked upon at the beginning — the care of the sick and the destitute. When plague broke out he volunteered to go with the other novices to pick people off the streets, to wash them, to prepare them for the sacraments and care for their souls. At first, he admitted to his director St Robert Bellarmine, this revolted him, but he soon learnt to see the image of Christ in these people, and to love them, not only in caring for them, but in seeing Christ in them. Never one to enjoy good health, Aloysius himself fell ill of plague, and died at the age of 23 on 21 June 1591, just a few years before St Philip’s death.
When we look at images of St Aloysius we normally see a rather pale young man who looks like so many other sickly young saints, distinguished perhaps only by the great ruff that he wears about his neck. But he was more than that. He was a young man who bothered about God and thus about other people. He was not yet in his mid-twenties, when he had discovered that real freedom comes from serving God with all ones heart; that Christian love has to be lived in the real, strength-sapping, heart-breaking, service of others; that there is joy in taking people off the streets, washing them, bandaging their wounds and restoring them to the dignity that is theirs as children of God.
The image attached to these words is a depiction of St Aloysius in Milan in the Chiesa di Santa Maria presso San Satiro. The saint looks rather weak and malnourished, but what strength he has is used to hold up a man who is either dying or dead, with St Aloysius pressing the Cross to him and holding the man’s head up with his hands. The look on St Aloysius’ face is one, simply, of love — of love for God and neighbour, and of joy found in bringing the love of God to others. How much this young man, St Aloysius, still has left to teach us…
These reflections are sent out each Wednesday to all those on our mailing list.Click here to sign up to our mailing list, and receive our Sunday E-newsletter and these reflections straight to your inbox.
Friday 16 June 2023
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Heart of Jesus, all-holy! Fountain of all blessings, I adore thee, I love thee, and with a lively sorrow for my sins, I offer thee this poor heart of mine. Make me humble, patient, pure, and wholly obedient to thy will. Good Jesus, grant that I may live in thee and for thee. Protect me in the midst of danger; comfort me in my afflictions; give me health of body, assistance in my temporal needs, thy blessing on all that I do, and the grace of a holy death. Amen.
#oxfordoratory
Thursday 15 June 2023
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A photo from Sunday’s Solemn Mass for Corpus Christi.
#oxfordoratory
June Music
Sunday 4 JuneSolemn Mass 11:00
The Most Holy Trinity
Kyrie Mundy
Missa Euge bone Tye
Libera nos Sheppard
Honor, virtus et potestas Tallis
Sunday 11 JuneSolemn Mass 11:00
Corpus Christi
Missa Pange lingua Josquin
Lauda Sion Palestrina
Oculi omnium Byrd
Friday 16 JuneSolemn Mass 18:00
The Most Sacred Heart of Jesus
Missa Dormendo un giorno Guerrero
Improperium Palestrina
Sancte Deus Tallis
Sunday 18 JuneSolemn Mass 11:00
11th Sunday of the Year
Missa Brevis in F Op.117 Rheinberger
Benedicam Dominum Victoria
Salve Regina Poulenc
Wednesday 21 JuneSolemn Mass 18:00
St Aloysius Gonzaga
Missa O quam gloriosum Victoria
Justitiae Domini A Scarlatti
O bone Jesu Anchieta
Sunday 25 JuneSolemn Mass 11:00
12th Sunday of the Year
Missa Repleatur os meum Palestrina
Perfice gressus meos Lassus
Homo quidam fecit coenam magnam Mouton
Thursday 29 JuneSolemn Mass 18:00
St Peter and St Paul
Missa Petre ego pro te rogavi Lobo
Petre ego pro te rogavi Guerrero
Janitor caeli Ortiz
The Sacred Heart
Love is a funny thing. Materialists will tell us that it is purely the result of a series of electro-chemical responses in the brain, and yet others will tell us that it is the result of fate, the conspiracy of the alignment of the planets or the times we find ourselves in. The heart has long been understood as the centre of a person, a place of knowledge as much as will. It makes us do unreasonable things like acts of unwarranted kindness and altruism and by the edge of its blade we can be hurt in ways that we just can’t speak about. And yet none of these express what love is in itself — only God does that.
On Friday we venerate the Heart of our Lord as the symbol of his human love in which God’s divine love is revealed to us. In most of the prayers to or the meditations on the Sacred Heart, even those very ancient prayers, the woundedness of our Lord’s heart comes to the fore. That heart pierced with a lance and bruised with outrages and blasphemies is a stark and realistic image of the extent to which Christ loves us. Christ, who is the image of the unseen God, the Icon of the Father, shows us precisely what God’s love for us looks like. And it looks like a heart pierced and bruised on account of our sins, yet burning with ardent love for you and for me. This divine love is not for softies.
The time when we celebrate this feast is very fitting. We have come to the end of the Church’s celebration of the mysteries of our redemption: the Passion, the Cross, the Resurrection, the Ascension, Pentecost, the Feast of the Blessed Trinity and Corpus Christi. But today we commemorate the divine-human love which motivated them all. In adoring the Sacred Heart, we adore the totality of Christ’s saving work — it represents the way in which God holds nothing back from us. And in order to share his divine life with us, he reaches down into the very depths of our life, even — and especially — where it is painful, difficult to speak of, hidden. By taking it all and joining it to himself, he scoops us up, he enables us to become like him. By sharing our life, and by sharing our pains, he heals us, he sanctifies us, and he strengthens us.
It is also true that his heart welcomes us precisely so that we might become like it. The whole thrust of our Christian life is that we might be conformed to our Saviour, that we might resemble him, and in this sense, in the life of faith, we should ask ourselves continually whether our heart resembles his. His Sacred Heart is both the example and the cause of our becoming like him. His love is attractive. The more we consider the love with which Jesus acted, and spoke and gave of himself for us, the more we can begin, by his grace, to imitate him — it is truly the school of Christian perfection.
And we begin in that school by prayer. When St John Henry Newman, our Cardinal, chose his motto, he looked to St Francis de Sales’ Treatise on the Love of God. The phrase he chose and paraphrased, Cor ad Cor loquiturrepresents for us the central mystery of the prayer that can begin to transform us. St Francis de Sales wrote:
Truly the chief exercise in mystical theology is to speak to God and to hear God speak in the bottom of the heart; and because this discourse passes in most secret aspirations and inspirations, we term it a silent conversing. Eyes speak to eyes, and heart to heart, and none understand what passes save those who speak.
We may be no great shakes at the spiritual life, or prayer, or we may feel that excelling in virtue is beyond us, but if we can in the simplest of ways open our poor heart to his Sacred Heart, and speak to him as to a friend, if we can entrust our lives to him and ask him devoutly and sincerely to shape us after the model of his Heart, then our Christian life will be all the more graced.
Tuesday 13 June 2023
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The Corpus Christi procession concluded with Benediction at the University Chaplaincy. #oxfordoratory
Tuesday 13 June 2023
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The procession finished at the University’s Catholic Chaplaincy. #oxfordoratory
Tuesday 13 June 2023
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The numbers caught the attention of the local media:
https://www.oxfordmail.co.uk/news/23582016.oxfords-catholic-congregations-take-part-corpus-christi-procession/
#oxfordoratory
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Children scattered flower petals before the Blessed Sacrament all the way. #oxfordoratory
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Our route now passes through the city in a straight line, taking us directly through the busiest shopping areas. #oxfordoratory
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The canopy was carried by members of the University of Oxford wearing their academic dress. #oxfordoratory
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Fr Robert Ombres OP preached a sermon. #oxfordoratory
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We paused at Blackfriars. #oxfordoratory
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We were joined by local clergy and religious orders as we processed through the streets to the Dominican Priory at Blackfriars. #oxfordoratory
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The processions sets off… #oxfordoratory
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We had record numbers for the procession this year. There wasn’t space in church for everyone at the beginning! There were more people outside too. #oxfordoratory
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The beginning of our Corpus Christi procession last Sunday.
#oxfordoratory
| https://www.oxfordoratory.org.uk/campaign/blog/post/10007-10007/blog/post/9998-9998/funerals.php |
(PDF) Quantified analysis of long-term settlement trends in the northern Oman peninsula
PDF | This paper sets out a tentative quantified analysis of long-term trends in the settlement history of the northern Oman peninsula from prehistoric... | Find, read and cite all the research you need on ResearchGate
Conference Paper
Quantified analysis of long-term settlement trends in the northern Oman peninsula
January 2011
Conference: Proceedings of the Seminar for Arabian Studies
Volume: 41
Authors:
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N. S. AlJahwari
Sultan Qaboos University
Abstract and Figures
This paper sets out a tentative quantified analysis of long-term trends in the settlement history of the northern Oman peninsula from
prehistoric times to the Late Islamic period, based on published archaeological evidence.
Although the data set used is undeniably problematic, it is argued that despite the sheer quantity of available evidence, the
database will have ironed out at least some of the specific and localized problems that exist, and will therefore give a broadly
correct indication of general long-term trends. It is clear from both academic conversations and the published material that implicit
and unsystematic reviews of precisely this data set are regularly used by many scholars in impressionistic and non-rigorous ways
— especially as the basis for consensus opinions on trends in the relative density of activity and occupation in different periods.
Therefore, the opportunity has been taken here to put such comparisons on a firmer footing and to make them more explicit and
testable. The robustness of the data can — and should — then be debated.
The stability of some of the longer-term trends suggests that this data could be acceptable in low-grade analyses such as those
presented here. Nonetheless, caution must still be applied until the conclusions can be more rigorously tested.
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Defined sub-regions for the purpose of the analysis of the sites database. …
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…
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The relationship between the three tables within the regional database. …
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The physical structure of the Location table as it appears in its 'design view'. …
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+2
The physical structure of the Teams' table as it appears in its 'design view'. …
Figures - uploaded by
N. S. AlJahwari
The development of Northern Ras al-Khaimah and the 14th-century Hormuzi economic boom in the lower Gulf.
Article
Full-text available
Jan 2002
<here is a image 244b613328eaacb8-6d775f19d2cd4001> Derek Kennet
Stone Age Nomadism in SE Arabia: Palaeo-Economic Considerations on the Neolithic Site of Al-Buhais 18 in the Emirate of Sharjah
Article
M. Uerpmann
<here is a image 9fd464c07f587a47-0f2e8807cc7c8749> Hans-Peter Uerpmann
<here is a image 1af4da783893d315-81c4aad22d248299> Sabah A. Jasim
Agricultural decline in the Siraf region, Iran
Article
Jan 1974
Paleorient
Tony J. Wilkinson
The region around the 9th-llth century city of Siraf, Iran, is examined to show how intensive surveys can help in the assessment of the economic geography of archaeological sites. Agricultural land, much of it terraced, was found to spread over 6 km inland from the city occupying land which is shunned by modern cultivators. Frequently this land was stripped and fragmented by sheet or gully erosion but cultural remains enabled me original ground surfaces to be re-constructed The total area of Siraf period agricultural land manured from city refuse is represented cartographically and the resulting distribution is shown to be clustered around the city in response to both economic and physical controls. It is hoped that similar studies if applied to earlier archaeological sites may aid in the interpretation of site catchment analyses.
New results on the Neolithic jewellery from al-Buhais 18
Jan 2006
175-187
R Beauclair
Jasim S A De
H-P Uerpmann
Beauclair R. de, Jasim S.A. & Uerpmann H-P.
2006. New results on the Neolithic jewellery from al-Buhais 18, UAE. Proceedings of the Seminar for
Arabian Studies 36: 175–187.
The Hinterland of Sohar
Jan 1987
79-88
P M Costa
T J Wilkinson
Costa P.M. & Wilkinson T.J.
1987. The Hinterland of Sohar. Journal of Oman Studies 9: 79–88.
Archaeological proxy-data for demographic reconstructions: facts, factoids or fiction? Pages 65–76 in The Archaeology of Mediterranean landscapes. i. Reconstructing past population trends in Mediterranean Europe
J Chapman
Chapman J.
1999. Archaeological proxy-data for demographic reconstructions: facts, factoids or fiction? Pages 65–76 in
J. Bintliff & K. Sbonias (eds), The Archaeology of Mediterranean landscapes. i. Reconstructing past
population trends in Mediterranean Europe. Oxford: Oxbow.
The Prehistoric Graveyard of RaΜs Al Hamra 5
S Salvatori
A Coppa
A Cucina
Salvatori S., Coppa A. & Cucina A.
2007. The Prehistoric Graveyard of RaΜs Al Hamra 5, Muscat, Sultanate of Oman. Muscat: Ministry of
Heritage & Culture.
Neolithic Jewellery from Jebel al-Buhais 18
Jan 2000
137-146
H Kiesewetter
H-P Uerpmann
S A Jasim
Kiesewetter H., Uerpmann H-P. & Jasim S.A.
2000. Neolithic Jewellery from Jebel al-Buhais 18. Proceedings of the Seminar for Arabian Studies 30: 137–
146.
Five thousand years of settlement at Khatt
Jan 1994
35-95
B De Cardi
D Kennet
L Stocks
de Cardi B., Kennet D. & Stocks L.
1994. Five thousand years of settlement at Khatt, UAE. Proceedings of the Seminar for Arabian Studies 24:
35–95.
Oman in the Third Millennium BCE al-Jahwari N.S. 2008. Settlement patterns, development and cultural change in northern Oman Peninsula: A multi-tiered approach to the analysis of long-term settlement trends A field methodology for the quantification of ancient settlement in an Arabian context
Jan 1975
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A Hastings
J H Humphries
R H Meadow
Hastings A., Humphries J.H. & Meadow R.H.
1975. Oman in the Third Millennium BCE. Journal of Oman Studies 1: 9–55.
al-Jahwari N.S.
2008. Settlement patterns, development and cultural change in northern Oman Peninsula: A multi-tiered
approach to the analysis of long-term settlement trends. PhD thesis, Durham University. [Unpublished].
Nasser Said al-Jahwari al-Jahwari N.S. & Kennet D.
2008. A field methodology for the quantification of ancient settlement in an Arabian context. Proceedings of
the Seminar for Arabian Studies 38: 203–214.
| https://www.researchgate.net/publication/255716705_Quantified_analysis_of_long-term_settlement_trends_in_the_northern_Oman_peninsula |
Electric/Hybrid - How ?Green? are Electric Cars? - Renewable Energy Magazine, at the heart of clean energy journalism
How ‘Green’ are Electric Cars?
The International Energy Agency predicts that by 2030, 125 million electric vehicles will be owned around the world. In the US, 14 new models of electric trucks and SUVs are expected to launch this year, which automakers say could appeal more to American consumers than the smaller electric vehicles seen elsewhere.
Biden has also pledged to convert the entire federal government's fleet (around 650,000 vehicles) to electric, and has promised that every US-made bus will be battery-powered by 2030.But just how green are they?Electric cars are undoubtedly cleaner than fossil fuel run cars. Although more energy is required to make electric vehicles than gas-powered, you still save more energy in the long run. The deficit is paid off quickly and even, when with no alternative, the electricity used to charge the vehicles is driven by fossil fuels, they are still greener.However, it is important to address the huge implications for our natural resources not only to produce green technologies like electric cars, but to keep them charged.ChallengesCurrently, electric cars rely on lithium and cobalt batteries to run, which is undoubtedly better for the environment than carbon, but isn’t entirely clean.Cobalt miningCobalt is a key ingredient in the lithium-ion batteries that power electric cars, because it enables the energy density required in batteries intended to last for hundreds of miles per charge.Lithium-ion batteries used in electric cars and other consumer electronics account for about half of all cobalt demand, and the demand for these batteries is projected to more than quadruple over the next decade.However, the mining of cobalt is fraught with political issues. Sixty percent of cobalt comes from the Dominican Republic of Congo where children as young as seven are mining it. The mining process also causes terrible pollution in local rivers.Lithium miningIn 2019, Australia was responsible for more than half of global lithium supply, with the bulk of the rest supplied by Chile, China and Argentina. Lithium deposits are also located near some of the most sensitive ecosystems in the world – The Amur River, on the border of Russia and China, the Andes Mountains (Chile) and the Salt Flats in Bolivia. Deforestation, water shortages and toxic leaks are unfortunately a devastating consequence of lithium mining. Lithium extraction in salt flats in Bolivia uses millions of liters of water.Prof. Richard Herrington, Head of Earth Sciences Department, Natural History Museum said, “Society needs to understand that there is a raw material cost of going green and that both new research and investment is urgently needed for us to evaluate new ways to source these. This may include potentially considering sources much closer to where the metals are to be used.”RecyclingResearch in Australia found that only 2% of the country’s 3,300 tons of lithium-ion waste was recycled. Because lithium cathodes degrade over time, they can’t simply be placed into new batteries. “That’s the problem with recycling any form of battery that has electrochemistry – you don’t know what point it is at in its life,” says Stephen Voller, CEO and founder of ZapGo. “That’s why recycling most mobile phones is not cost effective. You get this sort of soup.”At present, there are low volumes of electric-vehicle batteries that require recycling. As these volumes increase dramatically, there are questions concerning the economies (and diseconomies) of scale in relation to recycling operations.Charging inefficiencyOne of the biggest challenges is the installation of charging points. We need more, faster, more reliable charge points for people to be persuaded to take the plunge and purchase electric. Cars also need to be charged at smart times of day to avoid unnecessary costs for energy networks (and ultimately the consumers who pay for them).SolutionsAlternative mineral resourcesWe either need to find alternative sources of cobalt and lithium (e.g. the ocean), increase the pace of recycling, or ideally need to shift to batteries that use less, or none at all. Elon Musk’s car firm Tesla will make electric vehicle batteries with cobalt-free cathodes, it announced during its Battery Day event last Fall, but there is no set timeline on this yet.For short-range cars made and sold in China, Reuters says Tesla will instead use lithium-iron-phosphate batteries, which are much cheaper and don’t have the same environmental problems as those needing cobalt. The disadvantage is that these batteries tend to have a lower energy density, reducing how far a car can drive without needing to charge.Lithium-iron-phosphate batteries are already widely used by other Chinese firms, including BYD, the world’s biggest electric car manufacturer. If other electric car manufacturers follow internationally, we may be able to reduce our dependency on a dwindling mineral resource.Sourcing locallyThe USA currently imports most of the lithium it uses, which is costly, both economically and environmentally however, lithium production in Nevada is set to expand this year to tackle this issue, through looking into other resources to extrapolate lithium from things like clay.Biden also has plans to support domestic production of metals such as lithium, copper, nickel and other materials used to make electric vehicles, solar panels and green technologies, crucial to his $2 trillion climate plan.Environmentalists are crossing their fingers that improvements such as this will also provide water protection.Recycling researchIn the UK, researchers are using robotics technology developed for nuclear power plants to find ways to safely remove and dismantle potentially explosive lithium-ion cells from electric vehicles.A number of improvements could make the recycling processes economically more efficient, such as better sorting technologies, a method for separating electrode materials, greater process flexibility, design for recycling, and greater manufacturer standardization of batteries.Battery swap shopsChina, with electric vehicle sales of more than one million a year, is demonstrating how the charging issues can be addressed with battery ‘swap shops’ in which owners can drive into forecourts and swap batteries quickly. NIO, the Shanghai-based car manufacturer, claims a three-minute swap time at these stations.This also addresses the high cost of EVs currently. By using the swap concept, the battery could be rented, with part of the swap cost being a fee for rental.Electric alternativesIt’s the electric vehicles that have taken off in the world of green automotives. However, there is another player in the field - hydrogen. Hydrogen cars are powered by a chemical reaction. Hydrogen enters the fuel cell from a tank and mixes with oxygen to create H 2O, which generates electricity that is used to power the motors that drive the wheels.Hydrogen tanks are refueled in a process that’s pretty much the same as with a gasoline powered car. You could fill your car up just like fossil fuel, but instead of greenhouse gases being emitted, the exhaust would just be pure water vapor. Compared to waiting around for an EV’s battery to recharge, hydrogen appears to be the much more convenient option.The challenge is that hydrogen is very energy intensive to create as converting the electricity to hydrogen via electrolysis is only 75% efficient. Then the gas has to be compressed, chilled and transported, which loses another 10%. The fuel cell process of converting hydrogen back to electricity is only 60% efficient, after which you have the same 5% loss from driving the vehicle motor as for a BEV. The grand total is a 62% loss in energy – more than three times as much as an electric car.Nevertheless, hydrogen still has niches where its main strengths – lightness and quick refueling – give it a clear advantage. While you can fit your personal driving lifestyle around strategic battery charging stops, this is not ideal for commercial vehicles such as trains that need to run for very long periods and distances with only short waits to refuel. The weight of batteries for eight hours of continual usage would also be prohibitive for these vehicles. Therefore, hydrogen could be a viable option, despite the inefficiency.About the author:Sophie Johnson is a 26 year old Zoology graduate and passionate environmental and conservation blogger from the UK. Her blog site isbornwildstaywild.wordpress.comand her posts are both her own writing and interviews on a variety of sustainability topics.
Tags: Hydrogen , Hydro , Recycling , Electric vehicle , Fuel , China , Electricity , Australia , Fuel cell , Efficiency , International Energy Agency , Nuclear , Ocean , Argentina , SAF , Solar , Sustainability , Transport , Waste , Wind , Carbón
Martin
"...potentially explosive lithium-ion cells from electric vehicles." Where on Earth did you get this sensationalistic clap-trap from? Even if the cells were fully charged at the time of recycling, they are not little sticks of dynamite! The very worst they would do is \'catch fire\' albeit quite quickly if directly shorted. The sudden discharge of electrical energy might also cause a degree of \'plasma event\' serious arcing. In reality only a complete twit would attempt to recycle *any* battery when charged, let alone fully so. The simplest way to effect safe handling would be to soak the cells in salt water for 24 hours or so. So, there would be no \'bang\', \'pop\' or even a \'whimper\'... nothing. A real disapointment to an otherwise reasonably well-researched piece.
| https://www.renewableenergymagazine.com/electric_hybrid_vehicles/how-a-greena--are-electric-cars-20210311 |
08:23:00.073, 2018-04-02 08:23:00.710, 0.637, 0.000000, -0.000002063509, 0.000000273639, 0.000002333981, -0.7765475511550903, -0.0172888766974211, -0.5471662282943726, 0.3119040429592133, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 61, 0, 0, 0, 0, 100, 68, 0, 0, 0, 0, 0, 0, 37744096703657
1304, R, 2018-04-11 03:19:05, 2018-04-02 08:23:00.073, 2018-04-02 08:23:00.807, 0.734, 0.000000, 0.000000439681, 0.000000418209, -0.000001648531, -0.7765476107597351, -0.0172920543700457, -0.5471649765968323, 0.3119058907032013, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744096710058
1305, R, 2018-04-11 03:19:05, 2018-04-02 08:23:00.073, 2018-04-02 08:23:06.506, 6.434, 0.000000, 0.000000792753, 0.000000019476, 0.000000394830, -0.7765542268753052, -0.0172901302576065, -0.5471583008766174, 0.311901181936264, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097083561
1306, R, 2018-04-11 03:19:05, 2018-04-02 08:23:06.073, 2018-04-02 08:23:06.608, 0.535, 0.000000, 0.000000792753, 0.000000019465, 0.000000394831, -0.7765505313873291, -0.0172892138361931, -0.5471633672714233, 0.3119016587734222, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097090218
1307, R, 2018-04-11 03:19:05, 2018-04-02 08:23:06.073, 2018-04-02 08:23:06.710, 0.637, 0.000000, 0.000000792753, 0.000000019456, 0.000000394831, -0.7765474915504456, -0.0172879155725241, -0.547167181968689, 0.3119025826454163, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097096873
1308, R, 2018-04-11 03:19:05, 2018-04-02 08:23:06.073, 2018-04-02 08:23:06.807, 0.734, 0.000000, 0.000000792752, 0.000000019451, 0.000000394832, -0.7765448093414307, -0.0172887425869703, -0.54716956615448, 0.3119049370288849, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097103274
1309, R, 2018-04-11 03:19:05, 2018-04-02 08:23:06.073, 2018-04-02 08:23:06.905, 0.832, 0.000000, 0.000000792752, 0.000000019447, 0.000000394834, -0.7765432596206665, -0.0172893535345793, -0.5471715331077576, 0.3119053244590759, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097109673
1310, R, 2018-04-11 03:19:05, 2018-04-02 08:23:06.073, 2018-04-02 08:23:07.006, 0.934, 0.000000, 0.000000792750, 0.000000019443, 0.000000394837, -0.7765419483184814, -0.0172902420163155, -0.5471740961074829, 0.3119041323661804, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097116329
1311, R, 2018-04-11 03:19:05, 2018-04-02 08:23:06.073, 2018-04-02 08:23:07.108, 1.035, 0.000000, -0.000002072540, 0.000000275444, 0.000002338017, -0.7765405178070068, -0.0172900054603815, -0.5471765995025635, 0.3119032382965088, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 59, 0, 0, 0, 0, 100, 66, 0, 0, 0, 0, 0, 0, 37744097122986
1312, R, 2018-04-11 03:19:05, 2018-04-02 08:23:07.073, 2018-04-02 08:23:07.210, 0.137, 0.000000, 0.000000439702, 0.000000418223, -0.000001648522, -0.7765406370162964, -0.0172924213111401, -0.5471751093864441, 0.3119053840637207, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744097129642
1313, R, 2018-04-11 03:19:05, 2018-04-02 08:23:07.073, 2018-04-02 08:23:12.905, 5.832, 0.000000, 0.000000792754, 0.000000019460, 0.000000394829, -0.7765512466430664, -0.0172851700335741, -0.5471655130386353, 0.3118962645530701, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097502889
1314, R, 2018-04-11 03:19:05, 2018-04-02 08:23:12.073, 2018-04-02 08:23:13.006, 0.934, 0.000000, 0.000000792753, 0.000000019449, 0.000000394832, -0.7765477895736694, -0.0172849837690592, -0.5471706390380859, 0.3118959963321686, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097509545
1315, R, 2018-04-11 03:19:05, 2018-04-02 08:23:12.073, 2018-04-02 08:23:13.108, 1.035, 0.000000, 0.000000792752, 0.000000019441, 0.000000394833, -0.7765447497367859, -0.0172848273068666, -0.547174334526062, 0.3118970096111298, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097516202
1316, R, 2018-04-11 03:19:05, 2018-04-02 08:23:13.073, 2018-04-02 08:23:13.210, 0.137, 0.000000, 0.000000792752, 0.000000019435, 0.000000394833, -0.7765425443649292, -0.0172841958701611, -0.5471771955490112, 0.3118975460529327, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097522858
1317, R, 2018-04-11 03:19:05, 2018-04-02 08:23:13.073, 2018-04-02 08:23:13.307, 0.234, 0.000000, 0.000000792752, 0.000000019430, 0.000000394834, -0.7765404582023621, -0.0172838550060987, -0.5471795797348022, 0.3118984997272491, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097529258
1318, R, 2018-04-11 03:19:05, 2018-04-02 08:23:13.073, 2018-04-02 08:23:13.409, 0.336, 0.000000, 0.000000792752, 0.000000019429, 0.000000394834, -0.776539146900177, -0.0172851271927357, -0.5471795201301575, 0.311901867389679, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097535914
1319, R, 2018-04-11 03:19:05, 2018-04-02 08:23:13.073, 2018-04-02 08:23:13.506, 0.434, 0.000000, -0.000002081541, 0.000000277265, 0.000002342077, -0.776538074016571, -0.0172855351120234, -0.5471811890602112, 0.3119015991687775, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 57, 0, 0, 0, 0, 100, 64, 0, 0, 0, 0, 0, 0, 37744097542313
1320, R, 2018-04-11 03:19:05, 2018-04-02 08:23:13.073, 2018-04-02 08:23:13.608, 0.535, 0.000000, 0.000000439702, 0.000000418215, -0.000001648524, -0.7765383124351501, -0.0172868762165308, -0.5471805334091187, 0.3119021058082581, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744097548970
1321, R, 2018-04-11 03:19:05, 2018-04-02 08:23:13.073, 2018-04-02 08:23:19.307, 6.234, 0.000000, 0.000000792753, 0.000000019453, 0.000000394831, -0.7765508890151978, -0.0172837618738413, -0.5471689701080322, 0.3118911385536194, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097922474
1322, R, 2018-04-11 03:19:05, 2018-04-02 08:23:19.073, 2018-04-02 08:23:19.409, 0.336, 0.000000, 0.000000792753, 0.000000019444, 0.000000394832, -0.7765465974807739, -0.0172838531434536, -0.547173023223877, 0.3118947446346283, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097929130
1323, R, 2018-04-11 03:19:05, 2018-04-02 08:23:19.073, 2018-04-02 08:23:19.506, 0.434, 0.000000, 0.000000792752, 0.000000019435, 0.000000394833, -0.7765437364578247, -0.0172830000519753, -0.5471770167350769, 0.3118949234485626, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097935529
1324, R, 2018-04-11 03:19:05, 2018-04-02 08:23:19.073, 2018-04-02 08:23:19.608, 0.535, 0.000000, 0.000000792752, 0.000000019429, 0.000000394835, -0.7765412926673889, -0.0172834042459726, -0.5471800565719604, 0.3118956387042999, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097942186
1325, R, 2018-04-11 03:19:05, 2018-04-02 08:23:19.073, 2018-04-02 08:23:19.710, 0.637, 0.000000, 0.000000792751, 0.000000019424, 0.000000394837, -0.7765392661094666, -0.0172841381281614, -0.5471825003623962, 0.3118963241577148, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097948841
1326, R, 2018-04-11 03:19:05, 2018-04-02 08:23:19.073, 2018-04-02 08:23:19.807, 0.734, 0.000000, 0.000000792750, 0.000000019422, 0.000000394838, -0.7765377163887024, -0.0172852389514446, -0.5471837520599365, 0.3118979036808014, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744097955242
1327, R, 2018-04-11 03:19:05, 2018-04-02 08:23:19.073, 2018-04-02 08:23:19.909, 0.836, 0.000000, -0.000002077048, 0.000000276385, 0.000002340036, -0.7765365839004517, -0.0172867216169834, -0.5471851229667664, 0.3118982911109924, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 58, 0, 0, 0, 0, 100, 65, 0, 0, 0, 0, 0, 0, 37744097961897
1328, R, 2018-04-11 03:19:05, 2018-04-02 08:23:19.073, 2018-04-02 08:23:20.006, 0.934, 0.000000, 0.000000439722, 0.000000418206, -0.000001648521, -0.7765361666679382, -0.0172877293080091, -0.5471864938735962, 0.3118968605995178, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744097968297
1329, R, 2018-04-11 03:19:05, 2018-04-02 08:23:19.073, 2018-04-02 08:23:25.710, 6.637, 0.000000, 0.000000792752, 0.000000019445, 0.000000394834, -0.776542603969574, -0.0172887910157442, -0.5471727252006531, 0.3119048774242401, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098342057
1330, R, 2018-04-11 03:19:05, 2018-04-02 08:23:25.073, 2018-04-02 08:23:25.807, 0.734, 0.000000, 0.000000792751, 0.000000019437, 0.000000394835, -0.7765393257141113, -0.0172889567911625, -0.5471763014793396, 0.3119067251682281, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098348458
1331, R, 2018-04-11 03:19:05, 2018-04-02 08:23:25.073, 2018-04-02 08:23:25.909, 0.836, 0.000000, 0.000000792751, 0.000000019429, 0.000000394836, -0.7765364050865173, -0.0172884613275528, -0.5471798777580261, 0.3119077980518341, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098355113
1332, R, 2018-04-11 03:19:05, 2018-04-02 08:23:25.073, 2018-04-02 08:23:26.006, 0.934, 0.000000, 0.000000792751, 0.000000019422, 0.000000394837, -0.7765336036682129, -0.017288364470005, -0.5471831560134888, 0.311909019947052, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098361513
1333, R, 2018-04-11 03:19:05, 2018-04-02 08:23:25.073, 2018-04-02 08:23:26.108, 1.035, 0.000000, 0.000000792750, 0.000000019417, 0.000000394839, -0.776531994342804, -0.0172890461981297, -0.547185480594635, 0.3119090497493744, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098368170
1334, R, 2018-04-11 03:19:05, 2018-04-02 08:23:26.073, 2018-04-02 08:23:26.210, 0.137, 0.000000, 0.000000792749, 0.000000019412, 0.000000394841, -0.7765302062034607, -0.0172891654074192, -0.5471883416175842, 0.3119083046913147, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098374826
1335, R, 2018-04-11 03:19:05, 2018-04-02 08:23:26.073, 2018-04-02 08:23:26.307, 0.234, 0.000000, -0.000002068035, 0.000000274522, 0.000002335992, -0.7765286564826965, -0.0172891113907099, -0.5471903085708618, 0.3119088709354401, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 60, 0, 0, 0, 0, 100, 67, 0, 0, 0, 0, 0, 0, 37744098381226
1336, R, 2018-04-11 03:19:05, 2018-04-02 08:23:26.073, 2018-04-02 08:23:26.409, 0.336, 0.000000, 0.000000439723, 0.000000418248, -0.000001648510, -0.7765294909477234, -0.0172901432961226, -0.5471905469894409, 0.3119063079357147, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744098387882
1337, R, 2018-04-11 03:19:05, 2018-04-02 08:23:26.073, 2018-04-02 08:23:32.108, 6.035, 0.000000, 0.000000792752, 0.000000019437, 0.000000394834, -0.7765412926673889, -0.0172866582870483, -0.5471763014793396, 0.3119020760059357, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098761386
1338, R, 2018-04-11 03:19:05, 2018-04-02 08:23:32.073, 2018-04-02 08:23:32.210, 0.137, 0.000000, 0.000000792751, 0.000000019426, 0.000000394835, -0.7765377163887024, -0.0172858834266663, -0.5471811294555664, 0.3119025528430939, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098768042
1339, R, 2018-04-11 03:19:05, 2018-04-02 08:23:32.073, 2018-04-02 08:23:32.307, 0.234, 0.000000, 0.000000792751, 0.000000019418, 0.000000394837, -0.7765344977378845, -0.0172858294099569, -0.5471848845481873, 0.3119038939476013, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098774442
1340, R, 2018-04-11 03:19:05, 2018-04-02 08:23:32.073, 2018-04-02 08:23:32.409, 0.336, 0.000000, 0.000000792751, 0.000000019411, 0.000000394838, -0.776531994342804, -0.0172854885458946, -0.5471882224082947, 0.3119042813777924, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098781098
1341, R, 2018-04-11 03:19:05, 2018-04-02 08:23:32.073, 2018-04-02 08:23:32.506, 0.434, 0.000000, 0.000000792750, 0.000000019407, 0.000000394839, -0.7765305042266846, -0.0172858778387308, -0.5471901297569275, 0.311904639005661, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098787497
1342, R, 2018-04-11 03:19:05, 2018-04-02 08:23:32.073, 2018-04-02 08:23:32.608, 0.535, 0.000000, 0.000000792749, 0.000000019402, 0.000000394842, -0.776528537273407, -0.0172866806387901, -0.5471926927566528, 0.3119050562381744, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744098794154
1343, R, 2018-04-11 03:19:05, 2018-04-02 08:23:32.073, 2018-04-02 08:23:32.710, 0.637, 0.000000, -0.000002081559, 0.000000277246, 0.000002342063, -0.7765273451805115, -0.0172876846045256, -0.5471943020820618, 0.311905175447464, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 57, 0, 0, 0, 0, 100, 64, 0, 0, 0, 0, 0, 0, 37744098800809
1344, R, 2018-04-11 03:19:05, 2018-04-02 08:23:32.073, 2018-04-02 08:23:32.807, 0.734, 0.000000, 0.000000439730, 0.000000418254, -0.000001648507, -0.7765263915061951, -0.0172894243150949, -0.5471949577331543, 0.3119062781333923, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744098807210
1345, R, 2018-04-11 03:19:05, 2018-04-02 08:23:32.073, 2018-04-02 08:23:38.506, 6.434, 0.000000, 0.000000792751, 0.000000019434, 0.000000394836, -0.776538610458374, -0.0172887872904539, -0.5471779108047485, 0.311905711889267, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099180713
1346, R, 2018-04-11 03:19:05, 2018-04-02 08:23:38.073, 2018-04-02 08:23:38.608, 0.535, 0.000000, 0.000000792750, 0.000000019424, 0.000000394839, -0.7765354514122009, -0.0172885842621326, -0.5471829175949097, 0.3119048178195953, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099187370
1347, R, 2018-04-11 03:19:05, 2018-04-02 08:23:38.073, 2018-04-02 08:23:38.710, 0.637, 0.000000, 0.000000792749, 0.000000019415, 0.000000394842, -0.7765318155288696, -0.0172891933470964, -0.5471872687339783, 0.3119063675403595, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099194025
1348, R, 2018-04-11 03:19:05, 2018-04-02 08:23:38.073, 2018-04-02 08:23:38.807, 0.734, 0.000000, 0.000000792748, 0.000000019407, 0.000000394844, -0.7765299081802368, -0.0172886960208416, -0.5471911430358887, 0.3119041919708252, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099200426
1349, R, 2018-04-11 03:19:05, 2018-04-02 08:23:38.073, 2018-04-02 08:23:38.909, 0.836, 0.000000, 0.000000792747, 0.000000019403, 0.000000394845, -0.7765285968780518, -0.0172884799540043, -0.5471928715705872, 0.3119044005870819, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099207081
1350, R, 2018-04-11 03:19:05, 2018-04-02 08:23:38.073, 2018-04-02 08:23:39.010, 0.937, 0.000000, 0.000000792747, 0.000000019396, 0.000000394847, -0.7765267491340637, -0.0172881428152323, -0.5471962690353394, 0.3119032382965088, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099213737
1351, R, 2018-04-11 03:19:05, 2018-04-02 08:23:38.073, 2018-04-02 08:23:39.108, 1.035, 0.000000, -0.000002081570, 0.000000277259, 0.000002342052, -0.7765259742736816, -0.0172887034714222, -0.5471975207328796, 0.3119029104709625, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 57, 0, 0, 0, 0, 100, 64, 0, 0, 0, 0, 0, 0, 37744099220138
1352, R, 2018-04-11 03:19:05, 2018-04-02 08:23:39.073, 2018-04-02 08:23:39.210, 0.137, 0.000000, 0.000000439742, 0.000000418246, -0.000001648506, -0.7765256762504578, -0.0172899793833494, -0.5471981763839722, 0.3119024038314819, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744099226794
1353, R, 2018-04-11 03:19:05, 2018-04-02 08:23:39.073, 2018-04-02 08:23:44.909, 5.836, 0.000000, 0.000000792753, 0.000000019429, 0.000000394832, -0.776535153388977, -0.0172875225543976, -0.5471789836883545, 0.3119125664234161, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099600297
1354, R, 2018-04-11 03:19:05, 2018-04-02 08:23:44.073, 2018-04-02 08:23:45.010, 0.937, 0.000000, 0.000000792752, 0.000000019420, 0.000000394835, -0.7765318155288696, -0.0172882247716188, -0.5471833944320679, 0.3119130730628967, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099606953
1355, R, 2018-04-11 03:19:05, 2018-04-02 08:23:44.073, 2018-04-02 08:23:45.108, 1.035, 0.000000, 0.000000792752, 0.000000019414, 0.000000394835, -0.7765294909477234, -0.017287390306592, -0.5471863150596619, 0.311913937330246, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099613354
1356, R, 2018-04-11 03:19:05, 2018-04-02 08:23:45.073, 2018-04-02 08:23:45.210, 0.137, 0.000000, 0.000000792751, 0.000000019405, 0.000000394838, -0.7765265107154846, -0.0172875262796879, -0.5471907258033752, 0.3119134604930878, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099620010
1357, R, 2018-04-11 03:19:05, 2018-04-02 08:23:45.073, 2018-04-02 08:23:45.307, 0.234, 0.000000, 0.000000792750, 0.000000019401, 0.000000394840, -0.7765250205993652, -0.0172885041683912, -0.5471925735473633, 0.311913937330246, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099626410
1358, R, 2018-04-11 03:19:05, 2018-04-02 08:23:45.073, 2018-04-02 08:23:45.409, 0.336, 0.000000, 0.000000792750, 0.000000019399, 0.000000394840, -0.7765243053436279, -0.0172882229089737, -0.5471934676170349, 0.3119140863418579, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744099633066
1359, R, 2018-04-11 03:19:05, 2018-04-02 08:23:45.073, 2018-04-02 08:23:45.507, 0.434, 0.000000, -0.000002099581, 0.000000280787, 0.000002350177, -0.7765229940414429, -0.0172888375818729, -0.5471954941749573, 0.3119138479232788, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 53, 0, 0, 0, 0, 100, 60, 0, 0, 0, 0, 0, 0, 37744099639465
1360, R, 2018-04-11 03:19:05, 2018-04-02 08:23:45.073, 2018-04-02 08:23:45.608, 0.535, 0.000000, 0.000000439728, 0.000000418281, -0.000001648501, -0.7765231132507324, -0.0172918438911438, -0.5471956133842468, 0.3119130730628967, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744099646122
1361, R, 2018-04-11 03:19:05, 2018-04-02 08:23:45.073, 2018-04-02 08:23:51.307, 6.234, 0.000000, 0.000000792754, 0.000000019421, 0.000000394831, -0.7765364050865173, -0.0172824840992689, -0.5471826791763306, 0.311903178691864, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100019626
1362, R, 2018-04-11 03:19:05, 2018-04-02 08:23:51.073, 2018-04-02 08:23:51.409, 0.336, 0.000000, 0.000000792753, 0.000000019411, 0.000000394833, -0.776532769203186, -0.0172821544110775, -0.5471876263618469, 0.3119036257266998, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100026282
1363, R, 2018-04-11 03:19:05, 2018-04-02 08:23:51.073, 2018-04-02 08:23:51.507, 0.434, 0.000000, 0.000000792752, 0.000000019403, 0.000000394834, -0.7765293121337891, -0.0172825381159782, -0.5471910238265991, 0.3119062483310699, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100032681
1364, R, 2018-04-11 03:19:05, 2018-04-02 08:23:51.073, 2018-04-02 08:23:51.608, 0.535, 0.000000, 0.000000792752, 0.000000019397, 0.000000394836, -0.7765272259712219, -0.0172823891043663, -0.5471941232681274, 0.3119060099124908, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100039338
1365, R, 2018-04-11 03:19:05, 2018-04-02 08:23:51.073, 2018-04-02 08:23:51.710, 0.637, 0.000000, 0.000000792751, 0.000000019392, 0.000000394839, -0.7765256762504578, -0.0172832198441029, -0.5471966862678528, 0.3119054138660431, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100045993
1366, R, 2018-04-11 03:19:05, 2018-04-02 08:23:51.073, 2018-04-02 08:23:51.811, 0.738, 0.000000, 0.000000792749, 0.000000019387, 0.000000394842, -0.7765249013900757, -0.0172830168157816, -0.547199547290802, 0.3119023442268372, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100052649
1367, R, 2018-04-11 03:19:05, 2018-04-02 08:23:51.073, 2018-04-02 08:23:51.909, 0.836, 0.000000, -0.000002113103, 0.000000283572, 0.000002356242, -0.7765235304832458, -0.0172837451100349, -0.5472018122673035, 0.3119016587734222, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 50, 0, 0, 0, 0, 100, 57, 0, 0, 0, 0, 0, 0, 37744100059049
1368, R, 2018-04-11 03:19:05, 2018-04-02 08:23:51.073, 2018-04-02 08:23:52.010, 0.937, 0.000000, 0.000000439738, 0.000000418239, -0.000001648508, -0.7765238285064697, -0.0172844957560301, -0.5472020506858826, 0.3119003772735596, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744100065705
1369, R, 2018-04-11 03:19:05, 2018-04-02 08:23:51.073, 2018-04-02 08:23:57.710, 6.637, 0.000000, 0.000000792752, 0.000000019417, 0.000000394835, -0.776533842086792, -0.0172847006469965, -0.5471850633621216, 0.3119053840637207, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100439209
1370, R, 2018-04-11 03:19:05, 2018-04-02 08:23:57.073, 2018-04-02 08:23:57.811, 0.738, 0.000000, 0.000000792751, 0.000000019405, 0.000000394837, -0.7765296697616577, -0.0172839220613241, -0.5471909046173096, 0.3119055926799774, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100445865
1371, R, 2018-04-11 03:19:05, 2018-04-02 08:23:57.073, 2018-04-02 08:23:57.909, 0.836, 0.000000, 0.000000792751, 0.000000019397, 0.000000394838, -0.7765266299247742, -0.0172842983156443, -0.5471943020820618, 0.311907023191452, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100452265
1372, R, 2018-04-11 03:19:05, 2018-04-02 08:23:57.073, 2018-04-02 08:23:58.010, 0.937, 0.000000, 0.000000792749, 0.000000019391, 0.000000394842, -0.7765241265296936, -0.0172858573496342, -0.5471974611282349, 0.3119077086448669, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100458921
1373, R, 2018-04-11 03:19:05, 2018-04-02 08:23:57.073, 2018-04-02 08:23:58.108, 1.035, 0.000000, 0.000000792749, 0.000000019388, 0.000000394843, -0.776522696018219, -0.0172861497849226, -0.5471989512443542, 0.3119086921215057, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100465322
1374, R, 2018-04-11 03:19:05, 2018-04-02 08:23:58.073, 2018-04-02 08:23:58.210, 0.137, 0.000000, 0.000000792748, 0.000000019383, 0.000000394844, -0.7765211462974548, -0.0172857325524092, -0.5472015738487244, 0.3119078278541565, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100471978
1375, R, 2018-04-11 03:19:05, 2018-04-02 08:23:58.073, 2018-04-02 08:23:58.307, 0.234, 0.000000, -0.000002095085, 0.000000279934, 0.000002348137, -0.7765195369720459, -0.0172872934490442, -0.5472039580345154, 0.3119076490402222, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 54, 0, 0, 0, 0, 100, 61, 0, 0, 0, 0, 0, 0, 37744100478378
1376, R, 2018-04-11 03:19:05, 2018-04-02 08:23:58.073, 2018-04-02 08:23:58.409, 0.336, 0.000000, 0.000000439737, 0.000000418271, -0.000001648501, -0.7765206694602966, -0.0172884277999401, -0.5472017526626587, 0.3119086027145386, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744100485034
1377, R, 2018-04-11 03:19:05, 2018-04-02 08:23:58.073, 2018-04-02 08:24:04.108, 6.035, 0.000000, 0.000001935742, -0.000000231651, -0.000000597165, -0.7765325307846069, -0.0172873511910439, -0.5471789240837097, 0.3119192123413086, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 99, 100, 100, 0, 0, 0, 0, 0, 0, 37744100858538
1378, R, 2018-04-11 03:19:05, 2018-04-02 08:24:04.073, 2018-04-02 08:24:04.210, 0.137, 0.000000, -0.000013595037, 0.000001190096, 0.000010323348, -0.7765294909477234, -0.0172867123037577, -0.5471841096878052, 0.3119176626205444, 1, 1, 0, 1, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 2, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100865194
1379, R, 2018-04-11 03:19:05, 2018-04-02 08:24:04.073, 2018-04-02 08:24:04.307, 0.234, 0.000000, 0.000000792753, 0.000000019410, 0.000000394833, -0.776526689529419, -0.0172874853014946, -0.5471875667572021, 0.3119186758995056, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100871594
1380, R, 2018-04-11 03:19:05, 2018-04-02 08:24:04.073, 2018-04-02 08:24:04.409, 0.336, 0.000000, 0.000000792751, 0.000000019404, 0.000000394836, -0.7765247225761414, -0.0172881260514259, -0.5471907258033752, 0.3119180202484131, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100878250
1381, R, 2018-04-11 03:19:05, 2018-04-02 08:24:04.073, 2018-04-02 08:24:04.510, 0.438, 0.000000, 0.000000792750, 0.000000019399, 0.000000394839, -0.776524007320404, -0.0172882173210382, -0.5471934080123901, 0.3119150102138519, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100884906
1382, R, 2018-04-11 03:19:05, 2018-04-02 08:24:04.073, 2018-04-02 08:24:04.608, 0.535, 0.000000, 0.000000792748, 0.000000019391, 0.000000394844, -0.7765225768089294, -0.0172883737832308, -0.5471977591514587, 0.3119109570980072, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744100891306
1383, R, 2018-04-11 03:19:05, 2018-04-02 08:24:04.073, 2018-04-02 08:24:04.710, 0.637, 0.000000, -0.000002108614, 0.000000282613, 0.000002354208, -0.7765215039253235, -0.0172902029007673, -0.5472004413604736, 0.3119087815284729, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 51, 0, 0, 0, 0, 100, 58, 0, 0, 0, 0, 0, 0, 37744100897961
1384, R, 2018-04-11 03:19:05, 2018-04-02 08:24:04.073, 2018-04-02 08:24:04.811, 0.738, 0.000000, 0.000000439750, 0.000000418267, -0.000001648498, -0.7765214443206787, -0.0172921977937222, -0.5472018718719482, 0.3119062185287476, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744100904617
1385, R, 2018-04-11 03:19:05, 2018-04-02 08:24:04.073, 2018-04-02 08:24:10.510, 6.438, 0.000000, 0.000001935755, -0.000000231854, -0.000000597044, -0.776531457901001, -0.017288651317358, -0.5472091436386108, 0.3118687570095062, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 99, 100, 100, 0, 0, 0, 0, 0, 0, 37744101278122
1386, R, 2018-04-11 03:19:05, 2018-04-02 08:24:10.073, 2018-04-02 08:24:10.612, 0.539, 0.000000, -0.000013595476, 0.000001191794, 0.000010322575, -0.7765275239944458, -0.0172872208058834, -0.5472142100334167, 0.3118698000907898, 1, 1, 0, 1, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 2, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744101284777
1387, R, 2018-04-11 03:19:05, 2018-04-02 08:24:10.073, 2018-04-02 08:24:10.710, 0.637, 0.000000, 0.000000792734, 0.000000019362, 0.000000394872, -0.7765247225761414, -0.0172876883298159, -0.5472168922424316, 0.3118720352649689, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744101291177
1388, R, 2018-04-11 03:19:05, 2018-04-02 08:24:10.073, 2018-04-02 08:24:10.811, 0.738, 0.000000, 0.000000792733, 0.000000019355, 0.000000394876, -0.7765225172042847, -0.0172882620245218, -0.5472204685211182, 0.311871200799942, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744101297833
1389, R, 2018-04-11 03:19:05, 2018-04-02 08:24:10.073, 2018-04-02 08:24:10.909, 0.836, 0.000000, 0.000000792732, 0.000000019349, 0.000000394878, -0.7765211462974548, -0.0172877907752991, -0.5472235679626465, 0.3118691742420197, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744101304233
1390, R, 2018-04-11 03:19:05, 2018-04-02 08:24:10.073, 2018-04-02 08:24:11.010, 0.937, 0.000000, 0.000000792730, 0.000000019345, 0.000000394882, -0.7765206694602966, -0.017288526520133, -0.5472263693809509, 0.3118654489517212, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744101310889
1391, R, 2018-04-11 03:19:05, 2018-04-02 08:24:10.073, 2018-04-02 08:24:11.108, 1.035, 0.000000, -0.000002158279, 0.000000292773, 0.000002376377, -0.7765189409255981, -0.0172902196645737, -0.5472283363342285, 0.3118661642074585, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 40, 0, 0, 0, 0, 100, 47, 0, 0, 0, 0, 0, 0, 37744101317290
1392, R, 2018-04-11 03:19:05, 2018-04-02 08:24:11.073, 2018-04-02 08:24:11.210, 0.137, 0.000000, 0.000000439853, 0.000000418166, -0.000001648496, -0.7765187621116638, -0.0172915775328875, -0.5472286939620972, 0.3118659257888794, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744101323946
1393, R, 2018-04-11 03:19:05, 2018-04-02 08:24:11.073, 2018-04-02 08:24:16.909, 5.836, 0.000000, 0.000001935854, -0.000000231856, -0.000000597071, -0.7765286564826965, -0.0172888189554214, -0.5472100377082825, 0.3118742108345032, 1, 1, 0, 1, 0, 1, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 100, 0, 99, 100, 100, 0, 0, 0, 0, 0, 0, 37744101697449
1394, R, 2018-04-11 03:19:05, 2018-04-02 08:24:16.073, 2018-04-02 08:24:17.010, 0.937, 0.000000, -0.000013593242, 0.000001191472, 0.000010321155, -0.7765249013900757, -0.0172876622527838, -0.5472149848937988, 0.3118749856948853, 1, 1, 0, 1, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 2, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744101704105
1395, R, 2018-04-11 03:19:05, 2018-04-02 08:24:16.073, 2018-04-02 08:24:17.108, 1.035, 0.000000, 0.000000792791, 0.000000019361, 0.000000394896, -0.7765220999717712, -0.0172870960086584, -0.5472172498703003, 0.3118778765201569, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744101710506
1396, R, 2018-04-11 03:19:05, 2018-04-02 08:24:17.073, 2018-04-02 08:24:17.210, 0.137, 0.000000, 0.000000792790, 0.000000019354, 0.000000394899, -0.776520311832428, -0.0172873567789793, -0.547220766544342, 0.3118762373924255, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744101717162
1397, R, 2018-04-11 03:19:05, 2018-04-02 08:24:17.073, 2018-04-02 08:24:17.311, 0.238, 0.000000, 0.000000792788, 0.000000019348, 0.000000394902, -0.7765191197395325, -0.0172873921692371, -0.5472239851951599, 0.3118736147880554, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744101723818
1398, R, 2018-04-11 03:19:05, 2018-04-02 08:24:17.073, 2018-04-02 08:24:17.409, 0.336, 0.000000, 0.000000792787, 0.000000019343, 0.000000394906, -0.7765186429023743, -0.01728705316782, -0.5472270250320435, 0.3118694424629211, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744101730218
1399, R, 2018-04-11 03:19:05, 2018-04-02 08:24:17.073, 2018-04-02 08:24:17.510, 0.438, 0.000000, -0.000002203749, 0.000000301783, 0.000002396979, -0.776516318321228, -0.0172893181443214, -0.5472294092178345, 0.3118708729743958, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 30, 0, 0, 0, 0, 100, 37, 0, 0, 0, 0, 0, 0, 37744101736874
1400, R, 2018-04-11 03:19:05, 2018-04-02 08:24:17.073, 2018-04-02 08:24:17.612, 0.539, 0.000000, 0.000000439901, 0.000000418233, -0.000001648807, -0.776516854763031, -0.0172911658883095, -0.5472292304039001, 0.3118698596954346, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744101743529
1401, R, 2018-04-11 03:19:05, 2018-04-02 08:24:17.073, 2018-04-02 08:24:23.311, 6.238, 0.000000, 0.000000792793, 0.000000019379, 0.000000394890, -0.7765312194824219, -0.0172839649021626, -0.5472083687782288, 0.3118711113929749, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102117034
1402, R, 2018-04-11 03:19:05, 2018-04-02 08:24:23.073, 2018-04-02 08:24:23.413, 0.340, 0.000000, 0.000000792794, 0.000000019372, 0.000000394889, -0.7765268087387085, -0.0172840300947428, -0.547211229801178, 0.3118769526481628, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102123689
1403, R, 2018-04-11 03:19:05, 2018-04-02 08:24:23.073, 2018-04-02 08:24:23.510, 0.438, 0.000000, 0.000000792794, 0.000000019364, 0.000000394890, -0.7765234708786011, -0.0172839760780334, -0.5472147464752197, 0.3118792176246643, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102130090
1404, R, 2018-04-11 03:19:05, 2018-04-02 08:24:23.073, 2018-04-02 08:24:23.612, 0.539, 0.000000, 0.000000792794, 0.000000019359, 0.000000394891, -0.776520848274231, -0.0172847826033831, -0.5472168326377869, 0.3118820190429688, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102136745
1405, R, 2018-04-11 03:19:05, 2018-04-02 08:24:23.073, 2018-04-02 08:24:23.714, 0.641, 0.000000, 0.000000792794, 0.000000019356, 0.000000394890, -0.7765195965766907, -0.0172842405736446, -0.5472183227539062, 0.3118824660778046, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102143402
1406, R, 2018-04-11 03:19:05, 2018-04-02 08:24:23.073, 2018-04-02 08:24:23.811, 0.738, 0.000000, 0.000000792794, 0.000000019354, 0.000000394890, -0.7765180468559265, -0.0172844752669334, -0.5472191572189331, 0.3118848204612732, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102149801
1407, R, 2018-04-11 03:19:05, 2018-04-02 08:24:23.073, 2018-04-02 08:24:23.909, 0.836, 0.000000, -0.000001816202, 0.000000269437, 0.000002129246, -0.7765164375305176, -0.0172867625951767, -0.5472195148468018, 0.3118880689144135, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 31, 0, 0, 0, 0, 100, 37, 0, 0, 0, 0, 0, 0, 37744102156201
1408, R, 2018-04-11 03:19:05, 2018-04-02 08:24:23.073, 2018-04-02 08:24:24.010, 0.937, 0.000000, 0.000000439846, 0.000000418289, -0.000001648807, -0.776515781879425, -0.0172889139503241, -0.5472186803817749, 0.3118910789489746, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744102162857
1409, R, 2018-04-11 03:19:05, 2018-04-02 08:24:23.073, 2018-04-02 08:24:29.714, 6.641, 0.000000, 0.000000792823, 0.000000019432, 0.000000394829, -0.7765311598777771, -0.0172764603048563, -0.5471724271774292, 0.3119347393512726, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102536618
1410, R, 2018-04-11 03:19:05, 2018-04-02 08:24:29.073, 2018-04-02 08:24:29.811, 0.738, 0.000000, 0.000000792822, 0.000000019422, 0.000000394831, -0.7765266299247742, -0.0172771532088518, -0.5471770167350769, 0.3119378089904785, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102543017
1411, R, 2018-04-11 03:19:05, 2018-04-02 08:24:29.073, 2018-04-02 08:24:29.909, 0.836, 0.000000, 0.000000792821, 0.000000019416, 0.000000394833, -0.7765236496925354, -0.0172780435532331, -0.5471799373626709, 0.3119401037693024, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102549417
1412, R, 2018-04-11 03:19:05, 2018-04-02 08:24:29.073, 2018-04-02 08:24:30.010, 0.937, 0.000000, 0.000000792819, 0.000000019408, 0.000000394837, -0.7765213251113892, -0.0172785613685846, -0.5471842885017395, 0.3119382262229919, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102556073
1413, R, 2018-04-11 03:19:05, 2018-04-02 08:24:29.073, 2018-04-02 08:24:30.108, 1.035, 0.000000, 0.000000792819, 0.000000019402, 0.000000394838, -0.7765200734138489, -0.017278153449297, -0.547187089920044, 0.3119363188743591, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102562474
1414, R, 2018-04-11 03:19:05, 2018-04-02 08:24:30.073, 2018-04-02 08:24:30.210, 0.137, 0.000000, 0.000000792819, 0.000000019400, 0.000000394838, -0.7765191793441772, -0.0172775592654943, -0.5471882224082947, 0.3119367361068726, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 37744102569130
1415, R, 2018-04-11 03:19:05, 2018-04-02 08:24:30.073, 2018-04-02 08:24:30.311, 0.238, 0.000000, -0.000001807066, 0.000000267380, 0.000002125330, -0.7765178084373474, -0.0172789040952921, -0.5471892356872559, 0.3119382858276367, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 33, 0, 0, 0, 0, 100, 39, 0, 0, 0, 0, 0, 0, 37744102575786
1416, R, 2018-04-11 03:19:05, 2018-04-02 08:24:30.073, 2018-04-02 08:24:30.413, 0.340, 0.000000, 0.000000439712, 0.000000418396, -0.000001648815, -0.7765180468559265, -0.01728181168437, -0.5471899509429932, 0.3119363188743591, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 95, 0, 0, 0, 0, 0, 100, 0, 0, 0, 0, 0, 0, 0, 37744102582441 | https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20201228T221917/anc/eng/sff/mvn_rec_180327_180402_v03.sff |
(PDF) Effect of iron-intermetallics on the fluidity of 413 aluminum alloy
PDF | The effect of Fe content on the fluidity of 413 aluminum alloy has been investigated in both un-modified and Mn-modified states by vacuum fluidity... | Find, read and cite all the research you need on ResearchGate
Effect of iron-intermetallics on the fluidity of 413 aluminum alloy
January 2009
Journal of Alloys and Compounds 468(1):539-545
DOI: 10.1016/j.jallcom.2008.01.079
Authors:
Abstract
The effect of Fe content on the fluidity of 413 aluminum alloy has been investigated in both un-modified and Mn-modified states by vacuum fluidity test. Increasing Fe decreases the fluidity due to the formation of β-Al5FeSi and α-Al15(Fe, Mn)3Si2-intermetallic compounds. The effect of melt holding time was also studied. The fluidity of Mn-modified alloys decreases drastically with increasing holding time. Agglomeration of α-intermetallics and subsequent sludge formation is the main cause of fluidity descending. The fluidity of un-modified alloys is, however, less sensitive to holding time. Applying enough superheat and holding time, corresponding to segregation factor of the alloy, is an effective way to increase the fluidity of Mn-modified alloys by the dissolution of Fe-bearing intermetallics.
Journal of Alloys and Compounds 468 (2009) 539–545
Effect of iron-intermetallics on the fluidity of 413 aluminum alloy
E. T aghaddos a , M.M. Hejazi b , R. T aghiabadi a , S.G. Shabestari b , ∗
a Department of Materials and Metallurgical Engineering, International University , Qazvin, Iran
b Department of Materials and Metallurgical Engineering, Iran University
of Science and Tec hnology (IUST), Narmak, Tehran, Ir an
Received 6 December 2007; received in re vised form 5 January 2008; accepted 9 January 2008
Av ailable online 4 March 2008
Abstract
The effect of Fe content on the fluidity of 413 aluminum alloy has been inv estigated in both un-modified and Mn-modified states by vacuum
fluidity test. Increasing Fe decreases the fluidity due to the formation of b -Al 5 FeSi and a -Al 15 (Fe, Mn) 3 Si 2 -intermetallic compounds. The effect
of melt holding time was also studied. The fluidity of Mn-modified alloys decreases drastically with increasing holding time. Agglomeration of
a -intermetallics and subsequent sludge formation is the main cause of fluidity descending. The fluidity of un-modified alloys is, however , less
sensitive to holding time. Applying enough superheat and holding time, corresponding to segregation factor of the allo y, is an effecti ve way to
increase the fluidity of Mn-modified alloys by the dissolution of Fe-bearing intermetallics.
© 2008 Elsevier B.V . All rights reserved.
Keywor ds: Aluminum–silicon alloys; Fluidity; Iron-intermetallics; Manganese; Modification
1. Introduction
Al–Si alloys are most widely used aluminum alloys due to
their castability, high strength to weight ratio, corrosion resis-
tance, etc [1,2] . Aluminum alloys contain some impurities such
as Fe, Mn and Cr which deteriorate mechanical properties of the
casting parts [3–5] . Fe is one of the most common impurities
that cause formation of brittle intermetallics in commercial alu-
minum alloys. Platelet and needle-like b -Al 5 FeSi-intermetallics
form in Mn-free alloys at normal cooling rates usually employed
in the foundry. Increasing iron content will increase the size and
volume of b -Al 5 FeSi phase particularly above 0.7 wt.% Fe [6,7] .
The harmful effects of Fe can be minimized by various tech-
niques such as superheating or addition of Mn, Sr, K elements
[8–11] . Mn addition is the most common technique. Addition
of Mn will change b -Al 5 FeSi platelets to a -Al 15 (Fe, Mn) 3 Si 2
in Cu-free alloys or a -Al 15 (Fe, Mn, Cu) 3 Si 2 in Cu-bearing
alloys in the form of Chinese script or polyhedral morphology
[12–15] . For effectiv e modification of b phases, the ratio of Fe
to Mn should be kept about 2:1, as reported by several previous
researchers [16–18] .
∗ Corresponding author. T el.: +98 21 73912815; fax: +98 21 77240480.
E-mail address: Shabestari@iust.ac.ir (S.G. Shabestari).
In high-pressure die casting alloys, Fe is intentionally added
to the melt in range of 0.8–1.1 wt.% to prevent molten metal
soldering to the die [16,19] . Die casting parts are usually thin
walled and complicated. The fluidity of molten metal, therefore,
plays a significant role for the utter filling of the die. Controlling
b -Al 5 FeSi-intermetallics should be attentively focused in die
casting alloys since they are detrimental to castability [20] .
High-iron containing alloys have the tendency to form sludge.
Mn addition also promotes sludge formation. Modified inter-
metallics, have high-specific gravity and tend to settle to the
bottom of the furnace or crucible as sludge. Sludge formation
may also result in other problems such as the furnace wall
damage. Entrapment of sludge into the mold cavity has some
detrimental effects of mechanical and physical properties of
the casting part [21–23] . Holding the melt at low temperatures
encourages sludge formation [24] . Segregation factor (SF) is
useful to determine Fe, Mn, and Cr contents to prevent sludge
formation [25,26] :
SF = % Fe + 2% Mn + 3% Cr (1)
Heating the melt to a higher temperature than a specific one
(called sludge formation temperature) will cause the dissolution
of intermetallics [27,28] . Relation between segregation factor
and sludge formation temperature for some Al–Si alloys has
0925-8388/$ – see front matter © 2008 Elsevier B.V . All rights reserved.
doi: 10.1016/j.jallcom.2008.01.079
... Several researchers in the past two decades tried to find the correlation between micro-alloying treatments and the fluidity of cast aluminum alloys. Taghaddos et al.
[25]
pointed out that the fluidity of the molten Al-Si cast alloys with high iron content was relatively poor, owing to the formation of coarse iron phases with irregular shapes in the melts. But the fluidity was remarkably improved by micro-alloying the manganese into the melts. ...
A comparative study of iron, cobalt or cerium micro-alloying on microstructure and apparent viscosity of Al-5Ni alloy
Article
Full-text available
Apr 2023
J ALLOY COMPD
Kang Wang
Mingguang Wei
Zhongmiao Liao
Wenfang Li
... Also, removing the residual hydrogen content from the powder mixer can reduce the pore formation. Iron content also hampers the flowability and create pores in Al-Si composites by forming intermetallic compounds
(Taghaddos et al., 2009)
. Therefore, avoid iron balls during the milling solve such setback. ...
Review of the developments in composite materials over the last 15 years
Chapter
Full-text available
Jan 2023
Sarower Kabir
Chowdhury Ahmed Shahed
Md. Sazzad Hossain Ador
Faiz Ahmad
... Also, removing the residual hydrogen content from the powder mixer can reduce the pore formation. Iron content also hampers the flowability and create pores in Al-Si composites by forming intermetallic compounds
(Taghaddos et al., 2009)
. Therefore, avoid iron balls during the milling solve such setback. ...
Review of new developments in different types of sensors over the past 15 years
Chapter
Jan 2023
Md. Sazzad Hossain Ador
Prattusha Bhattacharjee
Sarower Kabir
Imtiaz Ahmed Choudhury
... According to this work, the most common phases in Al-Fe-Si systems are ternary α-AlFeSi (α-Fe) and β-AlFeSi (β-Fe) phases [13]. Among these, the β-Fe phase is considered the most harmful phase to the mechanical properties of the alloy due to its brittleness and morphology [18,
[20]
[21][22][23]. This phase presents a needle-like morphology when J o u r n a l P r e -p r o o f 3 observed in a two-dimensional micrography, even though the β-Fe phase has a platelet-like morphology in three dimensions [15]. ...
Effects of Mn addittion, cooling rate and holding temperature on the modification and purification of iron-rich compounds in AlSi10MnMg(Fe) alloy
Article
Full-text available
Feb 2023
Jon Mikel Sanchez
Maribel Arribas
Haize Galarraga
Franck Girot
The use of secondary aluminum alloys in industry is still limited by the high Fe contents in
recycled alloys. In general, the Fe-rich intermetallic compounds deteriorate the performance of
secondary Al-Si alloys, specially the β-Fe phase. To mitigate the detrimental effects of iron, the
influence of diferent cooling rates and holding temperatures on the modification and purification
of iron-rich compounds in commercial AlSi10MnMg alloy with 1.1 wt. % Fe was studied.
According to the results obtained by CALPHAD calculations, the alloy was modified by adding
a 0.7 wt.%, 1.2 wt.%. and 2.0 wt.% of Mn. The phase formation and morphology of iron-rich
compounds was systematically studied and correlated by different microstructural
characterization techniques. The experimental results showed that the detrimental β-Fe phase can
be avoided by adding at least 1.2 wt. % of Mn at the studied cooling rates . Finally, the effect of
different holding temperatures in the sedimentation of Fe-rich compounds also was studied.
Hence, the gravitational sedimentation experiments at different holding times and temperatures
were conducted to validate the feasibility of the methodology in different processing conditions.
The experimental results showed a high Fe removal efficiency up to 64 % and 61 %, after a
holding time of 30 min. at 600 °C and 670 °C, respectively. The addition of Mn improved the Fe
removal efficiency but not gradually, as the best results were obtained in the alloy containing 1.2
wt. % Mn.
... Further, iron has a very low solid solubility (max 0.05 wt%) in aluminium [3] and can form hard and brittle Fe-rich intermetallic compounds (IMCs) such as Al 13 Fe 4 [4,5] and β-Al 5 FeSi [6]. Their morphologies, sizes and distribution, if not controlled, can negatively impact castability
[7]
and reduce mechanical and corrosion properties of the final components [8,9]. IMCs in aluminium alloys can be controlled by their crystal structures and solidification conditions such as cooling rates, temperature gradients and external fields (e.g. ...
Magnetic field-assisted solidification of W319 Al alloy qualified by high-speed synchrotron tomography
Article
Full-text available
Mar 2023
Zihan Song
Elodie Boller
Alexander Rack
Biao Cai
Magnetic fields have been widely used to control solidification processes. Here, high-speed synchrotron X-ray tomography was used to study the effect of magnetic fields on solidification. We investigated vertically upward directional solidification of an Al-Si-Cu based W319 alloy without and with a transverse magnetic field of 0.5 T while the sample was rotating. The results revealed the strong effect of a magnetic field on both the primary α-Al phase and secondary β-Al5FeSi intermetallic compounds (IMCs). Without the magnetic field, coarse primary α-Al dendrites were observed with a large macro-segregation zone. When a magnetic field is imposed, much finer dendrites with smaller primary arm spacing were obtained, while macro-segregation was almost eliminated. Segregated solutes were pushed out of the fine dendrites and piled up slightly above the solid/liquid interface, leading to a gradient distribution of the secondary β-IMCs. This work demonstrates that rotating the sample under a transversal magnetic field is a simple yet effective method to homogenise the temperature and composition distributions, which can be used to control the primary phase and the distribution of iron-rich intermetallics during solidification.
... According to this work, the most common phases in Al-Fe-Si systems are ternary α-AlFeSi (α-Fe) and β-AlFeSi (β-Fe) phases [13]. Among these, the β-Fe phase is considered the most harmful phase to the mechanical properties of the alloy due to its brittleness and morphology [18,
[20]
[21][22][23]. This phase presents a needle-like morphology when J o u r n a l P r e -p r o o f 3 observed in a two-dimensional micrography, even though the β-Fe phase has a platelet-like morphology in three dimensions [15]. ...
Effects of Cooling Rate and Holding Temperature on the Modification and Purification of Iron-Rich Compounds in AlSi10MnMg(Fe) Alloy
Article
Jan 2022
Jon Mikel Sanchez
Maribel Arribas
Haize Galarraga
Franck Girot
Investigating the influences of Fe, Mn and Mo additions on the evolution of microstructure and mechanical performances of Al–Si–Mg cast alloys
The formation of iron (Fe) containing intermetallics during solidification is challenging due to the influences of cooling rate and chemical composition. Differential scanning calorimetry (DSC) is an accurate analysis method but merely replicates adjustable cooling conditions. Thereby, the solidification range is traversed several times before DSC measurement. For this purpose, thermal analysis cooling curves with double thermocouple are conducted to investigate the formation temperature of Fe-rich intermetallics in different AlSi casting alloys. In addition, the influence of chemical composition is examined by increasing the initial contents of iron, manganese, and chromium to 0.8 wt% each. The double thermocouple setup allows determining feeding points and solid fractions of the alloy compounds. To evaluate the data sets, the statistical program R is used to improve data processing and smoothing. The signature of Fe-rich intermetallics in the temperature-time plots corresponds to the detected phases in optical micrographs. In addition, scanning electron microscopy with energy dispersive spectroscopy and electron backscattering diffraction are used to measure the local chemical composition and identify the iron-rich intermetallics. Real-time evaluation (differential calculation, first derivative, incl. smoothing) for an applicable filtration process can be performed using thermocouples with analog-to-digital converter and Python programs with an interactive graphical interface.
This article is protected by copyright. All rights reserved.
| https://www.researchgate.net/publication/248179429_Effect_of_iron-intermetallics_on_the_fluidity_of_413_aluminum_alloy |
98524 Demographics 2023 (Income, Race, Gender, Population)
Find the most recent population, income, and race demographics data for the 98524 zip code. Download and use!
98524 Zip Code Income, Population and Demographics
Are you tired of spending 10+ hours searching for demographic and population data for the 98524 zip code? We have all of the data you need by state, county, city, and zip code that will save you many hours of research!
In this article, we'll explore most of the 190+ data points we have for 98524, covering popular demographics statistics like household income, race, age and gender, educational attainment, poverty, housing, and transportation.
98524 is a zip code in Mason County, Washington, which covers Union-Grapeview, with a total population of 4,326 people.
The data on this page is from the 2021 American Community Survey (ACS) 5-Year survey from the US Census Bureau.
Table of Contents
Median Income
Average Income
Income Tiers
Per Capita Income
Population by Race
Population by Age
Education Levels
Unemployment Rates
Median Age
Households and Families
Marial Status
Housing
Rental Rates
Property Values
Property Age
Vehicles
Commuting
Conclusion
Median Household Income
According to the latest ACS 5-year survey in 2021, the
median household income in 98524 is $99,975.00
.
The chart below shows the average household income by age in 98524.
Under 25
$0.00
25 to 44
$101,177.00
45 to 64
$171,190.00
65 and over
$75,000.00
Average Household Income
A very commonly asked question is "what is the average household income in the 98524 zip code?". The official term for the average household income is the
mean household income
. The mean household income is the total income of all households divided by the number of households.
The average (or mean) household income in 98524 is $107,018.00.
8.52% of households in the 98524 zip code are classed as high income households (making $200,000+ per year).
The difference between a median and an average income
The difference between a median and mean household income is thatthe median income is the middle point of the set of numberswhereasthe mean income is an average of all numbers.
Both metrics are important when looking at the income statistics for 98524 but because the median value doesn't depend on other numbers in the dataset, it doesn't change as much when some of the values are extremely low or extremely high.
Household Income Tiers for 98524
We can also look at the household income tiers. This lets you see how many households fall into each of the earnings brackets and what percentage that bracket is of the total number of households.
The chart below shows the household income brackets to see which age groups have the highest median income. The actual data is more granular than these brackets, but we've simplified them into bigger categories to make reviewing the data for the 98524 zip code easier to view.
You can purchase the raw data above, which will have the full income tiers with smaller jumps in household income.
Less than $24,999
12.24%
$25,000 to $49,999
4.44%
$50,000 to $74,999
16.79%
$75,000 to $99,999
16.56%
$100,000 to $149,999
28.27%
$150,000 to $199,999
13.19%
$200,000 or more
8.52%
Per Capita Income
The per capita income is the average income of all people in the 98524 zip code. This is calculated by dividing the total income of all people in 98524 by the total number of people in 98524.
It differs from the average or mean household income because it includes all people in 98524 and not just the people who earn an income (i.e. children, retirees, unemployed, etc.).
The per capita income in the 98524 zip code is $41,716.00.
Population in 98524 by Race and Ethnicity
The total population in 98524 is currently 4,326 people.
The race and ethnicity of the population in 98524 can be very important for social research, economics, and marketing to a multi-culturial society.
Whether you want to target products or services to a particular race or ethnicity, or provide housing and new businesses to improve areas with a larger ethnic minority population, this data is very valuable for discovering suitable areas.
The chart below breaks down the population and percentage for each race and ethnicity in the 98524 zip code.
91.10% White
3,942
0.00% Black/African American
0
0.00% Native
0
6.30% Hispanic
271
0.80% Asian
34
0.00% Hawaiian/Pacific Islander
0
1.80% Two or more races
79
0.00% Other
0
Population of 98524 by Age and Gender
Another very important demographics statistic for the 98524 zip code is the age and gender of the population. The age and gender of the population can be used to track trends in population growth or decline, and for businesses, the data can be used to identify people important to you and your business need.
In the table below, we show age groups at a 10 year granularity for ease of use. The raw data, which can be purchased above, includes age and gender at a 5 year granularity.
Age Group Male Female 0 to 9 Years 377 166 10 to 19 Years 280 94 20 to 29 Years 189 282 30 to 39 Years 388 310 40 to 49 Years 181 182 50 to 59 Years 324 346 60 to 69 Years 238 324 70 Years and over 404 241
Education Levels
Educational attainment is a very useful statistic that can give insights into other data such as the average household income, unemployment levels, and literacy.
What this means is that it is likely for areas that have higher levels of education to have higher average household incomes, lower unemployment rates, and higher literacy rates.
The chart below shows the educational attainment of the population in the 98524 zip code.
Master's degree or higher
20.30%
Bachelor's degree
27.82%
Some college or associate's degree
4.97%
High school diploma or equivalent
46.67%
Less than high school diploma
0.24%
Unemployment Rates
The unemployment rate is the percentage of the population that is actively looking for work but is unable to find a job. The unemployment rate is a very important statistic for 98524 because it can show how many people are actively looking for work and how many people are unable to find a job.
Lower levels of unemployment is generally seen as a positive sign for the economy. It also makes the government in 98524 look good because it shows that they are doing a good job of creating jobs, working to capacity, being efficient, and keeping the economy strong.
The unemployment rate is calculated using the total population in the 98524 zip code that are over the age of 16.
The current population in 98524 that are over the age of 16 is 3,572 people.
The unemployment rate in 98524 is 2.20%
, which means 1,479 people are unemployed.
Median Age in 98524
The median age is an interesting metric because it gives us an idea of the age distribution of people in the 98524 zip code. You know when you see a median age that it is the age where half of the population is older and half is younger than it.
For demographic studies, this can be used to infer and compare date to things such as birth rates, the age of parents, and so on.
An increasing median age can be a sign of an aging population, which can be a sign of a declining population. This is because older people tend to have fewer children and die more often than younger people.
The median age in 98524 is 41.8 years old.
We can also look at the median age by gender to compare the see how each group compares to the total median age:
Median age by gender in 98524
41.8
Total
39.4
Male
43.7
Female
Households and Families
There are a total of 1,691 households in 98524
, and the average household size is 2.55 people.
For families, the
total number is 1,281
, and the average family size is 2.89 people.
1.50% of those families in the 98524 zip code are living below the poverty line.
The table below shows the poverty thresholds for 98524 in 2022.
Household Size Poverty Threshold 1 Person $13,590.00 2 People $18,310.00 3 People $23,030.00 4 People $27,750.00 5 People $32,470.00 6 People $37,190.00 7 People $41,910.00 8 People $46,630.00
Please note that the poverty thresholds shown above are from 2022, while the latest demographics data we have is from 2021.
Households and Families by Marital Status
There are four types of household and family, as defined by the Census Bureau:
Married-couple
Male householder, no spouse present
Female householder, no spouse present
Nonfamily household
In the table below, you can see the total households and families in the 98524 zip code for each type, as well as the average sizes.
Married Male Female Nonfamily Total Households 1,127 53 101 410 Average Household Size 2.83 4.87 2.84 1.41 Total Families 1,127 53 101 0 Average Household Size 2.82 4.87 2.65 0
Housing Data in 98524
There are total of 2,151 housing units in the 98524 zip code. Of those units,
1,691 (78.61%) are occupied
, and
460 (21.39%) are vacant
.
Rental Rates
Of the 2,151 housing units in 98524,
165 (7.67%) are occupied by renters
. The median rent paid by renters
is $1,082.00
.
Owner occupied housing units make up the remaining 70.53% of housing units, with 1,517 housing units in total.
The table below breaks down how much rent is paid by renters in the 98524 zip code.
No rent paid
9
Less than $500
0
$500 to $999
74
$1,000 to $1,499
26
$1,500 to $1,999
65
$2,000 to $2,499
0
$2,500 to $2,999
0
$3,000 or more
0
Property Values
The median value of a property in 98524 is$393,400.00.
The table below breaks down the range of valuations for all properties in 98524.
Less than $50,000
19
$50,000 to $99,999
49
$100,000 to $149,999
97
$150,000 to $199,999
31
$200,000 to $299,999
216
$300,000 to $499,999
753
$500,000 to $999,999
352
$1,000,000 or more
0
Property Age
We can also look at the number of properties built in a given year to see the spread of property age in the 98524 zip code.
1939 or earlier
21
1940 to 1949
0
1950 to 1959
90
1960 to 1969
195
1970 to 1979
277
1980 to 1989
123
1990 to 1999
361
2000 to 2009
874
2010 to 2013
210
2014 or later
0
Vehicles Available per Household
Finally, we have data on how many vehicles each household in 98524 has. The table below breaks down the number of vehicles available per household.
No vehicles available
28
1 vehicle available
372
2 vehicles available
767
3 or more vehicles available
524
Commuting to Work in 98524
The time and means of commuting to work are useful metrics to look at because they can be correlated against other data such as income and education level.
Does a longer commuting time indicate a higher average income? If so, has the huge increase in home working during the pandemic changed this?
Using these metrics, we can get a better understanding of the demographics of the 98524 zip code, how they commute, and how that correlates to other data points.
The average travel time is 41 minutes
, and the chart below covers the range of travel times across the population of 98524.
Less than 5 minutes
89
5 to 9 minutes
112
10 to 14 minutes
172
15 to 19 minutes
99
20 to 24 minutes
0
25 to 29 minutes
142
30 to 34 minutes
243
35 to 39 minutes
186
40 to 44 minutes
202
45 to 59 minutes
279
60 to 89 minutes
71
90 or more minutes
277
We can also look at the means of transport in 98524 to see which modes of transport people are using to commute to work.
Drove alone
1,633
Carpooled
230
Public transportation
9
Walked
0
Other means
0
Worked from home
160
Conclusion
Hopefully this article has given you the demographics data you were looking for in the 98524 zip code.
If you need more demographics data, or you need the data listed above in spreadsheet form with more granular grouping, head back to the top of this page where you can purchase the complete demographics data for 98524.
Demographics for Surrounding Areas
The list below contains demographics and income statistics for zip codes in areas that surround 98524.
98620
98617
98603
98570
98593
98546
98559
98597
98580
98612
98588
98513
98447
98528
98584
98548
98571
98444
98516
98536
98575
98501
98438
98544
98531
98591
98439
98583
98530
Places in Washington
Wenatchee
Medical Lake
View Baby Name Data
First Names
| https://namecensus.com/demographics/washington/98524/ |
Figures and data in Signal integration at spherical bushy cells enhances representation of temporal structure but limits its range | eLife
Inhibition reduces the neuronal representation of acoustic signals to enhance temporal precision in the auditory brainstem.
Signal integration at spherical bushy cells enhances representation of temporal structure but limits its range
https://doi.org/10.7554/eLife.29639
Christian Keine
Rudolf Rübsamen
Bernhard Englitz
(2017)
Signal integration at spherical bushy cells enhances representation of temporal structure but limits its range
eLife 6 :e29639.
https://doi.org/10.7554/eLife.29639
Version of Record published
Accepted
September 25, 2017
Christian Keine
Rudolf Rübsamen
Bernhard Englitz
(2017)
Signal integration at spherical bushy cells enhances representation of temporal structure but limits its range
eLife 6 :e29639.
https://doi.org/10.7554/eLife.29639
5 figures, 1 table and 6 additional files
Figures
Figure 1
Acoustic stimulation with environmental sounds increases auditory nerve firing while leaving the SBC firing rates constant.
( A) Representative voltage trace of SBC recording during acoustic stimulation. Voltage signals could be divided into EPSP followed by postsynaptic AP (blue dots) and EPSPs which fail to trigger an … see more
https://doi.org/10.7554/eLife.29639.002
Figure 1—source data 1
Firing rates of auditory nerve (ANF) input and Spherical Bushy Cell (SBC) output during spontaneous activity, pure tone and natural acoustic stimulation.
Data are in Hz.
https://doi.org/10.7554/eLife.29639.003
Download elife-29639-fig1-data1-v2.xlsx
Figure 2 with 1 supplement
SBC output exhibits increased sparsity and reproducibility compared to ANF input which can be attributed to activity-dependent subtractive inhibition.
( A) During acoustic stimulation the threshold EPSP for AP generation (left) was increased and consequently so was the failure fraction (right), indicating strong inhibition during acoustic … see more
https://doi.org/10.7554/eLife.29639.005
Figure 2—source data 1
Threshold EPSP (in V/s) and failure fraction during acoustic spontaneous activity and natural acoustic stimulation.
Values of sparsity and reproducibility for ANF input and SBC output for both the complete stimulus and separated in stimulus segments.
https://doi.org/10.7554/eLife.29639.007
Figure 2—figure supplement 1
Comparison of different inhibition models in their ability to reproduce the response as well as its sparsity and reproducibility.
( A) Schematic of the activity-dependent subtractive inhibition (ADSI) model. The PSTH of the ANF input was time-shifted and integrated with an exponential kernel with time-constant τ Ito obtain an … see more
https://doi.org/10.7554/eLife.29639.006
Figure 3 with 1 supplement
Stimulus representation in the SBC responses is less accurate than in the ANF activity or in the inhibited EPSPs (EPSP fail ).
( A) Stimulus reconstruction was performed by estimating linear reconstruction kernels (2) for ANF-, EPSP fail- and SBC responses (1), separately. The respective reconstructions were then used to … see more
https://doi.org/10.7554/eLife.29639.008
Figure 3—source data 1
Correlation between real acoustic and reconstructed stimulus based on ANF input, SBC output and EPSP failsignals.
https://doi.org/10.7554/eLife.29639.010
Figure 3—figure supplement 1
For certain postsynaptic response properties, the effect of inhibition appears to be accounted for well by activity-dependent subtractive inhibition ( Figure 2 , and Keine et al., 2016 ).
We compared the stimulus reconstruction between the experimental SBC output and the ANF input subject to same subtractive inhibition as inFigure 2(ANF + SI, see Materials and methods for details). … see more
https://doi.org/10.7554/eLife.29639.009
Figure 4
Envelope fine-structure properties of the reconstructed stimulus differ between ANF and SBC responses.
( A) A 250 ms snippet of the real spectrogram (Figure 3B) zoomed in. The yellow box indicates a region for comparing the across frequency correlations across the different spectrograms (see G). ( B) … see more
https://doi.org/10.7554/eLife.29639.011
Figure 4—source data 1
Properties of the reconstructed stimulus based on ANF, SBC and EPSP failactivity.
https://doi.org/10.7554/eLife.29639.012
Author response image 1
Relation between spontaneous and driven failures.
(A) Acoustically driven failure rates always exceeded spontaneous failures, but correlated well with each other. This suggests that the effects of spontaneous failures and stimulus-driven failures … see more
Tables
Table 1
Summary of statistical comparisons.
https://doi.org/10.7554/eLife.29639.004
Source Parameter Group 1 (mean ± SD) Group 2 (mean ± SD) Test statistics Statistical test Figure 1 Panel Di (pure tones) Firing Rate ANF Spont = 71.3 ± 31.8 Hz Stim = 234.3 ± 53.9 Hz t(df = 31) = – 15.5, p=3.5e-16, U1=0.87 paired t test Firing Rate SBC Spont = 43.4 ± 18.3 Stim = 97.3 ± 33.9 t(31) = –10.9, p=3.5e-12, U1=0.59 paired t test Panel Dii (natural sounds) Firing Rate ANF Spont = 71.3 ± 31.8 Hz Stim = 129.7 ± 38.4 Hz t(31) = – 12.9, p=4.9e-14, U1=0.3 paired t test Firing Rate SBC Spont = 43.4 ± 18.3 Stim = 43.1 ± 22.1 t(31) = 0.12, p=0.9, U1=0.03 paired t test Figure 2 Panel A Threshold EPSP Spont = 7.5 ± 2.4 V/s Stim = 9 ± 2.8 V/s t(31) = – 10.2, p=1.8e-11, U1=0.1 paired t test Panel B Failure Fraction Spont = 0.36 ± 0.2 Stim = 0.65 ± 0.17 t(31) = – 16.3, p=9.1e-17, U1=0.28 paired t test Panel Ci Sparsity ANF input = 0.09 ± 0.05 SBC output = 0.17 ± 0.07 t(31) = – 6.9, p=8.2e-8, U1=0.17 paired t test Panel Di Reproducibility ANF input = 0.13 ± 0.09 SBC output = 0.28 ± 0.18 Z(N=32) = – 4.9, p=8.8e-7, U1=0.2 Wilcox. sig.-rank Figure 3 Panel K Corr. Section ANF = 0.66 ± 0.14 EPSP = 0.71 ± 0.11 Z(N=10) = – 2.8, p=0.006*, U1=0.1 Wilcox. sig.-rank Corr. Section ANF = 0.66 ± 0.14 SBC = 0.56 ± 0.16 Z(N=10) = – 2.8, p=0.006*, U1=0.1 Wilcox. sig.-rank Corr. Section EPSP = 0.71 ± 0.11 SBC = 0.56 ± 0.16 Z(N=10) = 2.8, p=0.006*, U1=0.35 Wilcox. sig.-rank Corr. Time Section ANF = 0.68 ± 0.14 EPSP = 0.71 ± 0.14 Z(N=10) = – 2.7, p=0.0117*, U1=0.1 Wilcox. sig.-rank Corr. Time Section ANF = 0.68 ± 0.14 SBC = 0.58 ± 0.15 Z(N=10) = 2.7, p=0.0117*, U1=0.15 Wilcox. sig.-rank Corr. Time Section EPSP = 0.71 ± 0.14 SBC = 0.58 ± 0.15 Z(N=10) = 2.8, p=0.006*, U1=0.25 Wilcox. sig.-rank Corr. Freq. Section ANF = 0.45 ± 0.042 EPSP = 0.44 ± 0.071 Z(N=10) = 1.6, p=0.39*, U1=0.2 Wilcox. sig.-rank Corr. Freq. Section ANF = 0.45 ± 0.042 SBC = 0.34 ± 0.058 Z(N=10) = 2.8, p=0.006*, U1=0.85 Wilcox. sig.-rank Corr. Freq. Section EPSP = 0.44 ± 0.071 SBC = 0.34 ± 0.058 Z(N=10) = 2.8, p=0.006*, U1=0.5 Wilcox. sig.-rank Factor 1 Factor 2 Figure 4 Panel E Autocorrelation Height: p=2.9e-25 Response Type: p=0.002 ANOVA, 2-factor Panel F Spectra Mod. Rate: p=1.7e-6 Response Type: p=2.1e-51 ANOVA, 2-factor Panel G Freq. XCorr Delta Freq: p=1.1e-14 Response Type p=0.023 ANOVA, 2-factor
*p-values Bonferroni-corrected for N = 3 comparisons.
Additional files
Source code 1
Calculation of threshold EPSP.
https://doi.org/10.7554/eLife.29639.013
Download elife-29639-code1-v2.m
Source code 2
Calculation of reproducibility.
https://doi.org/10.7554/eLife.29639.014
Download elife-29639-code2-v2.m
Source code 3
Calculation of sparsity.
https://doi.org/10.7554/eLife.29639.015
Download elife-29639-code3-v2.m
Source code 4
Simulation of activity-dependent subtractive inhibition.
https://doi.org/10.7554/eLife.29639.016
Download elife-29639-code4-v2.m
Supplementary file 1
Related toFigure 1.
Waveform audio file of presented natural stimulus. The stimulus was presented monaurally at a sampling rate of 97.65625 kHz.
https://doi.org/10.7554/eLife.29639.017
Download elife-29639-supp1-v2.wav
Transparent reporting form
https://doi.org/10.7554/eLife.29639.018
Download elife-29639-transrepform-v2.pdf
| https://elifesciences.org/articles/29639/figures |
An intelligent technique for generating equivalent KHN circuits using genetic algorithm | Request PDF
Request PDF | On Dec 1, 2015, Nariman A. Khalil and others published An intelligent technique for generating equivalent KHN circuits using genetic algorithm | Find, read and cite all the research you need on ResearchGate
Conference Paper
An intelligent technique for generating equivalent KHN circuits using genetic algorithm
December 2015
DOI: 10.1109/ICECS.2015.7440334
Conference: 2015 IEEE International Conference on Electronics, Circuits, and Systems (ICECS)
Authors:
<here is a image cad18239fce9acf3-646a9783b79e443c>
Nariman A. Khalil
Cairo University
<here is a image a8eada85d9dfe338-8d6a99a22ab739bc>
Rania Ahmed
Fayoum University
<here is a image 571d1f4cb8c18d86-b66b86e02b317806>
Rania Ahmed Abul Seoud
Fayoum University
<here is a image 408c13cbe7779723-c2c5e4e32a5fe885>
A.M. Soliman
Cairo University
Synthesis of CCII-s by superimposing VFs and CFs through genetic operations
Article
Full-text available
Jun 2008
IEICE ELECTRON EXPR
<here is a image 5b292c6d46e5efcb-d040119102e894ab> Esteban Tlelo-Cuautle
D. Moro-Frías
<here is a image b97e95091d94df3b-788fea7b2300f418> Carlos Sanchez-Lopez
<here is a image 7a195d785dc8be17-97d7354e5e5df596> Miguel Aurelio Duarte-Villaseñor
It is introduced a new genetic algorithm to synthesize the negative-type second generation current conveyor (CCII-) by superimposing a voltage follower (VF) with a current follower (CF). First, the VF and CF are described by binary genes. Second, the gene CF is inverted, rigth-shifted and multiplied (AND operation) with the gene VF to verify that both genes can be superimposed to synthesize the CCII-. Finally, some synthesized CCII-s are presented which electrical characteristics are measured using HSPICE and standard CMOS technology of 0.35 mu m.
Transconductance Amplifiers: NAM Realizations and Applications
Chapter
Full-text available
Feb 2012
<here is a image 408c13cbe7779723-c2c5e4e32a5fe885> A.M. Soliman
A systematic generation method of the single input single output transconductance amplifier (TA) based on using nodal admittance matrix (NAM) expansion is given. The four pathological elements used are the nullator, norator, voltage mirror (VM) and current mirror (CM). The single input single output TA also known as the voltage controlled current source (VCCS) includes two types depending on the direction of the output current. Two pathological realizations for each type using grounded resistor are given and eight pathological realizations for each type using floating resistor are also derived. Applications of TA in realizing grounded and floating resistors, grounded and floating inductors, first order voltage mode and current mode all pass filters, Tow Thomas second order filter, universal second order voltage mode and mixed mode filter using five single input differential output TA and one single input single output TA and oscillators using a single input single output TA are included.
On the Voltage Mirrors and the Current Mirrors
Article
Full-text available
Jul 2002
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Inas Awad
<here is a image 408c13cbe7779723-c2c5e4e32a5fe885> A.M. Soliman
The voltage mirror and the current mirror are two pathological elements used to represent active devices featuring voltage or current reversing properties. The properties of these ideal elements are presented and it is demonstrated that they form a complete set analogous to that formed by the nullator and the norator.
Generation of Kerwin‐Huelsman‐Newcomb biquad filter circuits using nodal admittance matrix expansion
Article
Full-text available
Jul 2011
INT J CIRC THEOR APP
<here is a image 408c13cbe7779723-c2c5e4e32a5fe885> A.M. Soliman
Nodal admittance matrix (NAM) expansion is used to generate a family of grounded passive component Kerwin Huelsman Newcomb (KHN) circuits. The generated KHN circuits have independent control on the selectivity factor and the radian frequency as in the original KHN, besides they have independent control on the gain, which is not achievable in the original KHN circuit. The NAM expansion is based on using nullor elements and voltage mirror and current mirror as well. Two types of the KHN circuit are considered, each includes four classes. For each class it is found that there are 32 different KHN circuit; therefore, there is a total of 128 circuits that belong to type-A KHN and a similar number for type-B KHN circuits. Simulation results are included to support the generation method. Copyright © 2010 John Wiley & Sons, Ltd.
Automatic Synthesis of VFs and VMs by Applying Genetic Algorithms
Article
Full-text available
Apr 2008
<here is a image 5b292c6d46e5efcb-d040119102e894ab> Esteban Tlelo-Cuautle
<here is a image 7a195d785dc8be17-97d7354e5e5df596> Miguel Aurelio Duarte-Villaseñor
Ivick Guerra-Gómez
An automatic synthesis method is introduced to design voltage followers (VFs) and voltage mirrors (VMs) by performing evolutionary
operations. It is shown that the nullor element is useful to introduce a new genetic representation to codify the behavior
of the VF by a chromosome divided by four genes: small-signal (genSS), synthesis of the nullor by MOSFET (genSMos), bias (genBias),
and synthesis of current mirrors (genCM). Further, it is shown that the behavior of the VM can be codified by evolving the
chromosome of the VF. The proposed synthesis method uses SPICE to evaluate the fitness of the VF and VM. Finally, we show
the synthesis of several VFs and VMs which are designed using standard CMOS technology of 0.35μm. The applications and evolution
of the VF and VM to synthesize more complex devices such as current conveyors (CCs) and inverting CCs are briefly discussed.
Noise performances of OTA-C filters
Conference Paper
Full-text available
Jul 1988
<here is a image af69ad80b4714f02-c9a353631157b6f7> Guillermo Espinosa
F. Montecchi
<here is a image cd822da2f0839ca4-ce043ff3e7c8f5b9> E. Sanchez-Sinencio
<here is a image d48bd8e8b6c36151-7e95bd35ccc1296b> Franco Maloberti
Noise performances of OTA-C (operational transconductance
amplifiers and capacitors) filters are presented in order to derive
their dynamic range limitations. In particular, the noise performances
of elementary building blocks are considered, and then the noise of
several OTA-C biquadratic structures is evaluated. Both white and
1/ f noise contributions are taken into account. Analytical
expressions and simulated results are given together with some practical
design considerations. The results put in evidence how the choice of any
topology affects the noise limitations of the filter. Topologies that
allow more degrees of freedom correspond to noisier structures
Use of Mirror Elements in the Active Device Synthesis by Admittance Matrix Expansion
Article
Full-text available
Nov 2008
IEEE T CIRCUITS-I
<here is a image 357c23d804bed170-c685d1cd287d0ad3> Ramy A. Saad
<here is a image 408c13cbe7779723-c2c5e4e32a5fe885> A.M. Soliman
This paper proposes a modification for the symbolic synthesis method of analog circuits using admittance matrix expansion. The modification involves a generalization of the synthesis approach to employ mirror elements (voltage mirrors and current mirrors) in the admittance matrix expansion and ideal description of active elements, rather than using only nullor elements (nullators and norators). Accordingly, more alternative ideal representations, based on nullor-mirror elements, can be realized and a wide range of active elements can be used in the circuit synthesis. Systematic synthesis of the CCII-based generalized impedance converters (GICs) is presented as an application example to illustrate the potential of this generalized approach. Multiple equivalent nullor-mirror realizations for the GIC could be extracted easily, by virtue of using mirror elements in the admittance matrix expansion. Consequently, numerous circuit realizations, spanning various combinations of CCII types, have been generated in a simple and direct way.
Current conveyors, operational amplifiers and nullors
Article
Dec 1989
IEE Proc G Circ Dev Syst
J. A. Svoboda
Nullors are used to provide a common framework for considering both current-conveyor and operational-amplifier circuits. A condition is established under which a current-conveyor circuit and an op-amp circuit can be said to be equivalent. A procedure is given for generating equivalent op-amp and current-conveyor circuits from a given op-amp (current-conveyor) circuit.
Inverting Second Generation Current Conveyors: The Missing Building Blocks, CMOS Realizations and Applications
Article
Apr 1999
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Inas Awad
<here is a image 408c13cbe7779723-c2c5e4e32a5fe885> A.M. Soliman
The concept of voltage mirror is introduced and used, together with the current mirror, to ideally represent the current and voltage inverting properties of some analogue building blocks. The properties of the nullor and mirror elements are used to relate the different devices in the ideal case as well as to define the adjoint network for each building block. Two new types of second generation current conveyor (CCII) are introduced. One is the adjoint of the CCII+ and is named the inverting second generation current conveyor ‘negative’ (ICCII–); the other is the ICCII+. CMOS realizations of the ICCII– are presented and new ICCII– based current mode circuits are obtained by applying a voltage-to-current-mode transformation to the CCII+ based circuits.
Pathological realizations of BOTA and FDDTA using grounded resistors
Article
May 2012
J CIRCUIT SYST COMP
<here is a image 408c13cbe7779723-c2c5e4e32a5fe885> A.M. Soliman
Sixteen pathological realizations of the balanced output transconductance amplifier (BOTA) using four grounded G are generated. Each of these circuits is realizable using four current conveyors (CCII) or four inverting current conveyors (ICCII) or a combination of four CCII and ICCII. Six new pathological realizations of the BOTA using two grounded G based on current subtraction are introduced. Four new pathological realizations of the BOTA using two grounded G based on voltage subtraction are introduced. Several new pathological realizations of the FDDTA as a voltage subtraction stage and a BOTA stage are also given. Simulation results are included.
A new approach for using the pathological mirror elements in the ideal representation of active devices
Article
Jan 2008
INT J CIRC THEOR APP
<here is a image 357c23d804bed170-c685d1cd287d0ad3> Ramy A. Saad
<here is a image 408c13cbe7779723-c2c5e4e32a5fe885> A.M. Soliman
This paper is adopting a new approach to investigate the capabilities of pathological mirror elements in the ideal representation of active building-blocks and shows that the voltage mirror (VM) and current mirror (CM) are the basic pathological elements. The descriptions for the floating mirror elements in the nodal admittance matrix (NAM), using infinity-variables, are derived. The descriptions for nullator and norator using infinity-variables in the NAM are shown to represent special cases from the derived descriptions of the floating VM and the CM, respectively. Hence, new representations for the nullator and norator in terms of the floating VM and CM, respectively, are obtained. A systematic procedure for the derivation of pathological configurations to ideally represent various analog signal-processing properties featured by active building-blocks is presented. This systematic approach became plausible by virtue of the versatility offered by the NAM descriptions of floating mirror elements. Novel pathological configurations ideally describing most popular signal-processing properties that involve differential or multiple single-ended signals; like conversion between differential and single-ended voltages, differential voltage conveying, current differencing, differential current conveying, and inverting current replication; are derived systematically using this procedure. The resulting pathological configurations are shown to be constructed mainly using mirror elements and hence the capabilities of the mirrors as basic pathological elements are further demonstrated. Pathological representations for some active building-blocks, using the derived pathological sections, are presented as application examples. Copyright © 2008 John Wiley & Sons, Ltd.
Systematic Synthesis of Active-RC Circuit Building-Blocks
Article
Jan 2005
D.G. Haigh
F. Q. Tan
<here is a image 1b45e5b11ae69206-bbc78889cb989afb> C. Papavassiliou
In this paper, we show how some basic building blocks for active-RC circuit design, such as amplifiers, impedance converters and simulated inductance circuits, may be synthesised in a systematic way by expansion of their port admittance matrices. The circuit topology emerges from the synthesis procedure, allowing all possible implementations to be identified and explored. Nullors representing ideal op-amps and transistors are represented within the nodal admittance matrix of a synthesised circuit by linked infinity parameters. In nodal admittance matrices describing ideal circuits synthesised, the replacement of linked infinity parameters by finite parameters provides a seamless transition to non-ideal analysis and practical circuit design.
Designing VFs by applying genetic algorithms from nullator-based descriptions
Conference Paper
Sep 2007
<here is a image 5b292c6d46e5efcb-d040119102e894ab> Esteban Tlelo-Cuautle
<here is a image 7a195d785dc8be17-97d7354e5e5df596> Miguel Aurelio Duarte-Villaseñor
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Carlos Alberto Reyes-Garcia
<here is a image 3625321ea81425da-d7e72a6930c77439> Gerardo Reyes Salgado
An automatic method is proposed to design CMOS compatible voltage followers (VFs) by applying genetic algorithms. It is described how an automatic system can deals with huge search spaces to design practical VFs by performing evolutionary operations from nullator-based descriptions. The proposed method consists of three main steps: generation of the small-signal circuitry, addition of biases, and sizing by using standard CMOS technology of 0.35 mum. Furthermore, it is described how to synthesize VFs by codifying the three main steps into three kinds of genes, and how to select small-signal, biased, and sized topologies to generate potential solutions. Finally, several applications are discussed along with the evolution of VFs to design current conveyors.
A nonlinear macromodel for CMOS OTAs
Conference Paper
Jan 1995
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Gabriel J Gomez
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Sherif Embabi
<here is a image cd822da2f0839ca4-ce043ff3e7c8f5b9> E. Sanchez-Sinencio
Martin C. Lefebvre
A nonlinear parameterizable macromodel for CMOS Operational
Transconductance Amplifiers (OTAs) is presented. The macromodel captures
the DC, AC and large signal features of the transistor level original
circuit, thus modeling accurately its time domain and nonlinear
performance. The main contribution of this work is to account for the
bias-dependent transconductance nonlinearities in the circuit, by
curve-fitting the desired output characteristics with n-dimensional
polynomials. The model can also account for the nonlinear dependence of
the circuit's characteristics on several design parameters. The
applicability of the model is demonstrated by modeling the response of
an OTA-C filter
Symbolic Framework for Linear Active Circuits Based on Port Equivalence Using Limit Variables
Article
Oct 2006
IEEE T CIRCUITS-I
D.G. Haigh
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Thomas J. Clarke
Paul M. Radmore
This paper proposes a new framework for linear active circuits that can encompass both circuit analysis and synthesis. The framework is based on a definition of port equivalence for admittance matrices. This is extended to cover circuits with ideal active elements through the introduction of a special type of limit-variable called the infinity-variable (infin-variable). A theorem is developed for matrices containing infin-variables that may be utilized in both circuit analysis and synthesis. The notation developed in this framework can describe nonideal elements as well as ideal elements and therefore the framework encompasses systematic circuit modeling
A Second-Generation Current Conveyor and Its Applications
IEEE Trans Circ Theor
A.S. Sedra
K.C. Smith
First Page of the Article
RC-Amplifier Resonators for Active Filters
IEEE Trans Circ Theor
Philip R. Geffe
Active filters may consist of a cascade of isolated resonators, with each resonator supplying a single pair of complexconjugate poles. This paper supplies a detailed analysis of some RC -amplifier resonators whose characteristics are well suited for practical filters. The calculations are facilitated by a set of sensitivity identities. One resonator, taken from the Sallen and Key catalog, is shown to have extremely low passive sensitivities: S_{Z}^{Q} = pm frac{1}{6} for all passive elements. Active Q multiplication is used to extend the usefulness of the circuit. Analysis of the dualintegrator feedback resonator shows that it is notably insensitive to amplifier parasitics. Finally, the dual-integrator concept is realized in a resonator that uses only two amplifiers. The several resonators supply a range of useful pole- Q 's from low values to several hundred.
Kerwin-Huelsman-Newcomb Circuit Using Current Conveyors
<here is a image 408c13cbe7779723-c2c5e4e32a5fe885> A.M. Soliman
Two equivalent circuits are generated using current conveyors to
realise the same three transfer functions as in the
Kerwin-Huelsman-Newcomb (KHN) biquad. Each circuit employs five current
conveyors; two of them act as buffers. In both circuits, the two
capacitors are grounded which is not the case in the KHN circuit
Symbolic analysis of networks containing current conveyors
Networks containing current conveyors can be analysed symbolically by the tree enumeration method. The procedures for incorporating inverting and noninverting current conveyors are different and involve operations on the voltage and current graphs.
Current conveyors, operational amplifiers and ors
IEE Proc G Circ Dev Syst
J.A. Svoboda
Nullors are used to provide a common framework for considering both current-conveyor and operational-amplifier circuits. A condition is established under which a current-conveyor circuit an an op-amp circuit can be said to be equivalent. A procedure is given for generating equivalent op-amp and current-conveyor circuits from a given op-amp (current-conveyor) circuit.
State-Variable Synthesis for Insensitive Integrated Circuit Transfer Functions
IEEE J SOLID-ST CIRC
W. J. Kerwin
L. P. Huelsman
<here is a image f5a6f174aae618d7-b0602d051d9a842f> Robert Newcomb
Using state-variable flow graphs and simple operational configurations suitable for integration, a theory for insensitive transfer function realization in terms of integrated circuits is discussed. The theory emphasizes the decomposition into second-order systems that are developed, following state-space concepts, with special reference to their sensitivity which is shown to be very low for high operational amplifier gains.
| https://www.researchgate.net/publication/304416860_An_intelligent_technique_for_generating_equivalent_KHN_circuits_using_genetic_algorithm |
(PDF) Electrical and microstructural properties of thermally annealed Ni/Au and Ni/Pt/Au Schottky contacts on AlGaN/GaN heterostructures
PDF | High work-function metals such as Ni, Pt, and Au in the form of multilayer structures, Ni/Au and Ni/Pt/Au, have been investigated as Schottky... | Find, read and cite all the research you need on ResearchGate
Article
Electrical and microstructural properties of thermally annealed Ni/Au and Ni/Pt/Au Schottky contacts on AlGaN/GaN heterostructures
July 2014
Semiconductor Science and Technology29(9):095005
DOI: 10.1088/0268-1242/29/9/095005
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Benedict Ofuonye
Benedict Ofuonye
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Jaesun Lee
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Minjun Yan
University of Illinois, Urbana-Champaign
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Changwoo Sun
Techinsights
Abstract and Figures
High work-function metals such as Ni, Pt, and Au in the form of multilayer structures, Ni/Au and Ni/Pt/Au, have been investigated as Schottky metallizations on AlGaN/GaN heterostructures under thermal annealing. As-deposited Ni/Pt/Au had slightly higher Schottky barrier height than its Ni/Au counterpart. Schottky barrier heights for Ni/Au diodes on AlGaN/GaN increased by about 20% from 1.02 eV for as-deposited to 1.21 eV after annealing at 500 °C for 2 min. Similar trends were observed for Ni/Pt/Au Schottky diodes. Thermal stability study for these devices showed that the interposition of Pt in Ni/Au systems improved the characteristics of the Schottky diodes after short-term anneal but cause significant degradation after long-term anneal at 500 °C. Ni/Au Schottky contacts exhibited excellent leakage response under thermal annealing for long periods. Microstructural studies were carried out on Ni/Pt/Au and Ni/Au Schottky contacts to elucidate the role of the Pt interlayer in the degradation of the Ni/Pt/Au metallization under long-term thermal anneal.
<here is a image 09f526cad8010e52-2d0b22a6060898e5>
Schottky barrier height of Schottky contacts to Al 0.25 Ga 0.75 N/GaN under 2 min furnace anneal. * Calculated relative to Al 0.25 Ga 0.75 N. …
<here is a image 9f6bece90d641b58-0b8186afed39bf30>
. High work function metals. …
<here is a image 049efd1f15607836-bd98293e11c5b61c>
Schottky barrier height of Schottky contacts to Al 0.25 Ga 0.75 N/GaN under cumulative furnace anneal at 500 °C. * Calculated relative to Al 0.25 Ga 0.75 N. …
<here is a image ad0c3ad619f9f7c4-87b1708775174ad4>
Ideality of Schottky contacts to Al 0.25 Ga 0.75 N/GaN under cumulative furnace anneal at 500 °C. * Calculated relative to Al 0.25 Ga 0.75 N. …
<here is a image 022ad62af219dbf5-eb4affde31c34247>
+3
Auger electron spectroscopy profiles of Ni/Au (30/50 nm) (a) to (c) and Ni/Pt/Au (30/30/50 nm) (d) to (f) before and after anneal at 500 °C. …
Figures - uploaded by
Minjun Yan
Electrical and microstructural properties of
thermally annealed Ni/Au and Ni/Pt/Au
Schottky contacts on AlGaN/GaN
heterostructures
Benedict Ofuonye
1
, Jaseun Lee
1
, Minjun Yan
1
, Changwoo Sun
2 ,3
,
Jian-Min Zuo
2
and Ilesanmi Adesida
1 ,2
1
Micro and Nanotechnology Laboratory, and Department of Electrical and Computer Engineering,
University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
2
Material Research Laboratory, and Department of Materials Science and Engineering, University of
Illinois at Urbana-Champaign, Urbana, Illinois 6180, USA
3
Department of Materials Science and Engineering, KAIST, Daejeon 305-701, Republic of Korea
E-mail: myan@illinois.edu
Received 8 May 2014
Accepted for publication 20 June 2014
Published 23 July 2014
Abstract
High work-function metals such as Ni, Pt, and Au in the form of multilayer structures, Ni/Au and
Ni/Pt/Au, have been investigated as Schottky metallizations on AlGaN/GaN heterostructures
under thermal annealing. As-deposited Ni/Pt/Au had slightly higher Schottky barrier height than
its Ni/Au counterpart. Schottky barrier heights for Ni/Au diodes on AlGaN/GaN increased by
about 20%from 1.02 eVfor as-depositedto1.21 eV afterannealing at500 °C for2 min. Similar
trends were observed for Ni/Pt/Au Schottky diodes. Thermal stability study for these devices
showed that the interposition of Pt in Ni/Au systems improved the characteristics of the Schottky
diodes after short-term anneal but cause signi fi cantdegradation after long-termanneal at500 °C.
Ni/Au Schottky contacts exhibited excellent leakage response under thermal annealingfor long
periods. Microstructural studies were carried out on Ni/Pt/Au and Ni/Au Schottky contacts to
elucidate the role of the Pt interlayer in the degradation of the Ni/Pt/Au metallization under long-
term thermal anneal.
Keywords: Schottky contact, AlGaN/GaN heterostructure, microstructure, thermal annealing
(Some fi gures may appear in colour only in the online journal)
1. Introduction
The high bandgap of GaN and AlGaN semiconductors puts a
restriction on the choice of metals for Schottky contacts to
only high work-function metals. n-GaN, for example, which
hasabandgapof3.4 eVandanelectronaf finityof4.1 eV
requires metals with work functions signi fi cantly higher than
4.1 eVtoformSchottkycontactswithappreciableSchottky
barrier heights (SBHs). With increasing Al mole fraction in
AlGaN, the electron af finity drops, so the barrier height
increases for the same work function metals [ 1 , 2 ]. However,
high Al mole fraction make it more dif fi cult to form excellent
ohmic contacts due to the high barrier to metals. Although
methods for enhancing the effective barrier heights by
exploiting the piezoelectric effects have been explored [ 3],
engineering the Schottky metal stack is perhaps a more pre-
ferable approach. Schmitz et al [ 4 , 5 ] undertook a compre-
hensive study of metal contacts to n-GaN and found that they
were ohmic or rectifying depending on the metal work-
function. The high work function metals had strong rectifying
behavior, however, the best gate metallizations for GaN-
based high electron mobility transistors (HEMTs) especially
for high temperature operation still remains to be determined.
Semiconductor Science and Technology
Semicond. Sci. Technol. 29 (2014) 095005 (10pp) doi:10.1088/0268-1242/29/9/095005
0268-1242/14/095005+10$33.00© 2014 IOP Publishing LtdPrinted in the UK1
Table 1 summarizes the metal work functions for some
selected metals [ 6 , 7 ]. As can be seen, the choice of metals for
Schottky metallization is limited to Pd, Ir, Ni, Au, and Pt,
which are the metals that provide the highest barrier heights.
Indeed, experimentally measured barrier heights on GaN have
shown that the high work function metals gave high barrier
heights [ 5 , 6 ]. However, some of these metals do not have
excellent adhesion to GaN [ 5 ]. Apart from excellent adhesion,
thermal stability is also critical to metallization for Schottky
gate contacts in order to obtain high performance GaN-based
HEMTs. The Schottky barrier height and leakage properties
of the Schottky contacts determine which contacts will pro-
vide the best gate control in AlGaN/GaN HEMTs. Ni-based
and Pt-based Schottky diodes are the most commonly used
gate structures for AlGaN/GaN HEMTs [ 1 , 8 –19 ]. Pt-based
Schottky diodes attracted recent interests for their applications
in hydrogen sensors [ 20 –22 ]. Ir and Re Schottky contacts
have also been investigated as possible gate metals with good
thermal stability and leakage behavior [ 23 , 24 ]. Se with a high
work function of 5.9eV has been investigated for Schottky
contacts on n-GaN recently [ 25 ]. TiN and RuOx were used on
AlGaN/GaN and InAlN/GaN heterostructures, with Schottky
barrierheightsof0.75 eV and1.24 eV,respectively[ 26 , 27].
Despite having a lower metal work function, Ni is more often
used than Pt as the Schottky metal especially for HEMT
devices. A major reason for using Ni over Pt is the stronger
adhesion of Ni to GaN than Pt. It should be noted that Au also
has very poor adhesion to GaN [ 5].
Miura et al [ 8 , 9 ] have investigated the interposition of Pt
between Ni and Au as a possible gate metallization for GaN-
based HEMTs. This serves two purposes. First, these metals
have the highest work functions and hence give the very high
Schottky barrier necessary for good gate control. Secondly, a
thin interfacial Ni layer ensures good metal-semiconductor
adhesion. The performance of this contact scheme showed
promise under thermal test in their study. A detailed study of
these Ni-based metallization schemes needs to be undertaken
both electrically and in terms of their microstructures to
determine the stack with the most ideal characteristics. In this
paper, we report a comprehensive electrical and micro-
structural characterization of Ni/Au and Ni/Pt/Au Schottky
contact metallizations to AlGaN/GaN HEMTs under thermal
annealing.
2. Experiment
A comprehensive investigation of the annealing effects on Pt
interposed Ni-based metals on n-GaN and AlGaN/GaN
Schottky contacts at a range of temperatures from 275°C to
575 °Cwascarriedout.ThelayerstructureofAlGaN/GaN
highelectronmobilitytransistor(HEMT) consistedof30 nm
ofAlGaN withAlconcentrationof 25%,followedby1.7 μm
of undoped GaN buffer layer. The following metallization
options were studied; (1) Ni/Au (30/50nm), (2) Ni/Pt/Au
(2.5/30/50 nm),and (3) Ni/Pt/Au (7.5/30/50 nm). To fabricate
Schottky diodes, optical lithography was used to de fi ne pat-
ternswith 300 μ m diameter circular gaps. Mo/Al/Mo/Au (15/
60/35/50 nm)ohmiccontactmetallizationwasdepositedin
the outer region by e-beam evaporation. Prior to ohmic con-
tact deposition, SiCl
4
plasma treatment at − 300 V for1 min in
a reactive ion etching (RIE) system was performed on the
ohmic region. After lift-off, the ohmic metallization for the
AlGaN/GaN layers was annealed at 575°C for 20min in a
furnace under N
2
ambient and was veri fi ed to have excellent
ohmic behavior. Schottky contact metallizations were then
patterned and deposited by e-beam evaporation in the inner
250 μ m diameter circle. Before ohmic and Schottky metal
evaporations, surface oxide was removed by dipping samples
in2:1DIwater:HClsolutionfor1 min.Formicrostructural
characterization, Ni/Au (30/50nm) and Ni/Pt/Au (30/30/
50 nm)metalschemesonAlGaN/GaNheterostructureswere
studied. Thicker interfacial Ni was used so that evolutions in
the metallizations could be quanti fi ed more clearly for
microstructure analysis. Current – voltage ( I –V ) characteristics
were measured using a semiconductor parameter analyzer.
Auger electron spectroscopy (AES) and scanning transmis-
sion electron microscopy (STEM) were performed to inves-
tigate microstructural characteristics of the Schottky contacts.
3. Results and discussion
Current – voltage measurements were used to characterize the
barrier heights of the AlGaN/GaN Schottky diodes. Ther-
mionic emission theory was used to extract the SBHs and
ideality factors for the AlGaN/GaN HEMT structures using
the electrical properties of AlGaN with aluminum con-
centration of 0.25. The values extracted in this manner are
relative because the impact of polarization and piezoelectric
charges from the 2-DEG formation were neglected
[ 10 , 12 , 13 ]. However, relative comparison of those values for
the different metallizations would give an indication of the
metallization with the best Schottky characteristics.
SBH characteristics for three different metal schemes
extracted from I – V measurements for the as-deposited and
furnace-annealed diodes in an N
2
ambient are presented in
fi gure 1 , as functions of annealing temperature. Squares are
for Ni/Pt/Au (2.5/30/50nm), circles are for Ni/Pt/Au (7.5/30/
Table 1. High work function metals.
Metal
Metal Work
Function
Φ
m
[eV]
Calculated Max SBH
ΦΦχ =−
Bm
Ga
N
[eV]
Contact
good for
Ta 4.250.15Ohmic
Al 4.280.18Ohmic
Ti 4.330.23Ohmic
Mo 4.60.5Ohmic/
Schottky
Au 5.11.0Schottky
Pd 5.121.02Schottky
Ni 5.151.05Schottky
Ir 5.251.15 Schottky
Pt 5.651.55Schottky
2
Semicond. Sci. Technol. 29 (2014) 095005B Ofuonye et al
50nm), and triangles are for Ni/Au (30/50nm) as shown in
the fi gure. The addition of Pt between Ni and Au enhanced
the barrier height of the as-deposited diodes signi fi cantly. It is
seen that all the metal schemes showed the same trend in
behavior forSchottky diodesamples annealedfrom275 °Cto
575 °C.Initially,the SBHsat275 °Cdecreasedslightlyfrom
their as-deposited values, then steadily increased to maximum
values at 500°C and dropped with further increase in tem-
perature. Theseresultsimply that 500 °Cmight be theoptimal
temperature for a 2min anneal. It is not clear why SBHs
droppedbelowtheas-depositedvaluesafter2 minannealing
at275 °Cforallthemetallizations.However,wehave
observed that, after annealing for a longer period at 275°C,
the typical SBH gradually increased above the as-deposited
value, indicating the quantity of heat applied to the Schottky
contacts might affect the barrier height. It is likely that
annealing enabled the e-beam evaporated Schottky metalli-
zations to form more intimate contacts to the GaN and
AlGaN/GaN, creating enhanced barrier heights due to the
difference in the metal work-function and the semiconductor
electron af finity.
The leakage of Schottky metallizations to GaN under
thermal storage is important because it impacts the perfor-
mance of the contacts. Several authors have used different
techniques to reduce leakage currents in n-GaN and AlGaN/
GaN Schottky contacts [ 28 –35 ]. Optimal thermal annealing
generally produces improvements in SBH and leakage char-
acteristics for Schottky diodes to n-GaN and AlGaN/GaN
[ 7 , 8 , 30 ]. Improvement in barrier height almost always
implies reduction in leakage current. Figures 2and 3show
SBH and ideality dependences on cumulative anneal time for
the different metallizations on AlGaN/GaN HEMT structure,
when subjected to thermal annealing in the furnace at 500°C
foruptoacumulativetimeof8 h.
Figure 2 shows that after 2h of annealing, the Ni/Au
metallization produced SBH greater than 1.2eV on the
AlGaN/GaN HEMT epilayer. The interposition of Pt between
the thin interfacial Ni (2.5nm and 7.5nm of Ni) and Au as
contacts resultedin SBHsof about 1.0 eVafter 4 hanneal and
was fairly constant at this value up to 8h of annealing. The
corresponding value of SBH for the equivalent Ni/Au was
∼ 1.3 eV,whichwas30%largerthanthatofNi/Pt/Au.The
degradation (i.e. higher values) in the ideality factors of the
Schottky diodes in the Ni/Pt/Au system as shown in fi gure 3
implies that under thermal anneal the diode quality degraded.
The thinner the thickness of Ni, the sooner the degradation of
Schottky contact occurred under thermal stress. The SBH of
theNi(2.5 nm)/Pt/Ausystemdroppedto ∼ 1.0 eVafter
30min of annealing, whereas the Ni (7.5nm)/Pt/Au dropped
to1.0 eVafter4 hofannealing.ItwasobservedthatNi/Au
exhibited the most increased barrier height and stability under
thermal stress, even though Ni/Pt/Au contacts had higher
Figure 1. Schottky barrier height of Schottky contacts to
Al
0.25
Ga
0.75
N/GaN under 2 minfurnaceanneal. * Calculated relative
to Al
0.25
Ga
0.75
N.
Figure 2. Schottky barrier height of Schottky contacts to
Al
0.25
Ga
0.75
N/GaNundercumulative furnaceannealat500 °C.*
Calculated relative to Al
0.25
Ga
0.75
N.
Figure 3. Ideality of Schottky contacts to Al
0.25
Ga
0.75
N/GaN under
cumulativefurnaceanneal at500 °C.*Calculatedrelative to
Al
0.25
Ga
0.75
N.
3
Semicond. Sci. Technol. 29 (2014) 095005B Ofuonye et al
SBH values at the initial stages of annealing. Contrary to
earlier investigations on Ni/Pt/Au [ 8 , 9 ], our study here
showed that Ni/Pt/Au Schottky diodes did not possess higher
barrier heights compared to Ni/Au Schottky diodes under
long-term thermal stress. The SBH of Ni/Au diodes increased,
albeit slowly, with the annealing time within the time
investigated.
In order to further investigate the behavior of the
Schottky diodes, it is essential to undertake microstructural
studies of contact metallizations. AES and STEM techniques
were used to analyze the contacts for intermetallic and
interfacial reactions after annealing. In order to elucidate the
interfacial and intermetallic evolution after anneal, thicker
interfacial metal layers were deposited. The thickness of
30 nm Ni layer was adopted as the metal stacks of Ni/Au (30/
50 nm)andNi/Pt/Au(30/30/50 nm),insteadofNi(7.5 nm)/
Pt/AuorNi(2.5 nm)/Pt/Au.
AES analyses of the Ni/Au (30/50 nm) and Ni/Pt/Au (30/
30/50nm) Schottky contacts to AlGaN/GaN before and after
500 °C annealfor2 minand1 h areshown in fi gures 4 (a) –(f).
After a 2 min anneal, the Ni/Au metal stack showed a trace of
out-diffusion of Ni to the surface, as shown in fi gure 4(b).
CompletemixingofNiandAuoccurredafter1 hannealas
shown in fi gure 4 (c). Up to 80% of the composition at the
surface was Ni while Au had also spread towards the interface
with AlGaN. It has been reported that many Ni-Au phases
wereformedat500 °C[ 36 ], due tothe af fi nity between Ni
and Au. Comparing AES pro fi les in fi gures 4 (d) – (f) for the
Ni/Pt/Au metallization stack, it is evident thatthere is mixing
of the metals after 1h anneal because of Ni out-diffusion
through Pt, all the way to the metal surface. Up to 70%
composition of the surface was Ni. A signi fi cant amount of Pt
(40%) and Ni (30%) composition near the AlGaN interface
suggests the possibility of Ni-Pt phase formation. There exist
someNi-PtandNi-Aualloyphaseswhichformat500 °C
such as NiPt, Ni
3
Pt, Pt
3
Ni, and Ni
x
Au
y
[ 36 –38 ]. This explains
the diffusion of Ni into Pt during anneal. The formation of
these Ni-Pt phases could be related to the degradation of the
Schottky contact as a function annealing time as the thin Ni
layer gradually intermixed with Au and Pt to form Ni-Pt and
Ni-Au alloys. The Ni-Pt and Ni-Au alloys contact the AlGaN
layer in parallel, resulting in a mixed-metal/semiconductor
interface. Consequently, these changed the Schottky proper-
ties of the Ni/Pt/Au metallization.
Figure 5 showsSTEMimagesofNi/Au(30/50 nm)and
Ni/Pt/Au(30/30/50 nm)contactstoAlGaN/GaNforas-
depositedandfor1 hannealingat500 °C.FortheNi/Au
contact,after1 hannealat500 °C,thelowmagni fication
STEM image exhibited the accumulation of Au at the inter-
face between the semiconductor and metal, as seen in
fi gure 5(b).
The high resolution image for Ni/Au in fi gure 6 (a) shows
the in-diffusion inlet of gold to the AlGaN interface with Ni
out-diffusing away from the surface, corroborating the
observation in the AES in fi gure 4 (c). No interfacial reaction
was observed at the metal – AlGaNinterface for1 hannealing
at500 °C,asthehighresolutionSTEMimagein fi gure 6(b)
indicates. A Z-intensity pro fi le characterization of the
interface area is shown in fi gure 6 (c). The Z-intensity is
proportional to the atomic number, Z, of the element. The
atomic number of Au is 79 and that of Ni is 28. With the high
Z-intensity at the metal – AlGaN interface, it was observed that
a thinAu-layerofatleast 2 nmwide haduniformly formedat
the interface. The sharpness of the Z-intensity pro fi le at the
interface indicates that no interfacial reaction occurred
between the metals and AlGaN. Therefore, the mechanism of
increased Schottky barrier height in the Ni/Au Schottky
contact to AlGaN/GaN in fi gure 2 could be explained from
the observation of a sustained accumulation of gold at the
interface, which created a uniform layer of Au contact to
AlGaN/GaN. As the thickness of the accumulated Au layer
increases beyond the critical Debye length necessary for
Schottky contacts, a higher barrier height is obtained that
approximates an Au-AlGaN Schottky contact. Since the metal
work function of Au is close to that of Ni, an increase in SBH
is seen when the metal contacting the AlGaN (Ni
x
Au
y
)
becomesmoreofAu.After1 hanneal,enoughAuhad
accumulatedtoforma2 nmAu-richregionattheinterface
(y ≫ x). Away from the interface, the Ni concentration
increasedsuchthatx ≫ yuntil itgot into thevery Au-rich
near outer surface regions, as shown in fi gures 4 (c), 6(a),
and (b).
Under annealing, the Ni/Pt/Au metallization exhibited
the formation of Ni-Pt phases as shown in fi gure 5 (d). Au also
accumulated at the interface, but unlike the case in the Ni/Au
metallization, there was no uniform accumulation of Au at the
interface. No interfacial reaction was observed, as shown in
the high resolution image in fi gure 7 (a). The formation of
mixed interface of Au-AlGaN and/or (Ni-Pt)-AlGaN explains
the degradation of barrier height in this metallization as
observed in the anneal results in fi gure 3 . The degradation of
idealities further solidi fi es the impact of the observed mixed
interfaces. Even thougha thick Ni (30 nm)was used in theNi/
Pt/Au contact for STEM studies, mixed interfaces were
observed. Hence, in the Ni/Pt/Au Schottky contacts,where Ni
waseither2.5 nmor 7.5 nm,itcouldbeexpectedthattheNi
was more aggressively consumed in forming Ni-Pt such that a
more mixed interface of Pt, Au, and thin Ni – Pt mixtures to
AlGaN resulted. The thicker the interfacial Ni, the more
degradation increased with annealing time. The reason for this
was due to the formation of Ni – Pt mixtures. The thicker the
interfacial Ni, the more Ni there was for the formation of Ni-
Pt alloys. Therefore, as the contact was continually annealed,
a more mixed interface resulted in degrading the Schottky
contact until all the interfacial Ni was consumed in forming
Ni – Pt. Inthe thinnerinterfacial Nimetallization (2.5 nm),this
happenedsoonerthaninthethickerinterfacialNi(7.5 nm)
and so it reached a constant SBH value during annealing
sooner, as seen in fi gure 2 . Also, the Ni – Pt phases formed at
the grain boundaries with dark spots segregating at these grain
boundaries, as shown in fi gures 7 (b) – (d). The dark spots were
probably due to some types of voids. These spots and the Ni-
Pt mixture boundary structures may also have contributed to
the degradation in barrier heights and diode idealities.
Due to the fact that the metallization at the AlGaN
interface is no longer uniform after annealing, the barrier
4
Semicond. Sci. Technol. 29 (2014) 095005B Ofuonye et al
became a mixture of many paths from the metal to the
AlGaN. This is like resistors in parallel where the net resis-
tance is smaller than the smallest value. Hence, the SBH is
smaller than one would expect for either Ni, Ni – Pt, Pt or Au
alone. Annealing thus created multi-paths due to a mixed
interface of (Ni – Pt)– AlGaN and Au – AlGaN as shown in the
illustrative schematic in fi gure 8 . Hence, the degradation of
the Ni/Pt/Au metallization can be attributed to the presence of
Figure 4. Auger electron spectroscopy pro fi les of Ni/Au (30/50 nm) (a) to (c) and Ni/Pt/Au (30/30/50 nm) (d) to (f) before and after anneal
at500 °C.
5
Semicond. Sci. Technol. 29 (2014) 095005B Ofuonye et al
Ni – Pt and Ni – Au phases and the formation of mixed interface
during thermal anneal, while the improved performance of the
Ni/Au contact was due to the accumulation of a uniformAu-
rich area at the interface. It should be noted that no interfacial
reactions of the metal with the AlGaN layer were observed
evenafter1 hannealforbothmetallizationcontacts.There-
fore, STEM analyses of the Ni/Au and Ni/Pt/Au contact
Figure 5. STEM images of Ni/Au and Ni/Pt/Au on AlGaN/GaN before and after anneal at 500 °C for 1h. (a) Ni/Au (30/50 nm) as deposited
on AlGaN/GaN, (b) Ni/Au (30/50 nm) on AlGaN/GaN after 500 °C anneal for 1 h, (c) Ni/Pt/Au (30/30/50 nm) as deposited on AlGaN/GaN
and (d) Ni/Pt/Au (30/30/50nm)on AlGaN/GaN after 500 °C anneal for 1h.
6
Semicond. Sci. Technol. 29 (2014) 095005B Ofuonye et al
Figure 6. High resolution STEM images of Ni/Au on AlGaN/GaN after 500 °C annealing for 1 h, (a) and (b), showing accumulation of Au at
the metal-AlGaN interface, (c) Z-intensity pro fi le of the Au/Ni-AlGaN/GaN interface showing a sharp interface and Au accumulation.
7
Semicond. Sci. Technol. 29 (2014) 095005B Ofuonye et al
metallizations to AlGaN do con fi rm the inter-metal mixing
observed in the AES plots in fi gure 4.
It has been reported that Ni/Ti/Pt/Au, Ni/Mo, and Ni/Au
Schottky contacts on n-type GaN under thermal annealing
have the similar trends, i.e. the optimal temperatures for
highest SBHs [ 39 –42 ]. There was a signi fi cant increase of Ni/
Ti/Pt/Au ’ s SBH at an annealing temperature of 400°C [ 39].
The Ni/Mo Schottky contact got the maximum SBH at
500 °C[ 40 ]. For an annealing temperature of 600°C for
5 min,theNi/AucontactobtainedahighestSBHof0.86 eV
[ 41 ]. For the same Ni/Au Schottky contact, another research
groupachievedtheoptimalvaluearound400 °C[ 42 ]. After
that, Schottky contacts got deteriorated. Schottky contacts
turned into Ohmic contacts when rapidly annealed at much
Figure 7. High resolution STEM images of Ni/Pt/Au on AlGaN/GaN after 500 °C annealing for 1h. (a) No interface reactions (b) Ni-Pt
phases formed, (c) Ni-Pt grain boundaries and (d) Dark spots at grain boundary.
8
Semicond. Sci. Technol. 29 (2014) 095005B Ofuonye et al
higher temperature of 750 °C [ 43 ]. The variance of SBHs and
associated ideality factors might be attributed to the interface
states or deep level defects below these Schottky contacts
[ 44 , 45 ]. The surface treatment with ammonium sul fi de or
tetramethylammonium hydroxide can reduce the interface
sate density and improve the electrical properties of Schottky
diodes [ 46 , 47 ]. Different surface passivation schemes with
additional thermal annealing and the temperature dependence
of SBHs will be explored for Ni-based Schottky contacts.
4. Conclusion
A comparative study of Ni/Au and Ni/Pt/Au Schottky contact
metallizations to AlGaN/GaN heterostructure has been
investigatedunder thermalannealtemperaturesupto 575 °C.
These Schottky contacts exhibited the same behaviors as they
wereprogressively annealedfor2 min Theinterpositionof Pt
improved the performance of the as-deposited Schottky
behavior.However,afterannealingat500 °Cforhours,the
Schottky characteristics of Ni/Pt/Au metallizationdegraded
due to the formation of Ni – Pt phases causing the Ni to diffuse
upward into the Pt and creating mixed interfaces, which
resulted in the lowering of the Schottky barrier heights. For
Ni/Au metallization, the uniform accumulation of Au at the
interface contributed to the increase of Schottky barrier
heights and also the stability of the contacts. Therefore, Ni/Au
contacts should be preferred to Ni/Pt/Au asSchottky gate
contacts for AlGaN/GaN HEMTs designed for operations at
temperatureupto500 °C.
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Temperature behavior of inhomogeneous Pt/GaN Schottky
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on structural and electrical properties of Ru/Au on n-GaN
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current mechanisms in Schottky contacts to GaN and
AlGaN/GaN grown by molecular-beam epitaxy J. Appl.
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[32]Kim H, Schuette M, Jung H, Song J, Lee J, Lu W and
Mabon J C 2006 Passivation effects in Ni/AlGaN/GaN
Schottky diodes by annealing Appl. Phys. Lett. 89 1 –3
[33]Kotani J, Kaneko M, Hasegawa H and Hashizume T 2006
Large reduction of leakage currents in AlGaN Schottky
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[34]Najo T, Oishi T, Suita M, Abe Y and Tokuda Y 2006 Effects
of a thin Al layer insertion between AlGaN and Schottky
gate on the AlGaN/GaN high electron mobility transistor
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[35]Sawada T, Kimura N, Imai K, Suzuki K and Tanahashi K 2004
Interpretation of current transport properties of Ni/n-GaN
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[36]Okamoto H and Massalski T B 1987 The Au-Ni (gold-nickel)
system Phase Diagrams of Binary Gold Alloys (Metals Park,
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[37]Nash P and Singleton M F 1991 Ni-Pt (nickel-platinum) Phase
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[38]Okamoto H and Massalski T B 1987 The Au-Pt (gold-
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[39]Mahony D O, Zimmerman W, Steffen S, Hilgarth J,
Maaskant P, Ginige R, Lewis L, Lambert B and Corbett B
2009 Free-standing gallium nitride Schottky diode
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[40]Jyothi I, Reddy V R, Reddy M S P, Choi C-J and Bae J-S 2010
Structural and electrical properties of rapidly annealed Ni/
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[41]Sun Y et al 2002 Thermal annealing behavior of Ni/Au on n-
GaN Schottky contacts J. Phys. D: Appl. Phys. 35 2648 –51
[42]Witte W, Fahle D, Koch H, Heuken M, Kalisch H and Vescn A
2012 Electrical properties of quasi-vertical Schottky diodes
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[43]Motayer A, Davydov A V, Bendersky L A, Wood M C,
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[46]Kumar A, Singh T, Kumar M and Singh R 2014 Sulphide
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[47]Reddy M S P, Son D-H, Lee J-H, Jang J-S and Reddy V R
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10
Semicond. Sci. Technol. 29 (2014) 095005B Ofuonye et al
... Then, the ohmic contacts were formed by depositing a Ti/Al/Ni/Au metal stack [145][146][147] and annealing at 850 • C for 30 s [148][149][150]. Next, the p-GaN gate was formed by depositing the Ni/Au metal stack and annealing at 500-800 • C [151]
[152]
[153]. Finally, the passivation layer was deposited to protect the device from environmental affecting. ...
A Brief Overview of the Rapid Progress and Proposed Improvements in Gallium Nitride Epitaxy and Process for Third-Generation Semiconductors with Wide Bandgap
In this paper, we will discuss the rapid progress of third-generation semiconductors with wide bandgap, with a special focus on the gallium nitride (GaN) on silicon (Si). This architecture has high mass-production potential due to its low cost, larger size, and compatibility with CMOS-fab processes. As a result, several improvements have been proposed in terms of epitaxy structure and high electron mobility transistor (HEMT) process, particularly in the enhancement mode (E-mode). IMEC has made significant strides using a 200 mm 8-inch Qromis Substrate Technology (QST®) substrate for breakdown voltage to achieve 650 V in 2020, which was further improved to 1200 V by superlattice and carbon-doped in 2022. In 2016, IMEC adopted VEECO metal-organic chemical vapor deposition (MOCVD) for GaN on Si HEMT epitaxy structure and the process by implementing a three-layer field plate to improve dynamic on-resistance (RON). In 2019, Panasonic HD-GITs plus field version was utilized to effectively improve dynamic RON. Both reliability and dynamic RON have been enhanced by these improvements.
... Whatever their values, however, the relevant point here is that a Schottky barrier like that depicted in Fig. 2b) is expected at the bottom interface. At the top interface we would expect a similar situation, even though the work function decreases among the series of electrodes employed (Ψ Pt ~ 5.65 eV, Ψ Ni ~ 5.15 eV, Ψ Ti ~ 4.33 eV, Ψ Cr ~ 4.5 eV) [14,
27]
so that different barrier heights can arise. From this picture, it clearly turns out that, in a perfectly symmetric capacitor (like in the case of Pt/KNN/Pt), there would be two counteracting rectifying barriers giving rise to a symmetric high impedance behavior. ...
Electrode-dependent asymmetric conduction mechanisms in K 0.5 Na 0.5 NbO 3 micro-capacitors
| https://www.researchgate.net/publication/264161831_Electrical_and_microstructural_properties_of_thermally_annealed_NiAu_and_NiPtAu_Schottky_contacts_on_AlGaNGaN_heterostructures |
Dr. Gabe Mirkin on Health, Fitness and Nutrition. | Sweet Drinks Raise Risk for Diabetes
Sweet Drinks Raise Risk for Diabetes
A just-published study shows that drinking either sugared or artificially-sweetened drinks is associated with increased risk for diabetes (Am J Clin Nutr, Jun 28, 2017). Of 64,850 post-menopausal women followed for 8.4 years, 4675 developed diabetes. Women who drank two 12-ounce cans (355 mL)/day of sugar-sweetened beverages had a 43 percent increased risk for developing diabetes, while those who drank the same amount of artificially-sweetened beverages had a 21 percent increased risk of developing diabetes. Replacing one can of artificially sweetened beverage with water reduced diabetes risk by five percent, and replacing one can of sugar sweetened beverage with water reduced the risk by 10 percent.Artificial Sweeteners May Change Colon BacteriaAnother team of researchers in Israel showed that artificial sweeteners (aspartame, saccharin and sucralose) raise blood sugar levels both in mice and in humans by changing the intestinal bacteria to favor those that appear to prevent the body from responding to insulin (Nature, September 17 2014).See Gut Bacteria Linked to DiabetesThe researchers found both lean and obese mice consuming the artificial sweeteners saccharin, sucralose or aspartame in their water over 11 weeks developed glucose intolerance, while those consuming plain water or water with glucose or sucrose did not. After a meal, mice given artificial sweeteners had blood sugar levels that rose higher and stayed higher longer.The mice that were given artificial sweeteners took in the same amounts of food and drinks and did the same amount of exercising (measured by how much they walked) as those not given the artificial sweeteners. Since the artificial sweeteners were the only variable, the authors felt that the higher blood sugar levels were caused by the artificial sweeteners and not by anything else. They found that:• Mice given saccharin developed new and different bacteria in their colons• When the mice taking the artificial sweeteners were given antibiotics, their blood sugar levels dropped to normal. The authors felt this showed that the artificial sweeteners raised blood sugar levels by changing the intestinal bacteria, since killing the new colon bacteria caused blood sugar levels to drop to normal.• Mice who had never taken artificial sweeteners and had normal blood sugar levels developed elevated levels of blood sugar after being given gut bacteria from mice fed large amounts of artificial sweeteners.• The new artificial-sweetener-induced-intestinal bacteria appeared to break down nutrients in food so that the mice absorbed more calories from the food they ate.• Giving stool from the people who took artificial sweeteners to bacteria-free mice caused the mice to develop glucose intolerance. Giving stool from non-diabetic humans who never took artificial sweeteners did not raise blood sugar levels in mice. Altering gut bacteria pathways may stimulate fat tissue to prevent obesity.Similar Results in HumansThe authors found that 381 people who were not diabetic but took artificial sweeteners regularly had higher blood sugar levels than those who took no artificial sweeteners.• Seven healthy adults who had not taken saccharin previously were given 120 mg/day of saccharin. This is the Food and Drug Administration's maximum acceptable dose (5 mg/kg body weight). In five weeks, four of the seven developed higher blood sugar levels, a decreased ability to respond to insulin and a change in their gut bacteria.• The 381 non-diabetic people who used artificial sweeteners regularly for a long time had more markers of diabetes: greater waist circumference (abdominal obesity), waist to hip ratio and blood levels of glucose after fasting, and decreased ability to respond to insulin.• Those who used artificial sweeteners had a different gut bacteria composition from people who did not consume artificial sweeteners.My RecommendationsRecent research strongly suggests that taking in large amounts of any sugared drinks, including fruit juices, is associated with increased risk for weight gain and diabetes. The data strongly suggest that sugared drinks are more harmful than those that contain artificial sweeteners.Recent research also suggests that artificial sweeteners increase risk for weight gain and diabetes in mice. However, we do not have enough data to prove that artificial sweeteners cause diabetes in humans. Criticism of studies on artificial sweeteners in humans centers on the fact that people who are overweight or diabetic may be more likely to use artificial sweeteners, so it is not possible to say that artificial sweeteners have any role in causing overweight or diabetes. Furthermore, we have suggestive data on saccharin but do not have strong data on any of the other artificial sweeteners. If artificial sweeteners do indeed increase risk for diabetes, I believe that they probably do so by changing bacteria in the colon.Checked 7/1/18
| https://www.drmirkin.com/bk9262019/amp/weekly-ezine-page/sweet-drinks-raise-risk-for-diabetes.html |
Blue Valley Lutheran Care Home: Nursing Home Overview
We gave Blue Valley Lutheran Care Home a A rating, see why this nursing home should/shouldn't be a fit for your family.
Blue Valley Lutheran Care Home
Blue Valley Lutheran Care Home
Nursing Home
Assisted Living
Historical Rating
Grade: A
Table of Contents
Quick Details
Specialized Services
Long-term Care Quality
Nurse Quality
Facility Inspections
Short-term Care Quality
Rating Over Time
Quality Metrics
Scores for Hebron, NE
Blue Valley Lutheran Care Home's website
P O Box 166, 755 South 3rd Street,Hebron NE 68370
•
(402) 768-3930
•
38.12% estimated occupancy 1
Quick Details
Specialized Services
Long-term Care Quality
Nurse Quality
Facility Inspections
Short-term Care Quality
Rating Over Time
Quality Metrics
Scores for Hebron, NE
Helpful Articles
With an address in Hebron, Nebraska, Blue Valley Lutheran Care Home is the only nursing home we identified in this city. It looks like this nursing home is among the most impressive nursing homes we found. A grade of this caliber requires top-notch scores across the board. We were so impressed with this nursing home that we ranked it in the top fifth of all facilities in the nation. Keep reading to see this facility's category scores, which are also strong. It's hard to find any major flaws in this nursing home's profile.
Quick Details
No Medicare 1
Accepts Medicaid 1
Is CCRC
Has Resident Council
No Family Council
Non profit - Church related
Offers Respite Care
Offers Inpatient Rehab
Specialized Services
Personal Care
Transportation
Dentistry
Respiratory Therapy
Nutritional Counseling
Optometry
Long-term Care Quality
Grade: A- plus
In addition to receiving a great overall grade, this facility also received an A+ long-term care grade. If you are seeking anything other than rehabilitation, you should take a close look at each facility's long-term care ratings. In addition to considering the amount of care provided by nurses and other staff, we analyzed the percentage of residents vaccinated against pneumonia. This facility gave the vaccine to 88.695656 percent of its residents. This is a bit below what we expected but still a decent percentage. While its vaccination rate was a bit lower than we like to see, at least this place was able to limit hospitalizations. Indeed, it had only 0.02 hospitalizations per 1,000 long-term resident days, which is a remarkably low figure.
Nurse Quality
Grade: A
Adding to its strong resume, this facility also received an excellent nursing score, with a grade of A. Nursing grades are primarily associated with the facility's nurse staffing. This nursing home provides 0 hours of nursing care per resident per day. Finally, our nursing grades also factor in quality-based assessments, such as avoiding major falls. This nursing home performed well in this area. Avoiding major falls is typically a good indicator that a place has reliable quality controls in place. Major falls can often be prevented if more nurses aids and better safety protocols are in place.
Facility Inspections
Grade: A- minus
Adding to this facility's impressive resume, we awarded this nursing home a grade of A- for our inspections rating. Inspection grades weigh several factors, including deficiencies, substantiated complaints and federal fines. You can learn more about each of these factors by reviewing copies of nursing homes' inspection reports. This place was hit with 3 deficiencies on its inspection report, but we were relieved to see that none were considered severe. This tells you that CMS did not deem any of these deficiencies to pose an imminent threat to resident safety or health. Finally, this facility had no substantiated complaints this year from residents, which is an excellent sign.
Short-term Care Quality
Grade: B- plus
In the final area, we awarded this facility a grade of A- for our short-term care rating. This finished off a very strong profile. With our short-term care rating, we strive to create a valuable barometer for rehabilitation services. In this process, we look at the nursing home's offerings of skilled nursing services, including both registered nurses and physical therapy, as well as respiratory therapy. Unfortunately, it does not look like this nursing home provided information on registered nurse or physical therapist staffing. Finally, we looked at the percentage of residents who returned home from this facility. We found that 0 percent of this nursing home's patients returned home.
Rating Over Time
Compared to national and state averages across all facilities.
F
D
C
B-
B
B+
A-
A
A+
Oct 18
Sep 22
Blue Valley Lutheran Care Home Quality Metrics
Minimizes Pressure Ulcers Grade: A- plus
In Blue Valley Lutheran Care Home, 5.27% of Patients had Pressure Ulcers
This indicates the percentage of residents who sustained a pressure ulcer. Pressure ulcers are skin damage resulting from staying in the same position for an excessive period of time.
Minimizes Serious Falls Grade: A
In Blue Valley Lutheran Care Home, 4.96% of Patients had Serious Falls
This figure gauges the percent of long-term stay residents who sustained falls leading to major injury. We use this statistic in determining our nursing scores.
Minimizes Urinary Tract Infections Grade: B- minus
In Blue Valley Lutheran Care Home, 3.66% of Patients had UTIs
This tells you the percent of residents who suffered from a urinary tract infection. UTI's are considered to be an indicator of nursing care . UTI's are routinely caused by a facility with worst hygiene practices. Nevertheless, this datapoint may be misleading for certain nursing homes due to varying reporting standards for urinary tract infections.
Appropriately Uses Anti-Psychotic Medication Grade: F
In Blue Valley Lutheran Care Home, 18.62% of Patients use Anti-Psychotic Medication
This figure gauges the percentage of long-term care patients who were given antipsychotic medication. Increased usage of these drugs may suggest that a facility is using these drugs to control patient behavior in scenarios where such medications are not medically indicated. However, some facilities need to rely more on these drugs due to having more patients suffering from cognitive disorders.
Appropriately Uses Anti-Anxiety Medication Grade: F
In Blue Valley Lutheran Care Home, 19.92% of Patients use Anti-Anxiety Medication
This tells you the percent of patients who were prescribed antianxiety drugs. Antianxiety drugs are prescribed to residents suffering from anxiety or depression.
Managing Depression Among Residents Grade: A+
In Blue Valley Lutheran Care Home, 4.32% of Patients
This indicates the percentage of patients who are showing symptoms of depression.
Appropriate Vaccine Usage Grade: C
In Blue Valley Lutheran Care Home, 93.19% of Patients
This datapoint is a measure of the percentage of long-term stay patients who received the flu and pneumonia vaccines.
Residents Maintain Autonomy Grade: B- minus
In Blue Valley Lutheran Care Home, 14.85% Percentage of Patients
This indicates the percent of residents who needed more assistance with activities of daily living over time.
Ability to Keep Residents Mobile Grade: C
In Blue Valley Lutheran Care Home, 18.85% Percentage of Residents
This tells you the percent of patients that maintained mobility over time. Optimizing mobility can be a great sign for residents' health.
Hospitalizations Grade: D
In Blue Valley Lutheran Care Home, 1.37 Hospitalizations per 1,000 resident days
This datapoint measures the number of hospitalizations per thousand days of patient care.
Short-term Care: Rehospitalizations Grade: A- minus
In Blue Valley Lutheran Care Home, 18.85 Percentage of Residents Rehospitalized
This is the number of rehospitalizations per thousand days of short-term patient care. There is typically a correlation between keeping patients out of the hospital and the quality of rehabilitation services.
Footnotes:
| https://elderguide.com/senior-living/blue-valley-lutheran-care-home-68370/ |
Unsupervised High-Dimensional Analysis Aligns Dendritic Cells across Tissues and Species | Request PDF
Request PDF | On Sep 20, 2016, Martin Guilliams and others published Unsupervised High-Dimensional Analysis Aligns Dendritic Cells across Tissues and Species | Find, read and cite all the research you need on ResearchGate
Unsupervised High-Dimensional Analysis Aligns Dendritic Cells across Tissues and Species
Immunity
Request full-text
... Les DC résidentes CD8 + correspondent aux cDC1 dans la nomenclature proposée par Guillams et al. D'autres marqueurs permettent de distinguer cette population tels que CD11b (intégrine M), CD172a (Sirp) ou encore XCR1 (récepteur à la chimiokine XCL1) [9]
[10]
[11]. Pour résumer, dans les organes lymphoïdes secondaires les cDC1 sont : CD8 + CD4 neg DEC-205 + CD24 + CD11b neg CD172a neg XCR1 + . ...
... Alors que, dans les autres tissus non lymphoïdes, les cDC2 sont toutes CD103 neg . Dans la peau les cDC2 CD11b neg sont dites doubles négatives (DN) et sont caractérisées par l'expression de CX3CR1, elles sont CD24 neg , CD103 neg et XCR1 neg
[10,
13,16,21]. ...
... Cependant, en condition inflammatoire ou dans certains tissus, elles peuvent exprimer F4/80 et CD64, marqueurs associés aux macrophages [9,
10]
. Néanmoins, CD64 reste le marqueur permettant de discriminer les cDC des populations monocytaires [22]. ...
Etude des voies de recrutement des cellules dendritiques dans une tumeur solide
Thesis
The concept of immunosurveillance suggests that the innate and adaptative immune system eliminate developing tumors. However, tumor development is associated with important modifications of the stroma which, by multiple mechanisms, restrain the immune response notably by affecting dendritic cells (DC) recruitment and functions. My thesis project aims at deciphering how the tumor environment alters the mechanisms and pathways of DC recruitment and impairs their functions. First, we determine if the site of tumor transplantation affects tumor immunogenicity. We show that tumors transplanted in the dermis (i.d.), an environment containing multiple DC subsets, induce a protective anti-tumoral immune response and tumor rejection. By contrast, the same tumor implanted in the subcutaneous tissue (s.c), mainly containing monocytes, is not rejected. Rejection of i.d. tumor is associated with a rapid (within 2 days) recruitment of DC within the tumor and rapid migration of DC towards tumor draining lymph nodes (dLN) where they present the tumor antigens (TAA) to CD4 and CD8 T lymphocyte. These events also occur for s.c. tumors but with a delayed kinetic. Thus the kinetic of DC mobilisation is decisive for tumor immunogenicity. Analysis of the DC subpopulations (TIDC) infiltrating the i.d. or s.c. tumors at 4 days (D4) and 8 days (D8) post-tumor transplantation, revealed that the different DC subpopulations are present at similar frequencies. Based on these findings, we proposed that i.d. tumor are rapidly infiltrated by dermal DC (DDC), whereas in s.c. tumor, the absence of inflammatory signals would limit DDC recruitment. In this latter case, DC would mainly come from local differentiation of blood-born precursors of DC (pre-cDC). Local differentiation of pre-cDC within the immunosuppressor tumor environment may affect their differentiation program and functions. We found that pre-cDC infiltrate i.d. and s.c. tumors starting at D4 and their frequency increases at D8. To determine the DC origin in tumors, we use CD11c-DTR-GFP mice in which CD11c+ cells express a fusion protein constituted by the diphtheria toxin receptor (DTR) and GFP. To track DDC trafficking within tumors, we injected anti-MHCII antibody before tumor implantation and analysed MHCII+ CD11c+ DDC infiltration in tumor by biphotonic microscopy. At D3 post-tumor transplantation, the DDC infiltration was higher in i.d. than s.c. tumors. To analyse the impact of this early DDC recruitment on anti-tumor immunity, we inhibit early recruitment of DC by injection of pertussis toxin (PTX), a chemokine receptor protein G inhibitor, during the three first days of tumor development. For i.d. tumors, PTX treatment induced 60% reduction of DC recruitment starting at D4. In s.c. tumor, while this effect was observable at D3 (60% reduction) and increased to 80% at D4. These results suggest that early recruitment of DDC to i.d. tumors may be be chemokine independent. PTX treatment, which inhibits DDC migration from tumors to dLN inhibits the early TAA presentation to CD4 and CD8 T cells but did not impaired i.d. tumor rejection. Collectively, these results suggest that a first wave of DDC may infiltrate i.d. tumor. The initial wave of DDC may rapidly activate the adaptive immune system and induce protective anti-tumoral immune response. For s.c. tumor, this first wave in delayed or limited. Tumor neoangioenesis would permit an input of pre-cDC which would differentiate locally into cDC1 and cDC2. To consolidate this model we are developing new protocols to efficiently inhibit early recruitment of DDC in i.d. tumor. Moreover, to determine the DC origin and pathways of DC recruitment in tumors, we exploit several experimental approaches to directly analyse DDC migration toward i.d. and s.c. tumor.
... Although F4/80 hi MPs phenotypically and transcriptionally resemble embryonic-derived macrophages (9,10) in adulthood they acquire prominent Clec9a-expression history (9). Because their affiliation as macrophages or DCs remains controversial (9)(10)(11)(12)(13)(14)
(15)
, we henceforth refer to these cells as F4/80 hi MPs. ...
... therapeutic purposes. Toxic acute kidney injury (AKI) is a common side effect resulting from cisplatin nephrotoxicity during cancer therapy
(15)
. In mice, cisplatin treatment similarly induces nephrotoxicity, but the role of individual MP subsets in disease remains unclear. ...
... Indeed, DT treatment of Clec9a cre Cd64 iDTR mice specifically and efficiently depleted CD64-expressing DCs from the kidney, while cDC1, cDC2, and other leukocytes were unaffected. CD64-expressing cells in other organs, which constitute mainly macrophages or monocytederived cells
(15)
were also unaffected. Importantly, F4/80 hi cells showed a stronger reduction following DT treatment than CD11b hi DCs, despite the fact that CD11b hi cells also exhibit Clec9a cre expression history and express CD64. ...
Selective depletion of a CD64-expressing phagocyte subset mediates protection against toxic kidney injury and failure
Article
Full-text available
Sep 2021
Natallia Salei
Xingqi Ji
Dalia Pakalniškyt _ E
Barbara Schraml
Significance
There continues to be a paucity in models to target mononuclear phagocyte (MP) subsets selectively and in specific tissues. We report a mouse model allowing for selective depletion of a specific subset of kidney MPs that is based on a Cre-inducible lox-STOP-lox-diphtheria toxin receptor gene controlled by the endogenous CD64 promoter. Combined with specific targeting of conventional DC1 (cDC1) and cDC2, we revealed that CD64 ⁺ MPs account for the reported ability of CD11c ⁺ cells to limit cisplatin nephrotoxicity, while cDC1 and cDC2 are dispensable. Our study highlights that individual MP subsets have unique functions in kidney pathology. Combined with various CRE drivers, CD64-lox-STOP-lox-diphtheria toxin receptor mice might be used to study CD64-expressing cells in other tissues.
... Specifically, cDC1 cells (expressing Itgae, Naaa, Xcr1 and Clelc9a) and cDC2 cells (expressing Sirpa and Cd209), as well as migratory (or mature) DCs (mDCs; expressing Ccr7, Tspan3, Tmem123, Cd40, Cd83 and Cd86) were expanded up to fourfold, as early as 2 weeks following MCDD (Fig. 1d,e and Extended Data Fig. 2b-d). Under physiological conditions, as well as in the case of damage or infection, cDCs integrate information about the immune environment in tissues (including antigens and surface-bound and soluble stimulatory and inhibitory signals) to instruct T cell differentiation in draining lymphoid organs
33
. As the role of cDCs in metabolic liver pathology development and progression has not been comprehensively studied so far, we decided to investigate the role of cDCs in NASH. ...
... We first confirmed the increased numbers of cDCs in the livers of mice fed an MCDD for 2 weeks using fluorescence activated cell sorting (FACS) and standard cDC markers, where cDCs were defined as CD45 + Lin − (CD3, CD19, B220, Ly6g, Ly6c, NK1.1 and Ter119) MHC-II + CD11c + (Extended Data Fig. 3a). As cDC are a heterogeneous cell type and their markers may vary across tissues
33
we used scRNA-seq analysis of index-sorted cDCs from Xcr1 Cre-mTFP1 (cDC1 reporter) mice to confirm the use of this gating strategy to define cDCs with high precision (Extended Data Fig. 3b). FACS analysis confirmed elevated frequency of cDCs among CD45 + liver cells in MCDD ( Fig. 2a and Extended Data Fig. 3c). ...
... To test whether NASH is associated with elevated frequencies of hepatic cDC1, cDC2 and mDCs, as observed in scRNA-seq ( Fig. 1) we applied flow cytometry analysis with standard markers; CD45 + Lin − MHC-II + CD11c + for cDCs, which were further separated into CD103 + CD11b − cDC1 cells, CD103 − CD11b + cDC2 cells (ref.
33
) and CCR7 + or CD86 + mDCs (Extended Data Fig. 3a). Combination of scRNA-seq with surface staining of cDCs confirmed that FACS-based quantifications using this gating strategy is robust and precise (Extended Data Fig. 3b). ...
XCR1 type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis
Article
Full-text available
NAT MED
Aleksandra Deczkowska
Eyal David
Pierluigi Ramadori
Ido Amit
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1⁺ cDC1 as an important driver of liver pathology.
... Further analysis of activation markers such as CD86 and CD40 revealed that LP increased the proportion of CD86 + CD11c + DCs in the orthotopic iKPC* mice ( Figure 2J). While pancreatitis induced an increase in the percentage CD11c + cells, murine macrophages can also express dendritic cell markers such as CD11c and MHC-II
(26)
. We confirmed that pancreatitis resulted in an increase in frequencies of MHC-II + F4/80 -CD11c + cells ( Figure 2K). ...
... We confirmed that pancreatitis resulted in an increase in frequencies of MHC-II + F4/80 -CD11c + cells ( Figure 2K). DCs are subdivided into distinct functional subsets, conventional DCs (cDCs), plasmacytoid DCs (pDCs) and monocytic DCs (mDCs)
(26)
(27)(28). Among conventional DCs, the cDC1s are important for the priming of tumor antigen specific T cell and facilitating their responses to restrain tumors, whereas cDC2s were found to be involved in tolerance induction that facilitate tumor growth (27). ...
Antigen-presenting type-I conventional dendritic cells facilitate curative checkpoint blockade immunotherapy in pancreatic cancer
Preprint
Mar 2023
Krishnan K. Mahadevan
Allison M. Dyevoich
Yang Chen
Raghu Kalluri
Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type-I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8 ⁺ T cell activation and eradication of ptPDAC with restoration of lifespan even upon PDAC re-challenge. Such eradication of ptPDAC was reversed following specific depletion of dendritic cells. Employing PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with a curative outcome. Analysis of the T-cell receptor (TCR) sequences in the tumor infiltrating CD8 ⁺ T cells following cDC1 vaccination coupled with iCBT identified unique CDR3 sequences with potential therapeutic significance. Our findings identify a fundamental difference in the immune microenvironment and adaptive immune response in PDAC concurrent with, or without pancreatitis, and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.
... Other studies have shown DC-committed cells among lymphoid-primed multipotent progenitors [4]. cDCs can be found in the T cell zone of the LN and the spleen and the thymus medulla, as well as in non-lymphoid organs [6]
[7]
[8]. Different cDC subtypes exist that express different surface markers (see next section) and perform different functions. Type 1 cDCs (cDC1) are characterized by the expression of the C-type lectin receptor Clec9a (also known as DNGR-1), and the X-C motif chemokine receptor 1 (XCR1). ...
... Mice deficient in cDC1s exhibit impaired antigen cross-presentation, cytotoxic lymphocyte responses against viral infection, and responses to tumor challenges [16]. cDC2s are more abundant and heterogeneous than cDC1s, and mediate antigen presentation via MHC-II to CD4 + T cells, promoting their differentiation into T helper type 17 (Th17) and 2 (Th2)
[7,
10,11,[18][19][20]. It has been suggested that cDC2s can be further classified into cDC2As and cDC2Bs depending on the expression of T-bet and RORγt, respectively [21]. ...
Dendritic Cells in Energy Balance Regulation
Article
Full-text available
Dec 2022
IMMUNOL LETT
Ana Redondo Urzainqui
Elena Hernández-García
Emma CL Cook
Salvador Iborra
Besides their well-known role in initiating adaptive immune responses, several groups have studied the role of dendritic cells (DCs) in the context of chronic metabolic inflammation, such as in diet-induced obesity (DIO) or metabolic-associated fatty liver disease. DCs also have an important function in maintaining metabolic tissue homeostasis in steady-state conditions. In this review, we will briefly describe the different DC subsets, the murine models available to assess their function, and discuss the role of DCs in regulating energy balance and maintaining tissue homeostasis.
... For example, the human F4/80 homologue, EMR1, is not present in myeloid cells and is expressed exclusively by eosinophils 227 . CD64 and merTK are more reliable positive markers to identify bona fide mature tissue macrophages in mice 228 , whereas CD26 is specifically expressed by the conventional dendritic cell (cDC) subsets cDC1 and cDC2 across all tissues
129
. ...
... By contrast, pDCs rapidly respond to viral pathogens by secreting type I interferons such as IFNα [125][126][127][128] across tissues can be identified by the expression of the surface receptor dipeptidyl peptidase 4 (also known as CD26) and the transcription factor ZBTB46 (reF.
129
). ...
A cardioimmunologist’s toolkit: genetic tools to dissect immune cells in cardiac disease
Article
May 2022
Anthony Wong
Homaira Hamidzada
Slava Epelman
Cardioimmunology is a field that encompasses the immune cells and pathways that modulate cardiac function in homeostasis and regulate the temporal balance between tissue injury and repair in disease. Over the past two decades, genetic fate mapping and high-dimensional sequencing techniques have defined increasing functional heterogeneity of innate and adaptive immune cell populations in the heart and other organs, revealing a complexity not previously appreciated and challenging established frameworks for the immune system. Given these rapid advances, understanding how to use these tools has become crucial. However, cardiovascular biologists without immunological expertise might not be aware of the strengths and caveats of immune-related tools and how they can be applied to examine the pathogenesis of myocardial diseases. In this Review, we guide readers through case-based examples to demonstrate how tool selection can affect data quality and interpretation and we provide critical analysis of the experimental tools that are currently available, focusing on their use in models of ischaemic heart injury and heart failure. The goal is to increase the use of relevant immunological tools and strategies among cardiovascular researchers to improve the precision, translatability and consistency of future studies of immune cells in cardiac disease.
... Non-macrophage cell populations included monocytes (cluster 0; marker genes: Ly6a, Ly6c2, Fcgr1 and Dpep2), neutrophils (cluster 7; Retnlg, S100a8, Cxcl2 and Hdc), B cells (cluster 11; Cd79a, Fcmr, Ly6d and Mzb1), conventional DC type 2 (cDC2) (cluster 12; Cd209a, Flt3, Ctnnd2 and Epcam),
27
The macrophage populations were examined in more detail, and the expression of the top 20 marker genes of each macrophage population was compared with their expression across all macrophage cell populations ( Figure 2f). Specific gene expression patterns differentiating these MΦ populations and certain overlaps could be determined. ...
... natural killer (NK) cells (cluster 14; Gzma, Xcl1, Ncr1 and Klrb1c), migratory DCs (migDC) (cluster 16; Ccl22, Bcl2l14, Fscn1 and Cacnb3), 28 plasmacytoid dendritic cells (pDCs) (cluster 18; D13Ertd608e, Siglech, Ccr9 and Pacsin1)
27
and four clusters with gene signatures suggesting various phenotypes of T cells (clusters 5, 10, 13 and 15). ...
Intratumoral injection of caerin 1.1 and 1.9 peptides increases the efficacy of vaccinated TC‐1 tumor‐bearing mice with PD‐1 blockade by modulating macrophage heterogeneity and the activation of CD8 + T cells in the tumor microenvironment
Article
Full-text available
Aug 2021
Guoying Ni
Xiaodan Yang
Junjie Li
Tianfang Wang
Objectives
Developing a vaccine formula that alters the tumor-infiltrating lymphocytes to be more immune active against a tumor is key to the improvement of clinical responses to immunotherapy. Here, we demonstrate that, in conjunction with E7 antigen-specific immunotherapy, and IL-10 and PD-1 blockade, intratumoral administration of caerin 1.1/1.9 peptides improves TC-1 tumor microenvironment (TME) to be more immune active than injection of a control peptide.
Methods
We compared the survival time of vaccinated TC-1 tumor-bearing mice with PD-1 and IL-10 blockade, in combination with a further injection of caerin 1.1/1.9 or control peptides. The tumor-infiltrating haematopoietic cells were examined by flow cytometry. Single-cell transcriptomics and proteomics were used to quantify changes in cellular activity across different cell types within the TME.
Results
The injection of caerin 1.1/1.9 increased the efficacy of vaccinated TC-1 tumor-bearing mice with anti-PD-1 treatment and largely expanded the populations of macrophages and NK cells with higher immune activation level, while reducing immunosuppressive macrophages. More activated CD8⁺ T cells were induced with higher populations of memory and effector-memory CD8⁺ T subsets. Computational integration of the proteome with the single-cell transcriptome supported activation of Stat1-modulated apoptosis and significant reduction in immune-suppressive B-cell function following caerin 1.1 and 1.9 treatment.
Conclusions
Caerin 1.1/1.9-containing treatment results in improved antitumor responses. Harnessing the novel candidate genes preferentially enriched in the immune active cell populations may allow further exploration of distinct macrophages, T cells and their functions in TC-1 tumors.
... Flow cytometry confirmed high expression of TIM4 protein in lung cDC1 and lack of expression in the other lung phagocytic subsets ( Supplementary Fig. 6a, b). Further profiling across multiple mouse tissues
38
showed the expected high expression in tissue resident macrophages, in a consistent fraction of Langerhans cells in the skin and in a fraction of dermal cDC1 32 . Slight TIM4 expression was present on liver cDC1, on a small fraction of migratory cDC1/cDC2 in mediastinal LNs and in splenic and bone marrow cDC1/cDC2, confirming the highest expression on lung cDC1 in naive mice ( Supplementary Fig. 6c, d). ...
... The pattern of expression and specific function of TIM4 in the DCs compartment has remained controversial, likely because of a lack of proper definition of DCs subset in past analysis 26,28,29,[49][50][51] . To fill this gap, we performed an extensive characterization of DCs subsets across mouse tissues using recently established gating strategies
38
. Besides the wellestablished expression in most tissue resident macrophages, we found a selective expression of TIM4 in mouse lung cDC1 that was higher than in any other tissues DCs. ...
TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses
Article
Full-text available
Apr 2021
Nicoletta Caronni
Giulia M Piperno
Francesca Simoncello
Federica Benvenuti
Acquisition of cell-associated tumor antigens by type 1 dendritic cells (cDC1) is essential to induce and sustain tumor specific CD8⁺ T cells via cross-presentation. Here we show that capture and engulfment of cell associated antigens by tissue resident lung cDC1 is inhibited during progression of mouse lung tumors. Mechanistically, loss of phagocytosis is linked to tumor-mediated downregulation of the phosphatidylserine receptor TIM4, that is highly expressed in normal lung resident cDC1. TIM4 receptor blockade and conditional cDC1 deletion impair activation of tumor specific CD8⁺ T cells and promote tumor progression. In human lung adenocarcinomas, TIM4 transcripts increase the prognostic value of a cDC1 signature and predict responses to PD-1 treatment. Thus, TIM4 on lung resident cDC1 contributes to immune surveillance and its expression is suppressed in advanced tumors.
... Наравне с макрофагами в почках описаны CD11c + -клетки, что указывает на наличие дендритных клеток
Guilliams et al., 2016;
Kawakami et al., 2013). Совокупная популяция макрофагов и дендритных клеток составляет менее 1% всех клеток почки, при этом преобладают в ней именно дендритные клетки (George et al., 2017;Soos et al., 2006). ...
МАКРОФАГИ
Book
Full-text available
May 2023
Andrey Elchaninov
Timur Fatkhudinov
В книге обобщены обширные литературные данные и собственные
экспериментальные исследования, касающиеся моноцитарно-макрофа-
гальной системы млекопитающих и человека как в норме, так и при пато-
логических состояниях, а также в условиях экспериментальных моделей
репаративных процессов. Рассмотрена новая концепция так называемой
макрофагальной ниши, которая призвана объяснить механизмы форми-
рования популяции органных макрофагов. Отдельное внимание уделено
специфическому для каждой из популяций органных макрофагов феноти-
пу. Приведены данные о гетерогенности моноцитов крови, их функциях,
роли различных субпопуляций моноцитов в воспалении, чувствительности
к факторам активации, значении селезенки в депонировании моноцитов.
Издание предназначено клеточным биологам, патофизиологам, био-
логам и врачам, интересующимся вопросами кроветворения и воспаления.
... Conventional type 1 DCs (cDC1) are the primary subset that cross-presents antigen to CD8 + T cells and predominantly produce IL-12 [23][24][25][26] . In contrast, conventional type 2 DCs (cDC2) have been associated with CD4 + T FH cell responses including GC T FH responses 22,26,
27
. Additionally, we monitored CD14 + CD16 − , CD14 + CD16 + and CD14 dim CD16 + Fig. 1 eLNP treatment promotes robust innate immune response and maturation. ...
Lipid nanoparticles (LNP) induce activation and maturation of antigen presenting cells in young and aged individuals
Article
Full-text available
Feb 2023
Jennifer Connors
David Joyner
Nathan Mege
Elias K Haddad
Herein, we studied the impact of empty LNP (eLNP), component of mRNA-based vaccine, on anti-viral pathways and immune function of cells from young and aged individuals. eLNP induced maturation of monocyte derived dendritic cells (MDDCs). We further show that eLNP upregulated CD40 and induced cytokine production in multiple DC subsets and monocytes. This coincided with phosphorylation of TANK binding kinase 1 (pTBK1) and interferon response factor 7 (pIRF7). In response to eLNP, healthy older adults (>65 yrs) have decreased CD40 expression, and IFN-γ output compared to young adults (<65 yrs). Additionally, cells from older adults have a dysregulated anti-viral signaling response to eLNP stimulation, measured by the defect in type I IFN production, and phagocytosis. Overall, our data show function of eLNP in eliciting DC maturation and innate immune signaling pathways that is impaired in older adults resulting in lower immune responses to SARS-CoV-2 mRNA-based vaccines.
... To resolve these conflicts, we applied scTriangulate, which produced a single high-confidence and comprehensive lung atlas, borrowing the best cell-type definitions from independent studies ( Fig. 5a-d). For example, scTriangulate was able to subdivide dendritic cells (DCs) and alveolar macrophages into more informative sub-populations than present in any singlereference lung atlas (Fig. 5e)
28
. Comparison of scTriangulate predictions to a cross-tissue mononuclear phagocytes atlas called MNP-VERSE, supports our finding of expanded DC and macrophage heterogeneity in the lung (Supplementary Figure 8b) 29 . ...
Decision level integration of unimodal and multimodal single cell data with scTriangulate
Article
Full-text available
Jan 2023
Baobao Song
Harinder Singh
Nathan Salomonis
Guangyuan Li
Decisively delineating cell identities from uni- and multimodal single-cell datasets is complicated by diverse modalities, clustering methods, and reference atlases. We describe scTriangulate, a computational framework to mix-and-match multiple clustering results, modalities, associated algorithms, and resolutions to achieve an optimal solution. Rather than ensemble approaches which select the “consensus”, scTriangulate picks the most stable solution through coalitional iteration. When evaluated on diverse multimodal technologies, scTriangulate outperforms alternative approaches to identify high-confidence cell-populations and modality-specific subtypes. Unlike existing integration strategies that rely on modality-specific joint embedding or geometric graphs, scTriangulate makes no assumption about the distributions of raw underlying values. As a result, this approach can solve unprecedented integration challenges, including the ability to automate reference cell-atlas construction, resolve clonal architecture within molecularly defined cell-populations and subdivide clusters to discover splicing-defined disease subtypes. scTriangulate is a flexible strategy for unified integration of single-cell or multimodal clustering solutions, from nearly unlimited sources.
... In contrast to the epidermis, the dermis harbors different subpopulations of dermal DC (dDC) comprising a small population of Langerin + DC and a major heterogeneous population of Langerin − CD11b low/+ DC [130]. Langerin + conventional DC (cDC)1, identified by the expression of the chemokine receptor XCR1
[131]
, can be further subdivided into CD103 + and CD103 − subsets, which both display low expression of CD11b and Epcam [130]. These Langerin + cDC1 are critical to cross-present exogenous Ag to CD8 + T cells promoting cytotoxicity [132], however, cross-presentation capacity was also demonstrated for Langerin − CD11b low cDC2 [133] and LC [134]. ...
Guidelines for mouse and human DC functional assays
Article
Full-text available
Dec 2022
EUR J IMMUNOL
Björn E Clausen
Lukas Amon
Thomas Hieronymus
Ronald Backer
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state‐of‐the‐art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non‐lymphoid tissues. Recent studies have provided evidence for an increasing number of phenotypically distinct conventional DC (cDC) subsets that on one hand exhibit a certain functional plasticity, but on the other hand are characterized by their tissue‐ and context‐dependent functional specialization. Here, we describe a selection of assays for the functional characterization of mouse and human cDC. The first two protocols illustrate analysis of cDC endocytosis and metabolism, followed by guidelines for transcriptomic and proteomic characterization of cDC populations. Then, a larger group of assays describes the characterization of cDC migration in vitro, ex vivo, and in vivo. The final guidelines measure cDC inflammasome and antigen (cross)‐presentation activity. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer‐reviewed by leading experts and approved by all co‐authors, making it an essential resource for basic and clinical DC immunologists.
... The priming and migration of T cells were determined by DCs. In addition, DCs can also generate the tertiary lymphoid structures in tumor microenvironment
[29]
. DCs were correlated with immunity in radiotherapy, chemotherapy, and checkpoint blockade. ...
Prognostic Biomarkers Identification in Esophageal Cancer Based on WGCNA and Single-Cell Analysis
Article
Full-text available
Dec 2022
DIS MARKERS
Wen-Jun Zhao
Yao Liu
Jing Guo
Hua Liu
Background:
Esophageal cancer is one of the most common cancers worldwide. Dysregulation of genes plays an important role in cancer. In this study, we aimed to investigate the prognostic biomarkers in esophageal cancer based on comprehensive bioinformatics analysis including WGCNA and single cell analysis.
Methods:
RNA sequencing data of esophageal cancer was downloaded from GSE75241 dataset in the GEO database. We also selected esophageal cancer patients from public databases (Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA)). WGCNA was used to construct a scale-free coexpression network of genes. Multifactor Cox analysis model was constructed as the prognostic model in esophageal cancer. Furthermore, single-cell gene analysis was used to discover the mechanism of hub genes in esophageal cancer.
Results:
WGCNA discovered 182 genes for further analysis. Among 182 genes, four genes including ANGPT2, VCAN, MS4A4A, and FOS had significant prognostic value in esophageal cancer. In single cell analysis, seven types of cells subsets were distinguished including T cells, B cells, NK cells, monocytes, macrophages, DCs, neutrophils. The expression of four hub genes (ANGPT2, VCAN, MS4A4A, and FOS) in inflammatory cell subsets was evaluated, respectively. Hub genes were correlated with inflammatory cells in esophageal cancer. In addition, the subgroups of specific inflammatory cells such as macrophages, monocytes, and DCs were analyzed to identify the function of hub genes, either. Hub genes were correlated with differentiation of inflammatory cells including monocytes, macrophages, and DCs in tumor environment.
Conclusions:
We identified specific hub genes correlated with prognosis of esophageal cancer. These hub genes play critical roles by regulating inflammatory cells status in esophageal cancer.
... Conventional type 1 DCs (cDC1) are the primary subset that cross-presents antigen to CD8+ T cells and predominantly produce IL-12 18,19,20,21 . In contrast, conventional type 2 DCs (cDC2) have been associated with CD4+ T FH cell responses including GC T FH responses 17,21,
22
. Additionally, we monitored CD14+CD16-, CD14+CD16+ and CD14 dim CD16 + monocytes. ...
Lipid nanoparticles (LNP) induce activation and maturation of antigen presenting cells in young and aged individuals
Preprint
Full-text available
Oct 2022
Jennifer Connors
David Joyner
Nathan Mege
Elias K Haddad
Despite the overwhelming success of mRNA-based vaccine in protecting against SARS-CoV-2 infection and reducing disease severity and hospitalization, little is known about the role lipid nanoparticles (LNP) play in initiating immune response. In this report we studied the adjuvantive impact of empty LNP with no mRNA cargo (eLNP) on anti-viral pathways and immune function of cells from young and aged individuals. We found that eLNP induced maturation of monocyte derived dendritic cells by measuring the expression of CD40, CD80, HLA-DR and production of cytokines including IFN-α,IL-6, IFN-γ, IL-12, and IL-21. Flow cytometry analysis of specific dendritic cell subsets showed that eLNP can induce CD40 expression and cytokine production in cDC1, cDC2 and monocytes. Empty LNP (eLNP) effects on dendritic cells and monocytes coincided with induction pIRF7 and pTBK1, which are both important in mitigating innate immune signaling. Interestingly our data show that in response to eLNP stimulus at 6 and 24 hrs, aged individuals have decreased CD40 expression and reduced IFN- γ output compared to young adults. Furthermore, we show that cDC1, cDC2, and CD14 dim CD16 ⁺ monocytes from healthy aged individuals have dysregulated anti-viral signaling response to eLNP stimulation as measured by the defect in type I IFN production, phosphorylation of IRF7, TBK-1, and immune function like phagocytosis. These data showed a novel function of eLNP in eliciting DC maturation and innate immune signaling pathways and that some of these functions are impaired in older individuals providing some suggestion of why older individuals (> 65 yrs of age) respond display lower immune responses and adverse events to SARS-CoV-2 mRNA-based vaccines.
... Based on their functions and transcriptional identities, DCs can be divided into two major subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can be further divided into type 1 cDCs (cDC1s) and type 2 cDCs (cDC2s)
[6]
. cDC1 can be either resident in the lymph node (LN) (characterized by CD8α-expression in mice) or migratory (characterized by expression of CD103 in mice). ...
The CD8+ memory T cell response following PLGA microparticle immunization
Thesis
Jan 2021
Anna MacKerracher
... To confirm the DC phenotype of the iPSC-derived cells in our new protocol, we analysed canonical DC markers by FACS and functionally interrogated the cells using an antigen processing (DQ-OVA) and T cell activation assays. We observed positive cells for DC markers (CD1C, CD209, CD11c, HLA-DR, CD86) and low levels of the macrophage marker CD14, thus validating the DC phenotype
56
(Fig. 5g and Supplementary Fig. 9F). Functionally, DQ-OVA antigen processing is higher in adult moDCs at earlier time points (15 to 30 min), whereas cDC processing capacity peaks at 60 min 57 . ...
Robust temporal map of human in vitro myelopoiesis using single-cell genomics
Article
Full-text available
May 2022
Clara Alsinet
Maria Primo
Valentina Lorenzi
Roser Vento-Tormo
Myeloid cells are central to homeostasis and immunity. Characterising in vitro myelopoiesis protocols is imperative for their use in research, immunotherapies, and understanding human myelopoiesis. Here, we generate a >470K cells molecular map of human induced pluripotent stem cells (iPSC) differentiation into macrophages. Integration with in vivo single-cell atlases shows in vitro differentiation recapitulates features of yolk sac hematopoiesis, before definitive hematopoietic stem cells (HSC) emerge. The diversity of myeloid cells generated, including mast cells and monocytes, suggests that HSC-independent hematopoiesis can produce multiple myeloid lineages. We uncover poorly described myeloid progenitors and conservation between in vivo and in vitro regulatory programs. Additionally, we develop a protocol to produce iPSC-derived dendritic cells (DC) resembling cDC2. Using CRISPR/Cas9 knock-outs, we validate the effects of key transcription factors in macrophage and DC ontogeny. This roadmap of myeloid differentiation is an important resource for investigating human fetal hematopoiesis and new therapeutic opportunities.
... In our study, immune cell infiltration analysis showed that infiltration of antigen-presenting cells, such as DCs, neutrophils, and B cells, was higher in the LR group. DC cells can be divided into conventional type 1 (cDC1s), con-ventional type 2 (cDC2s), and plasmacytoid DC (pDCs)
[41,
42]. In the mouse model, loss of cDC1s in the lung increased the tumor burden and decreased the infiltration of CD8 + T cells [43]. ...
Prognostic Risk Signature and Comprehensive Analyses of Endoplasmic Reticulum Stress-Related Genes in Lung Adenocarcinoma
Article
Full-text available
May 2022
CaiZhen Yang
YuHui Wei
Wentao Li
Guangnan Liu
Lung adenocarcinoma (LUAD) is the main pathological subtype of non-small-cell lung cancer. Endoplasmic reticulum stress (ERS) has been found to be involved in multiple tumor-related biological processes. At present, a comprehensive analysis of ERS-related genes in LUAD is still lacking. A total of 1034 samples from TCGA and GEO were used to screen differentially expressed genes. Further, Random Forest algorithm was utilized to screen characteristic genes related to prognosis. Then, LASSO Cox regression was used to construct a prognostic signature. Taking the median of signature score as the threshold, patients were separated into high-risk (HR) group and low-risk (LR) group. Tumor mutation burden (TMB), immune cell infiltration, cancer stem cell infiltration, expression of HLA, and immune checkpoints of the two risk groups were analyzed. TIDE score was used to evaluate the response of the two risk groups to immunotherapy. Finally, the gene expression was verified in clinical tissues with RT-qPCR. An eight-gene signature (ADRB2, AGER, CDKN3, GJB2, SFTPC, SLC2A1, SLC6A4, and SSR4) was constructed. TMB and cancer stem cell infiltration were higher in the HR group than the LR group. TIDE score and expression level of HLA were higher in the LR group than the HR group. Expression level of immune checkpoints, including CD28, CD27, IDO2, and others, were higher in the LR group. Multiple drugs approved by FAD, targeting ERS-related genes, were available for the treatment of LUAD. In summary, we established a stable prognostic model based on ERS-related genes to help the classification of LUAD patients and looked for new treatment strategies from aspects of immunity, tumor mutation, and tumor stem cell infiltration.
View
... After centrifugation at 1240rpm for 3 minutes, cells were washed in 2% serum PBS and then stained with Fc block (anti-CD16/32, clone 2.4G2; produced in-house from corresponding hybridomas obtained from ATCC) for 15 minutes at room temperature in the dark. Cells were washed once in 2% serum PBS then stained with the master stain (modified from a large multiparameter panel previously described in
26
) for 28 minutes on ice in the dark. After incubation, cells were washed twice in 2% serum PBS and then strained through 35µm strainers into FACS tubes (BD) for acquisition. ...
Maturation of Tolerogenic Dendritic Cells
Thesis
Apr 2021
Courtney A. Iberg
Dendritic cells (cDCs or DCs) comprise a heterogeneous population of antigen presenting cells (APCs) that are crucial in the promotion of both tolerogenic and effector T cell immune responses. Natural tolerogenic DCs (ntDCs), which are defined by high cell surface expression of B and T lymphocyte associated (BTLA), maintain tolerance in the absence of specific extrinsic signals (“steady state”), predominantly via their induction of peripheral regulatory T cells (pTreg cells). In contrast, through a phenomenon known as “maturation,” the capacities of some DCs to respond to specific, extrinsic, pro-inflammatory stimuli are increased, thereby resulting in the enhanced capacities of DCs to present antigen and stimulate effector T cell responses. Ultimately, though it is understood that inflammation (such as that induced by the archetypical DC maturation-inducing stimulus lipopolysaccharide (LPS)) increases the immunogenic potential of DCs, it remains unclear how naturally-tolerogenic, BTLA-expressing DCs respond to such specific, extrinsic signals in vivo. Here we elucidated the mechanisms and outcomes of LPS-induced maturation of natural tolerogenic DCs, and we discuss the implications of these newly-clarified mechanisms on the maintenance of immune homeostasis in vivo.
ProQuest Document ID: 2554354793
... We have used this tool to quantify the complex shifts in phenotypic markers present in T cells of different regions of brain, or transcriptional shifts occurring in microglia in the presence or absence of CD4 T cells 17 . Valid targets for the Cross Entropy test include any high-dimensional single cell dataset, routinely generated by single cell sequencing, flow cytometry or mass cytometry in fields ranging from immunology
18
to neuroscience 19 to cancer 20 . The growth of single cell technologies expands the potential range to techniques such as CODEX or other high-dimensional imaging technology 21 , single cell proteomics 22 or mutation analysis in single cell sequencing 23 . ...
A Cross Entropy test allows quantitative statistical comparison of t-SNE and UMAP representations
Preprint
Full-text available
Dec 2021
Carlos P.
Oliver T Burton
Julika Neumann
Adrian Liston
The advent of high dimensional single cell data in the biomedical sciences has necessitated the development of dimensionality-reduction tools. t-SNE and UMAP are the two most frequently used approaches, allowing clear visualisation of highly complex single cell datasets. Despite the ubiquity of these approaches and the clear need for quantitative comparison of single cell datasets, t-SNE and UMAP have largely remained data visualisation tools due to the lack of robust statistical approaches available. Here, we have derived a statistical test for evaluating the difference between dimensionality-reduced datasets, using the Kolmogorov-Smirnov test on the distributions of cross entropy of single cells within each dataset. As the approach uses the interrelationship of single cells for comparison, the resulting statistic is robust and capable of distinguishing between true biological variation and rotational symmetry generation during dimensionality reduction. Further, the test provides a valid distance between single cell datasets, allowing the organisation of multiple samples into a dendrogram for quantitative comparison of complex datasets. These results demonstrate the largely untapped potential of dimensionality-reduction tools for biomedical data analysis beyond visualisation.
... Notably, relative to the original source dataset publication 24 , scTriangulate was able to subdivide dendritic cells and alveolar macrophages into multiple populations delineated by well-defined literature markers 25,
26
(Figure 2i, Supplementary Figure 5b-f). ...
scTriangulate: Decision-level integration of multimodal single-cell data
Preprint
Full-text available
Oct 2021
Guangyuan Li
Song Baobao
H. Leighton Grimes
Nathan L Salomonis
Hundreds of bioinformatics approaches now exist to define cellular heterogeneity from single-cell genomics data. Reconciling conflicts between diverse methods, algorithm settings, annotations or modalities have the potential to clarify which populations are real and establish reusable reference atlases. Here, we present a customizable computational strategy called scTrianguate, which leverages cooperative game theory to intelligently mix-and-match clustering solutions from different resolutions, algorithms, reference atlases, or multi-modal measurements. This algorithm relies on a series of robust statistical metrics for cluster stability that work across molecular modalities to identify high-confidence integrated annotations. When applied to annotations from diverse competing cell atlas projects, this approach is able to resolve conflicts and determine the validity of controversial cell population predictions. Tested with scRNA-Seq, CITE-Seq (RNA + surface ADT), multiome (RNA + ATAC), and TEA-Seq (RNA + surface ADT + ATAC), this approach identifies highly stable and reproducible, known and novel cell populations, while excluding clusters defined by technical artifacts (i.e., doublets). Importantly, we find that distinct cell populations are frequently attributed with features from different modalities (RNA, ATAC, ADT) in the same assay, highlighting the importance of multimodal analysis in cluster determination. As it is flexible, this approach can be updated with new user-defined statistical metrics to alter the decision engine and customized to new measures of stability for different measures of cellular activity.
... Functionally, Langerin + cDC1 are primarily involved in the cross-presentation of circulating apoptotic cells, IL-12p70 production, and viral and bacterial clearance, while Langerin -cDC1 are less efficient in executing these tasks (1,(11)(12)(13)(14). CD11b + SIRP-α + cDC2 on the other hand are more heterogeneous than cDC1 and express cell-surface markers that overlap with monocyte-derived DC (Mo-DC) and macrophages
(15)
. cDC2 consist of at least two predominant lineages based on the mutually exclusive expression of the transcription factors (TF) T-bet and ROR-γt (16). ...
Posttranslational modifications by ADAM10 shape myeloid antigen-presenting cell homeostasis in the splenic marginal zone
Article
Full-text available
Sep 2021
Nathalie Diener
Jean-Fred Fontaine
Matthias Klein
Ronald Backer
Significance
Conventional dendritic cells (cDC) and macrophages display a high phenotypic and functional heterogeneity. ADAM10 regulates diverse cellular activities via so-called ectodomain shedding of cell-surface proteins. Here, we report that mice with a CD11c-specific deletion of ADAM10 exhibit defective cDC subset homeostasis in the splenic marginal zone (MZ). Specifically, ESAM hi cDC2A are replaced by a CX3CR1 ⁺ cDC2B population, and terminal differentiation of cDC1 is abrogated. Moreover, absent ADAM10 leads to the selective expansion of marginal metallophilic macrophages. Thus, ADAM10 represents an essential molecular switch on splenic antigen-presenting cells, shaping the anatomical niche of the MZ. Thereby, ADAM10-mediated posttranslational processes constitute a pathway beyond the usual and well-characterized transcriptional decisions governing tissue-specific cDC and macrophage subset commitment and homeostasis.
... Intestinal cDCs are heterogeneous and comprise two main subpopulations, termed cDC1 and cDC2 3 . These represent the two developmentally, phenotypically, and functionally distinct cDC lineages which can be distinguished in both mouse and human tissues by the expression of the chemokine receptor XCR1 and CD172a (SIRPα), respectively
22,
23 . However, whereas XCR1 represents a specific marker of cDC1s, mouse cDC2s share expression of CD172a as well as other markers, such as the alpha-M integrin CD11b, with macrophages (Table 1). ...
Dendritic cell functions in the inductive and effector sites of intestinal immunity
Article
Full-text available
Aug 2021
Cécilia Luciani
Fabian T. Hager
Vuk Cerovic
Hugues Lelouard
The intestine is constantly exposed to foreign antigens, which are mostly innocuous but can sometimes be harmful. Therefore, the intestinal immune system has the delicate task of maintaining immune tolerance to harmless food antigens while inducing tailored immune responses to pathogens and regulating but tolerating the microbiota. Intestinal dendritic cells (DCs) play a central role in these functions as sentinel cells able to prime and polarize the T cell responses. DCs are deployed throughout the intestinal mucosa but with local specializations along the gut length and between the diffuse effector sites of the gut lamina propria (LP) and the well-organized immune inductive sites comprising isolated lymphoid follicles (ILFs), Peyer’s patches (PPs), and other species-specific gut-associated lymphoid tissues (GALTs). Understanding the specificities of each intestinal DC subset, how environmental factors influence DC functions, and how these can be modulated is key to harnessing the therapeutic potential of mucosal adaptive immune responses, whether by enhancing the efficacy of mucosal vaccines or by increasing tolerogenic responses in inflammatory disorders. In this review, we summarize recent findings related to intestinal DCs in steady state and upon inflammation, with a special focus on their functional specializations, highly dependent on their microenvironment.
... We further validated these markers for DC from the CNS by analysis of the cDC-specific transcription factor Zbtb46 and cDC-specific gene expression. Several recent studies have sought to identify DC subset-specific transcriptomes and to identify novel DC subsets by gene expression in mouse and humans 145,
[164]
[165][166] . This includes further division of cDC into cDC1 and cDC2 subsets, specialized for activation of CD8 + or CD4 + T cells, respectively. ...
Distinct Myeloid Cell Subsets with Divergent Functions in Central Nervous System Autoimmunity
Thesis
Multiple sclerosis (MS) is a disabling disorder of the central nervous system (CNS) characterized by motor, visual, and sensory deficits. It is believed to be an autoimmune process in which immune cells infiltrate the brain and spinal cord leading to demyelination and cell death. Myeloid cells, such as macrophages and dendritic cells, are a major component of the cellular infiltrates in the CNS. Initial studies described these myeloid cells as pathogenic, but recent evidence in other systems has revealed that myeloid cells may also be anti-inflammatory and even pro-regenerative. Little is known about the heterogeneity of myeloid cells in MS. We set out to investigate the diverse phenotypes and functional properties of myeloid cells in CNS autoimmunity. Pro-inflammatory and anti-inflammatory myeloid cells have been termed classically or alternatively activated myeloid cells (CAMC, AAMC), respectively. We began by identifying markers of CAMC and AAMC in MS lesions. We observed a spectrum of activation such that CAMC were present at the active lesion rim while AAMC were predominant in the relatively quiescent lesion core. Using the animal model experimental autoimmune encephalomyelitis, we identified similar CAMC and AAMC in the CNS with the markers iNOS and Arg1, respectively. Myeloid cell phenotypes evolved such that iNOS+ CAMC were present early in disease while Arg1+ AAMC were present at peak and late disease. We further demonstrated that individual cells were plastic and shifted from expression of iNOS to Arg1 over the course of disease. One function of myeloid cells is the activation of T cells. Activation is critical for the initiation of disease. We compared the functional properties of Arg1+ and Arg1- cells and found that Arg1+ cells were deficient in activating CD4+ T cells compared with Arg1- cells. Investigation of the mechanism of this defect led to the elucidation of additional myeloid cell subsets. We identified that the dendritic cell population was heterogenous, not only in activation state or phenotype, but also in developmental lineage. We identified cells of both the conventional (cDC) and monocyte-derived dendritic cell (moDC) lineages in the CNS during EAE and demonstrated functional specialization between these subsets. iNOS and Arg1 expression were restricted to the moDC subset, and this subset as a whole was deficient in T cell activation but proficient in phagocytosis. Conversely, cDC were highly efficient in activating T cells but weak phagocytes. It is not clear which antigen presenting cell activates T cells to initiate disease. We observed that cDC were present in the naïve brain and meninges and that these cells from the naïve CNS could activate myelin-specific T cells. We further demonstrated that specific depletion of cDC reduces the incidence of EAE. This identifies cDC as critical antigen presenting cells for the initiation of CNS autoimmunity. Together, these studies clarify the diversity of myeloid cells and demonstrate functional differences with implications for clinical disease. The results presented herein provide a foundation for the development of myeloid cell-targeted therapies for MS.
... Additionally, BM macrophage signatures have been repeatedly under-or un-represented in high throughput tissue profiling studies [149][150][151] and macrophage ontogeny studies
[152]
[153][154]. The bone and BM environment present challenges that have contributed to this lagging discovery path. ...
Role of macrophages and phagocytes in orchestrating normal and pathological haematopoietic niches
Article
Full-text available
Susan Millard
The bone marrow (BM) contains a mosaic of niches specialised in supporting different maturity stages of haematopoietic stem and progenitor cells such as haematopoietic stem cells, myeloid, lymphoid and erythroid progenitors. Recent advances in BM imaging and conditional gene knock-out mice have revealed that niches are a complex network of cells of mesenchymal, endothelial, neuronal and haematopoietic origins, together with local physicochemical parameters. Within these complex structures, phagocytes such as neutrophils, macrophages and dendritic cells, all of which are of haematopoietic origin, have been shown to be important in regulating several niches in the BM, including haematopoietic stem cell niches, erythropoietic niches and niches involved in endosteal bone formation. There is also increasing evidence that these macrophages have an important role in adapting haematopoiesis, erythropoiesis and bone formation in response to inflammatory stressors and play a key part in maintaining the integrity and function of these. Likewise, there is also accumulating evidence that subsets of monocytes, macrophages and other phagocytes contribute to the progression and response to treatment of several lymphoid malignancies such as multiple myeloma, Hodgkin's and non-Hodgkin's lymphoma as well as lymphoblastic leukemia, and may also play a role in myelodysplastic syndrome, myeloproliferative neoplasms associated with Noonan syndrome and aplastic anaemia. In this review, the potential functions of macrophages and other phagocytes in normal and pathological niches will be discussed, as well as the challenges to studying BM and other tissue-resident macrophages at the molecular level.
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... These special features of macrophages might contribute to the B cell reaction in the omentum, as the omental germinal centre reaction occurs in the absence of the FDCs. Also, the maintenance of IL-10 producing regulatory B cells required an immunosuppressive environment, which might be attributed to the enrichment of M2 macrophages and the type 2 conventional dendritic cells (cDC2) in the omentum
[27]
. On the other hand, the presence of those cells such as B1 cells, cDC2 and M2 macrophages could suppress the anti-tumor immunity, which is correlated with the fact that tumor metastasis to the omentum, especially ovarian cancer, is associated with poor prognosis. ...
Characterization of specialized innate immune cells in the omentum
Article
The great omentum is an intraperitoneal organ and plays an important role in protecting the environment of the peritoneal cavity. Several specialized innate immune cells including B1 cells and resident macrophages are found in the omentum, which may be attributed to the unique niche and its special stromal cells. However, it is not clear how these omental innate immune cells contribute to the peritoneal immunity. This review attempts to summarize the latest research on the omental innate immunity and discuss its involvement in the immune response of the peritoneal cavity.
... Because macrophages and eosinophils also can express CD11c and MHC II to varying levels and might be contained in the CD11b þ subset, we excluded macrophages and eosinophils in advance using CD64, Siglec F, and CD11b markers. 48 The DCs and their subset populations adequately expressed the transcription factors ZBTB46, IRF8, and IRF4, as well as the DC subset surface markers SIRPa, CD24, and XCR1, 25,[49]
[50]
[51][52][53] and were dependent on the Flt3-Flt3-ligand pathway. Moreover, these populations were ablated by DT injection in Zbtb46-DTR BMT mice. ...
Programmed Death Ligand 1-Expressing Classical Dendritic Cells Mitigate Helicobacter-Induced Gastritis
Article
Full-text available
Seunghyun Lee
Su-Hyung Lee
Dae-Yong Kim
Background & aims:
Helicobacter pylori has been reported to modulate local immune responses in order to colonize persistently in gastric mucosa. Although the induced expression of programmed cell death ligand 1 (PD-L1) has been suggested as an immune modulatory mechanism for persistent infection of Helicobacter pylori, the main immune cells expressing PD-L1 and their functions in Helicobacter-induced gastritis still remain to be elucidated.
Methods:
The blockades of PD-L1 with antibody or PD-L1 deficient bone marrow transplantation were performed in Helicobacter-infected mice. The main immune cells expressing PD-L1 in Helicobacter-infected stomach were determined by flow cytometry and immunofluorescence staining. Helicobacter felis or pylori-infected dendritic cell (DC)-deficient mouse models including Flt3-/-, Zbtb46-DTR, and BDCA2-DTR mice were analyzed for pathological changes and colonization levels. Finally, the location of PD-L1-expressing DCs and the correlation with Helicobacter pylori infection were analyzed in human gastric tissues using multiplexed immunohistochemistry.
Results:
Genetic or antibody-mediated blockade of PD-L1 aggravated Helicobacter-induced gastritis with mucosal metaplasia. Gastric classical DCs (cDCs) expressed considerably higher levels of PD-L1 than other immune cells and co-localized with T cells in gastritis lesions from Helicobacter-infected mice and humans. Helicobacter felis or pylori-infected Flt3-/- or cDC-depleted mice showed aggravated gastritis with severe T cell and neutrophil accumulation with low bacterial loads compared with that in control mice. Finally, PD-L1 expressing DCs are co-localized with T cells and showed positive correlation with Helicobacter pylori infection in human subjects.
Conclusions:
The PD-1/PD-L1 pathway may be responsible for the immune modulatory function of gastric DCs that protects the gastric mucosa from Helicobacter-induced inflammation, but allows persistent Helicobacter colonization.
... As IL-27 is mainly produced by macrophages, and the liver has the largest proportion of macrophages among all solid organs of the human body
[40]
, we speculated that macrophages may affect liver injury partly by regulating IL-27 production. As the resident macrophages in the liver, KCs play a vital role in maintaining homeostasis in the liver itself and throughout the body, including removing bacteria and microorganisms that reach the liver and acting as a gatekeeper, initiating, or suppressing the immune response [41]. ...
Gadolinium Chloride Inhibits the Production of Liver Interleukin-27 and Mitigates Liver Injury in the CLP Mouse Model
Article
Full-text available
Background. Liver macrophages play an important regulatory role in the inflammatory response of liver injury after severe infection. Interleukin- (IL-) 27 is an inflammatory cytokine that plays an important role in diseases caused by bacterial infection. However, the relationship between IL-27 and liver macrophages in liver injury after severe infection is not yet clear. Methods. A cecal ligation puncture (CLP) model was established in wild-type (WT) and IL-27 receptor- (WSX-1-) deficient (IL-27r-/-) mice, and recombinant IL-27 and gadolinium chloride (GdCl3) were injected into WT mice in the designated groups. The serum and liver IL-27, IL-6, tumor necrosis factor alpha (TNF-α), and IL-1β expression levels were evaluated by ELISA, quantitative PCR, or Western blotting; serum ALT and AST were detected by detection kits; and the severity of liver damage was evaluated by hematoxylin and eosin staining and the TUNEL assay of the liver tissue from the different groups. Liver macrophage polarization was evaluated by immunofluorescence. In addition, the polarization of peritoneal macrophage was evaluated by flow cytometry. Results. The serum and liver IL-27 expression levels were elevated in WT mice after CLP-induced severe infection, which were consistent with the changes in HE scores in the liver tissue. The levels of serum ALT, AST, liver IL-6, TNF-α, and IL-1β mRNA and liver pathological injury scores were further increased when pretreated with recombinant IL-27 in WT mice, but these levels were decreased in IL-27r−/− mice after CLP-induced severe infection compared to WT mice. In WT mice pretreated with GdCl3, liver pathological scores, serum ALT and AST, TUNEL-positive cell proportion from liver tissues, liver IL-27 expression, and the liver macrophages M1 polarization proportion decreased after CLP; however, the serum IL-27, IL-6, TNF-α, and IL-1β levels and the pathological lung and kidney scores were not significantly changed. When supplemented with exogenous IL-27, the liver pathological scores, serum ALT, AST, TUNEL-positive cell proportion of liver tissues, liver IL-27 expression, and the liver macrophage M1 polarization proportion increased. The in vitro, IL-27 expression increased in peritoneal macrophages when stimulated with LPS. Recombinant IL-27 together with LPS promoted the elevations in IL-6, TNF-α, and IL-1β levels in supernatant and the M1 polarization of peritoneal macrophages. Conclusion. IL-27 is an important cytokine in the inflammatory response to liver injury after severe infection. The reduction of liver injury by gadolinium chloride in severe infection mice models may relate to the inhibition of liver IL-27 production. These changes may be mainly related to the decrease of liver macrophages M1 polarization. IL-27 may have a positive feedback on these macrophages.
1. Introduction
Acute liver dysfunction is a concomitant manifestation of many critical illnesses.
Liver dysfunction is sometimes closely related to poor prognosis in critical patients [1, 2]. Severe infection is one of the most important causes of liver dysfunction in critical patients [3]. In severe infection, the liver plays crucial roles in pathogen defense, clearance, and mediating inflammatory responses in the pathophysiology process [4]. However, this involvement is a double-edged sword: the liver removes bacteria and toxins and can also cause inflammation, immune suppression, and organ damage due to an overwhelming systemic inflammatory storm [5]. Interleukin- (IL-) 27 is a heterodimeric cytokine of the IL-12 family composed of the Epstein-Barr virus- (EBV-) induced gene 3 (EBI3) and the p28 subunit and plays an important regulatory role in the inflammatory responses of infectious disease [6, 7]. IL-27 is a biphasic regulator, acting as a pro- or anti-inflammatory factor under different conditions. It is involved in the induction of IL-10 production, Foxp32, and T-regulatory 1 (Tr1) cells and plays an anti-inflammatory effect [8, 9]; in contrast, it can act as a promotor in peritonitis and in ConA-induced liver injury animal models [10, 11].
Liver macrophages, especially Kupffer cells (KCs), play an important role in the regulation of inflammatory after severe infection [12]. In severe infection, activated Kupffer cells can release large amounts of cytokines, chemokines, prostaglandins, leukotrienes, and complement factors, playing an important role in regulating liver and systemic inflammation and promoting liver damage [13–15]. As IL-27 is mainly produced by macrophages and DCs [16], we speculate that macrophages may regulate liver damage by producing IL-27 in severe infections.
Gadolinium chloride (GdCl3) is an inhibitor of Kupffer cells [17]. It has been reported that GdCl3 contributes to the reduction of liver damage by inhibiting the activation of KCs according to many types of liver injury, including ethanol, dimethylnitrosamine, carbon tetrachloride administration (CCl4), and cadmium-induced liver injury [18, 19]. GdCl3 treatment reduced the proinflammatory cytokine levels of liver, including IL-6, TNF-α, IL-1β, and alleviated liver injury after CLP [20]. However, the exact mechanisms involved in the reduction of liver injury after GdCl3 treatment are not yet clearly known. Therefore, the aim of this study is to investigate whether GdCl3 can reduce liver injury by affecting IL-27 production.
2. Materials and Methods
2.1. Animal Models
Male C57BL/6 J mice aged 8–10 weeks were used to establish the cecal ligation puncture (CLP) model [21]. The sham group mice have underwent exactly the same procedures as the CLP group, without the cecum ligation and puncture. Wild-type (WT) C57BL/6 J mice were obtained from the Experimental Animal Center of Chongqing Medical University, and IL-27r-/- (WSX-1 knockout) C57BL/6 J mice were purchased from the Jackson Laboratory (Bar Harbor, ME, USA). All the mice were raised under the specific pathogen-free conditions. The animal experiments were approved by the Institutional Animal Care and Use Committee of Chongqing Medical University.
2.2. GdCl3 and Recombinant IL-27 Treatment
In the animal experiments, mice were intravenously injected (via tail vein) with GdCl3 (20 mg/kg body weight, Sigma-Aldrich) 24 h before CLP and then injected intraperitoneally with recombinant mouse IL-27 [7] (1 μg; ProSpec-Tany TechnoGene Ltd, Ness-Ziona, Israel) 2 h before CLP; all the groups were observed for 24 h after CLP injection. In the cell experiments, peritoneal macrophages were treated with recombinant IL-27 (50 ng/mL) 2 h before the addition of lipopolysaccharide (LPS, 100 ng/mL; Sigma–Aldrich, St. Louis, MO, USA), followed by incubation for 12 h.
2.3. Cell Extraction and Culture
Intraperitoneal injection of 3% thioglycollate is being used in C57BL/6 J mouse for 3 days, then the peritoneal cavity of each mouse was lavaged with 20 mL of PBS. After that, three to five milliliters of abdominal cavity liquid was extracted with a syringe and injected into a sterile centrifuge tube, which was then centrifuged at 1000 r/min for 5 min. The collected macrophages were resuspended in the medium (RPMI-1640 with 10% fetal bovine serum, 100 U/mL penicillin, and 10 μg/mL streptomycin) and then incubated in a 24-well plate at the concentration of cells/ml with the same medium, in the incubator at 37°C in a humidified atmosphere containing 5% CO2. After 2 h of incubation, warm PBS was used to wash the plate, nonadherent cells were removed with PBS, and then the adherent cells were incubated in the same medium and cultivation environment as before. The total liver macrophages of mice in the WT-CLP group and WT-CLP with GdCl3 pretreatment group were extracted as described [22].
2.4. HE and TUNEL
The liver, lung, and kidney tissues of mice obtained from each group at the indicated time point were fixed in paraformaldehyde, embedded in paraffin, and stained with hematoxylin and eosin (H&E) or using a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay kit (apoptosis detection kit (Roche, Mannheim, Germany)) to evaluate the cell apoptosis. Every tissue section was analyzed by light microscopy under ×200 and ×400 magnifications, and dark brown stained cell is positive. The liver, lung, and kidney pathology scoring methods used to evaluate the degree of tissue damage were previously described [23–25]. The degree of apoptosis was quantified based on the proportion of TUNEL-positive cells, counted under ×400 magnification of the microscope, 5 fields of view were taken for each tissue section, and 200 cells were counted in each field of view; the proportion of positive cells was calculated, and the final result of each tissue section is the average of the positive cell proportion of 5 fields of view.
2.5. Quantitative Polymerase Chain Reaction Assay
We followed the methods of Dr. Fan et al. 2019 [26]. Quantitative PCR (qPCR) for EBI3, P28, IL-6, TNF-α, and IL-1β was performed following the protocol by GeneCopoeia, Rockville, MD, USA. Total RNA was extracted from the liver tissue or cells using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) and reverse transcribed into cDNA using a high-capacity cDNA reverse transcription kit (Takara, Tokyo, Japan). The primer sequences were designed and chemically synthesized by Sangon Bio (Shanghai, China): EBI3 forward 5-GCT GCT CTT CCT GTC ACT TGC C-3 and reverse 5-TGA AGG ACG TGG ATC TGG TGG AG-3; p28 forward 5-CTG CTT CCT CGC TAC CAC ACT TC-3 and reverse 5-CTC TTC CTC CTT GTC CTC CTC CTC-3 (antisense); TNF-α forward 5-GCG ACG TGG AAC TGG CAG AAG-3 and reverse 5-GCC ACA AGC AGG AAT GAG AAG AGG-3; IL-6 forward 5-ACT TCC ATC CAG TTG CCT TCT TGG-3 and reverse 5-TTA AGC CTC CGA CTT GTG AAG TGG-3; IL-1β forward 5-TCG CAG CAG CAC ATC AAC AAG AG-3 and reverse 5-TGC TCA TGT CCT CAT CCT GGA AGG-3; glyceraldehyde 3-phosphate dehydrogenase (GAPDH) forward 5-AGC GAG ACC CCA CTA ACA-3 and reverse 5-GGG GCT AAG CAG TTG GTG-3.
2.6. Western Blot Analysis
Following the methods of Dr. Fan et al. 2019 [26], protein samples were harvested from the liver tissue or cells by lysis buffer containing protease and phosphorylation inhibitors, and the protein concentration was determined using a BCA Protein Assay Kit (Beyotime Biotechnology, Shanghai, China). The protein samples were separated by 10% SDS-PAGE and electrotransferred to polyvinylidene fluoride membranes (Millipore, Burlington, MA, USA). The membranes were blocked in QuickBlock™ Blocking Buffer for Western blotting (Beyotime Biotechnology) and then incubated with the following primary antibodies at 4°C overnight: rabbit polyclonal anti-IL-27-A antibody (p28) (1 : 500; Abcam, Cambridge, UK), rabbit polyclonal anti-IL-27-B (EBI3) antibody (1 : 500; AbKlean, Sangon Biotech, Shanghai, China), β-actin monoclonal antibody (1 : 1000), and β-tubulin monoclonal antibody (1 : 1000) (Boster Biological Technology, Wuhan, China); β-actin and β-tubulin were used as the sample loading controls. The next day, the membrane was incubated for 1 h at room temperature with peroxidase-conjugated goat anti-rabbit IgG (1 : 5000; ZSGB-BIO, Beijing, China) or goat anti-mouse IgG (1 : 1000; Boster Biological Technology, Wuhan, China) secondary antibody. Enhanced chemiluminescence was used to detect the proteins using a Chemiluminescent Detection Kit (Advansta, San Jose, CA, USA).
2.7. Cytokine and Liver Enzymes Assay
Following the methods of Dr. Fan et al. 2019 [26], IL-27 levels (R&D Systems, Minneapolis, MN, USA) in mouse serum and IL-6 (Boster Biological Technology, Wuhan, China) and TNF-α and IL-1β(R&D Systems) levels in cell supernatant were detected by enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer’s protocol.
Alanine aminotransferase (ALT) and aspartate transaminase (AST) in serum were measured at 24 h after CLP and normal controls using detection kits (Nanjing JianCheng Bioengineering Institute, Jiangsu, China).
2.8. Immunofluorescence
The immunofluorescence method for detecting liver macrophages is as follows: first, frozen liver sections were recovered by PBS and then 0.3% Triton X-100 (50 μL) was applied for 15 minutes to rupture the cell membrane. Later, we used sodium citrate solution and heating for antigen retrieval and normal goat serum to block the section. After that, rabbit anti-mouse F4/80 polyclonal antibody was added to the section, and incubation was performed in a humid chamber at 4°C overnight. The next day, the section was kept for 1 h at room temperature, washed in PBS, and then the goat anti-rabbit PE-Cy3 secondary antibody was added for 1 h at room temperature. After that, the section was washed in TBST for 3 times and used sodium citrate solution and heating for antigen retrieval and normal goat serum to block the section again. And then, rabbit anti-mouse CD206 polyclonal antibody was added to the section, incubated in a humid chamber at 4°C overnight. The following day, goat anti-rabbit FITC secondary antibody was added, and the detailed steps were the same as before. After that, the section was washed in TBST for 3 times again and used sodium citrate solution and heating for antigen retrieval and normal goat serum to block the section one more time. Later, rabbit anti-mouse iNOS polyclonal antibody was added to the section, and incubation was performed in a humid chamber at 4°C overnight. The following day, the goat anti-rabbit PE-Cy5 secondary antibody was added, and the detailed steps were the same as before. After washed, the section was added with autofluorescence quencher for 5 minutes and washed with running water for 10 minutes. Then, 4,6-diamidino-2-phenylindole (DAPI) was used to dye the cell nuclei; after that, the section was washed for 3 times, and antifade mounting medium was used for sealing. Positive cells were counted and analyzed by fluorescence microscope under ×200 magnifications of the microscope, 5 fields of view were taken for each tissue section, the total macrophage numbers, the M1 type macrophages, and the M2 type macrophages numbers were counted separately, the proportion of M1 and M2 type macrophages were calculated, and the final result of each tissue section is the average of the M1 and M2 type macrophage proportion of 5 fields of view. The primary and secondary antibodies were purchased from Servicebio, Wuhan, China.
The immunofluorescence method has also been used to detect the expression of IL-27p28 in liver macrophages. The detailed steps were the same as before. Rabbit anti-mouse F4/80 polyclonal antibody and goat anti-rabbit CY3-TSA secondary antibody were used for identifying the macrophages. And rabbit polyclonal IL-27p28 antibody and goat anti-rabbit FITC secondary antibody were used for detecting the expression of IL-27p28. The expression of IL-27p28 in F4/80-positive cells was analyzed by confocal microscopy under ×200 magnifications of the microscope, and 5 fields of view were taken for each tissue section. Total F4/80-positive cells, both F4/80 and IL-27p28-positive cells, were counted in each view, and the proportion of IL-27p28-positive cells in total F4/80-positive cells wascalculated. The average result of the 5 fields of view is the final result of each tissue section.
2.9. Flow Cytometry
The membrane surface molecules of cells were stained with 3 μL/test of PE-conjugated anti-mouse CD86 MAb (Invitrogen, California, USA) or APC-conjugated anti-mouse CD206 MAb (Invitrogen, California, USA) for 30 min at room temperature in the dark as per the manufacturer’s instructions. The mean fluorescence intensity (MFI) of the cell surface molecules was assessed by flow cytometry (FCM).
2.10. Statistical Analysis
The data in this study are expressed as the (SDs), and the statistical significance of differences between two groups was statistically analyzed with the independent -test. The one-way ANOVA or two-way ANOVA analysis was used when three or more groups were being compared. All of the analysis were performed with SPSS 23.0 statistical software and GraphPad Prism 7.04. was considered to be statistically significant.
3. Results
3.1. IL-27 Expression Is Upregulated in Liver Damage Mice after CLP
To verify the relationship between IL-27 and liver injury in a CLP-induced severe infection mouse model, we first detected IL-27 levels in serum by ELISA and the expression levels of EBI3 and P28 (subunits of IL-27) in the liver tissue by q-PCR and Western blot. We found that, compared to the sham group, the serum level of IL-27 was increased after CLP (; Figure 1(a)), and the liver EBI3 and P28 mRNA (by q-PCR) and protein expression levels (by Western blot) were also upregulated after CLP (; Figures 1(b) and 1(c)). Meanwhile, the levels of the inflammatory factors IL-6, TNF-α, and IL-1β in the liver tissue, determined by q-PCR, were also increased at the same time point after CLP (; Figure 1(e)). The histological scores of liver injury and serum ALT and AST levels also increased under the same conditions (; Figures 1(d) and 1(f)).
(a)
... 1 They encompass plasmacytoid DC (pDC) and type 1 and 2 conventional DCs (cDCs), identified in humans and mice based on ontogenic, phenotypic, and functional criteria.
[2]
[3][4][5] DCs originate in the bone marrow (BM), either as fully-differentiated pDCs, arising from both lymphoid and myeloid progenitors [5][6][7] , or as myeloid-derived cDC precursors (pre-cDCs), which complete their differentiation in peripheral tissues (PTs) or lymphoid organs (LOs) 3,8 . Langerhans cells (LCs) 9 are an additional DC-like subset that collaborate with bona fide DCs to shape immune responses. ...
CXCR4 signaling controls dendritic cell location and activation at steady-state and in inflammation
Article
Full-text available
Mathias Vétillard
Géraldine Schlecht-Louf
Dendritic cells (DCs) encompass several cell subsets that collaborate to initiate and regulate immune responses. Proper DC localization determines their function and requires the tightly controlled action of chemokine receptors. All DC subsets express CXCR4, but the genuine contribution of this receptor to their biology has been overlooked. We addressed this question using natural CXCR4 mutants resistant to CXCL12-induced desensitization and harboring a gain of function that cause the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) Syndrome (WS), a rare immunodeficiency associated with high susceptibility to the pathogenesis of human papillomavirus (HPV). We report a reduction in the number of circulating plasmacytoid DCs (pDCs) in WHIM patients, whereas that of conventional DCs is preserved. This pattern was reproduced in an original mouse model of WS, enabling us to show that the circulating pDC defect can be corrected upon CXCR4 blockade and that pDC differentiation and function are preserved, despite CXCR4 dysfunction. We further identified proper CXCR4 signaling as a critical checkpoint for Langerhans-cell and DC migration from the skin to lymph nodes, with corollary alterations of their activation state and tissue inflammation in a model of HPV-induced dysplasia. Beyond providing new hypotheses to explain the susceptibility of WHIM patients to HPV pathogenesis, this study shows that proper CXCR4 signaling establishes a migration threshold that controls DC egress from CXCL12-containing environments and highlights the critical and subset-specific contribution of CXCR4 signal termination to DC biology.
... DCs in lung are a highly heterogeneous population, containing conventional DCs (cDC), plasmacytoid DCs, and monocytederived DCs
(48)
. We were able to determine the increase of two cDC populations, CD103 − DCs and CD8 − DCs, which had increased expression of proinflammatory cytokines including IL-1α, IL-1β, IL-2, and IL-10. ...
Single-cell transcriptomic analysis reveals the immune landscape of lung in steroid-resistant asthma exacerbation
Article
Lingli Wang
Keilah Netto
Lujia Zhou
Ming Yang
Significance
Asthma exacerbation is not prevented by standard corticosteroid-based therapy and is the major burden in terms of morbidity, mortality, and health care costs associated with asthma. Etiology of disease exacerbation is highly heterogeneous. Using single-cell RNA deep sequencing, we undertook a large-scale, high-dimensional analysis of the immune landscape in lung following dexamethasone treatments in a mouse model of asthma exacerbation. We found multicellular signaling pathways closely associated with disease progression during the exacerbation. IL-13 produced by CD8 ⁺ memory T cells, ILC2, and basophils is key a cytokine in driving the pathogenesis of asthma exacerbation in this model. These data provide important insights into how the immune landscape in lung during asthma exacerbation can shape the progress of disease.
... thousand and one kinase | dendritic cell | Notch signaling C onventional dendritic cells (cDCs) orchestrate innate and adaptive immunity by taking up and presenting soluble and particulate antigens at sites of high exposure. Two subtypes of cDCs differ in molecular signature, function, and lineagedefining transcription factors
(1)
. Type 1 cDCs (cDC1s) are identified by high surface levels of XCR1 and CD24 and additionally express CD8α or the integrin α E (CD103) when they reside in lymphoid or nonlymphoid tissues, respectively. ...
TAO-kinase 3 governs the terminal differentiation of NOTCH2-dependent splenic conventional dendritic cells
Article
Dec 2020
Matthias Vanderkerken
Bastiaan Maes
Lana Vandersarren
Bart N Lambrecht
Significance
Dendritic cells (DC) play a crucial role in the immune system by bridging innate and adaptive immunity. In the spleen, a specific subset of DCs accumulates around the blood-filtering marginal zone to capture particulate antigens such as red blood cells. We show here that these specialized DCs develop in response to NOTCH2 instruction that is regulated by a poorly studied kinase, called Thousand and One Kinase 3 (TAOK3). This kinase controls DC development in a cell-intrinsic manner, rendering cells receptive to NOTCH2 signaling. Interfering with this kinase opens up ways to manipulate a specific subset of DCs.
... The expression profiles and surface markers of different DC groups can differ not only between species, but also in distinct tissues from the same organism
[116,
117]. Single-cell technologies have recently allowed the identification of additional DC subsets and redefining of existing ones. In this regard, a single-cell RNA-seq analysis of human peripheral blood has enabled the identification of six clusters of DCs [13]: DC1, corresponding to cDC1; DC2 and DC3, corresponding to a new subdivision of cDC2; DC4, corresponding to CD11c + CD141-CD1c-CD16 + DCs; DC5, a previously uncharacterized group [13]; and DC6, which corresponds to pDCs. ...
Tolerogenic Dendritic Cells in Autoimmunity and Inflammatory Diseases
Article
Dec 2020
Octavio Morante Palacios
Federico Fondelli
Esteban Ballestar
Eva Martinez Caceres
Dendritic cells (DCs), the most efficient antigen-presenting cells, are necessary for the effective activation of naïve T cells. DCs can also acquire tolerogenic functions in vivo and in vitro in response to various stimuli, including interleukin (IL)-10, transforming growth factor (TGF)-β, vitamin D3, corticosteroids, and rapamycin. In this review, we provide a wide perspective on the regulatory mechanisms, including crosstalk with other cell types, downstream signaling pathways, transcription factors, and epigenetics, underlying the acquisition of tolerogenesis by DCs, with a special focus on human studies. Finally, we present clinical assays targeting, or based on, tolerogenic DCs in inflammatory diseases. Our discussion provides a useful resource for better understanding the biology of tolerogenic DCs and their manipulation to improve the immunological fitness of patients with certain inflammatory conditions.
... These technologies have allowed researchers to assimilate a lot of new knowledge without a priori assumptions, such as screening for immune cell subsets present in a variety of different tissues and species [54] and how that changes in autoimmune diseases [55], harmonizing the markers used to identify cell types across different species
[56]
, and to better understand the ontogeny of immune subsets [36,54]. There are efforts underway to map the entire human body at single-cell resolution using these technologies, in the Human Cell Atlas project [57]. ...
The progression & delivery of adoptive cellular immune therapies: leveraging single-cell resolution & novel algorithms to overcome the challenges associated with allogeneic & autologous immune cell therapies
Article
Full-text available
Vicki Moignard
Alessandra De Riva
Raul Elgueta
... Alors que les cDC1 expriment spécifiquement certains marqueurs (CADM1, XCR1, CLEC9A) permettant leur délimitation précise, les cDC2 sont très hétérogènes et ont un phénotype chevauchant souvent celui des monocytes, en particulier dans certains tissus en situation inflammatoire, où des cellules dérivées de monocytes peuvent adopter un phénotype très proche de celui des cDC2
[6]
. Les monocytes sont également divisés en sous-populations définies en fonction de leur expression du récepteur pour la région Fc des immunoglobulines G (RFcgIIIA, CD16) et de CD14, un corécepteur du lipopolysaccharide bactérien (LPS). ...
Identification of circulating inflammatory dendritic cells by a multi-omic approach
Article
Full-text available
Nov 2020
M S-MED SCI
Charles-Antoine Dutertre
Florent Ginhoux
... In the draining aLN and spleen, the expansion and activation of macrophages, type 2 conventional dendritic cells (cDC2s), Langerhans cells and cDC1s was quantified by flow cytometry (Sup. Fig. 1b; gating strategy from
(35)
). In both the aLN and spleen of ChAdOx1 nCoV immunised mice there was a significant increase in the total number of CD11c + macrophages at day 2, while the total number of cDC2s, Langerhans and cDC1s remained unperturbed compared to PBS-immunised controls (Sup. ...
A booster dose enhances immunogenicity of the COVID-19 vaccine candidate ChAdOx1 nCoV-19 in aged mice
Preprint
Full-text available
Oct 2020
Alyssa Silva Cayetano
William Stefan Foster
Silvia Innocentin
Michelle A Linterman
The spread of SARS-CoV-2 has caused a global pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection, and may enable the relaxation of social distancing measures. Age is one of the most significant risk factors for poor health outcomes after SARS-CoV-2 infection, therefore it is desirable that any new vaccine candidates should elicit a robust immune response in older adults. Here, we test the immunogenicity of the adenoviral vectored vaccine ChAdOx1 nCoV-19 (AZD-1222) in aged mice. We find that a single dose of this vaccine induces cellular and humoral immunity in aged mice, but at a reduced magnitude than in younger adult mice. Furthermore, we report that a second dose enhances the immune response to this vaccine in aged mice, indicating that a primeboost strategy may be a rational approach to enhance immunogenicity in older persons.
... Alors que les cDC1 expriment spécifiquement certains marqueurs (CADM1, XCR1, CLEC9A) permettant leur délimitation précise, les cDC2 sont très hétérogènes et ont un phénotype chevauchant souvent celui des monocytes, en particulier dans certains tissus en situation inflammatoire, où des cellules dérivées de monocytes peuvent adopter un phénotype très proche de celui des cDC2
[6]
. Les monocytes sont également divisés en sous-populations définies en fonction de leur expression du récepteur pour la région Fc des immunoglobulines G (RFcgIIIA, CD16) et de CD14, un corécepteur du lipopolysaccharide bactérien (LPS). ...
Identification des cellules dendritiques inflammatoires par analyse multi-omique
Article
Nov 2020
Charles-Antoine Dutertre
Florent Ginhoux
Senescence-induced immune remodeling facilitates metastatic adrenal cancer in a sex-dimorphic manner
Article
Full-text available
Kate Warde
Lorenzo J. Smith
Lihua Liu
Katie Basham
Aging markedly increases cancer risk, yet our mechanistic understanding of how aging influences cancer initiation is limited. Here we demonstrate that the loss of ZNRF3, an inhibitor of Wnt signaling that is frequently mutated in adrenocortical carcinoma, leads to the induction of cellular senescence that remodels the tissue microenvironment and ultimately permits metastatic adrenal cancer in old animals. The effects are sexually dimorphic, with males exhibiting earlier senescence activation and a greater innate immune response, driven in part by androgens, resulting in high myeloid cell accumulation and lower incidence of malignancy. Conversely, females present a dampened immune response and increased susceptibility to metastatic cancer. Senescence-recruited myeloid cells become depleted as tumors progress, which is recapitulated in patients in whom a low myeloid signature is associated with worse outcomes. Our study uncovers a role for myeloid cells in restraining adrenal cancer with substantial prognostic value and provides a model for interrogating pleiotropic effects of cellular senescence in cancer.
Myocardial Immune Cells: The Basis of Cardiac Immunology
Article
Full-text available
J IMMUNOL
Charles D. Cohen
Sylvie Rousseau
Kevin Bermea
Luigi Adamo
The mammalian heart is characterized by the presence of striated myocytes, which allow continuous rhythmic contraction from early embryonic development until the last moments of life. However, the myocardium contains a significant contingent of leukocytes from every major class. This leukocyte pool includes both resident and nonresident immune cells. Over recent decades, it has become increasingly apparent that the heart is intimately sensitive to immune signaling and that myocardial leukocytes exhibit an array of critical functions, both in homeostasis and in the context of cardiac adaptation to injury. Here, we systematically review current knowledge of all major leukocyte classes in the heart, discussing their functions in health and disease. We also highlight the connection between the myocardium, immune cells, lymphoid organs, and both local and systemic immune responses.
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The role of dendritic cells in COVID-19 infection
Article
Mar 2023
Xuying Wang
Fei Guan
Heather Miller
Chaohong Liu
The persistent pandemic of coronavirus disease in 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently poses a major infectious threat to public health around the world. COVID-19 is an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potential multiple organ dysfunction. SARS-CoV-2 infection is closely related to the innate immune system and adaptive immune system. Dendritic cells (DCs), as a "bridge" connecting innate immunity and adaptive immunity, play many important roles in viral diseases. In this review, we will pay special attention to the possible mechanism of dendritic cells in human viral transmission and clinical progression of diseases, as well as the reduction and dysfunction of DCs in severe SARS-CoV-2 infection, so as to understand the mechanism and immunological characteristics of SARS-CoV-2 infection.
Type 2 Dendritic Cells Orchestrate a Local Immune Circuit to Confer Antimetastatic Immunity
Article
Mar 2023
J IMMUNOL
Orr-El Weizman
Sophia Luyten
Irina Krykbaeva
Akiko Iwasaki
The progression of transformed primary tumors to metastatic colonization is a lethal determinant of disease outcome. Although circulating adaptive and innate lymphocyte effector responses are required for effective antimetastatic immunity, whether tissue-resident immune circuits confer initial immunity at sites of metastatic dissemination remains ill defined. Here we examine the nature of local immune cell responses during early metastatic seeding in the lung using intracardiac injection to mimic monodispersed metastatic spread. Using syngeneic murine melanoma and colon cancer models, we demonstrate that lung-resident conventional type 2 dendritic cells (DC2) orchestrate a local immune circuit to confer host antimetastatic immunity. Tissue-specific ablation of lung DC2, and not peripheral DC populations, led to increased metastatic burden in the presence of an intact T cell and NK cell compartment. We demonstrate that DC nucleic acid sensing and transcription factors IRF3 and IRF7 signaling are required for early metastatic control and that DC2 serve as a robust source of proinflammatory cytokines in the lung. Critically, DC2 direct the local production of IFN-γ by lung-resident NK cells, which limits the initial metastatic burden. Collectively, our results highlight, to our knowledge, a novel DC2-NK cell axis that colocalizes around pioneering metastatic cells to orchestrate an early innate immune response program to limit initial metastatic burden in the lung.
Role of Immune Cells in the Tumor Microenvironment
Chapter
Feb 2023
B. Handan Özdemir
The tumor microenvironment (TME) encloses a repertoire of immune cells besides cancer cells. The role of immune cells in the TME plays an essential role in tumorigenesis, and it has gained more and more attention. The action of immune cells in tumor development and progression is nevertheless complex and bivalent depending on the nature of TME. These tumor-associated immune cells may generate tumor-antagonizing or tumor-promoting functions. It is crucial to understand and identify the interrelation between immune cells and tumor cells, which are closely related to the development and progression of the tumor. Even though the primary task of immune cells with antitumor properties is to destroy cancer cells during tumor development, tumor cells sometimes manage to escape the surveillance of immune cells. In addition, cancer cells can inhibit the cytotoxic functions of antitumor features of immune cells by using various mechanisms. Various immunotherapy treatments have been developed and applied to patients based on immune eradication mechanisms. Contrary to traditional chemotherapy, immunotherapy destroys cancer cells by harnessing the immune cells within or outside the TME. Immune checkpoint treatments and the application of adoptive immune cells, which have been used frequently recently, have shown successful antitumor effects in many different types of cancer, and such administrations have started a new era in cancer treatment. This chapter summarizes the features and functions of immune cells within TME and their participation in cancer immunotherapy.
HIV-1 cell-to-cell transfer and dissemination in myeloid cells
Thesis
Full-text available
Oct 2019
Maorong Xie
Dendritic cells (DCs), macrophages as well as osteoclasts (OCs) are emerging as target cells of HIV-1 involved in i) sexual transmission, ii) virus dissemination in different tissues, and iii) establishment of persistent virus reservoirs. While the mechanisms of virus cell-to-cell transmission toward these myeloid cells remain poorly understood, we recently reported a novel very efficient mechanism for virus transfer and dissemination in macrophages trough a two-step cell fusion process, leading to the formation of long-lived and highly HIV-1-productive multinucleated giant cells (MGCs). In the work presented here, we show that HIV-1 uses similar cell-fusion mechanisms for virus transfer from infected T lymphocytes to macrophages, OCs and immature DCs (iDCs), and subsequent dissemination in these target cells. The establishment of contacts with infected T cells leads to heterotypic cell fusion for the fast and massive transfer of viral material in macrophage, OC and iDC targets. This process subsequently triggers homotypic fusion with non-infected neighboring macrophages (or OCs, or iDCs) for intercellular virus dissemination. Both cell fusion steps are mediated by viral envelope-receptor interactions, and are highly efficient for macrophage-tropic CCR5- and CXCR4-using viruses, dual-tropic R5X4 viruses, and to a lesser extent for non-macrophage-tropic R5 viruses, including transmitted/founder viruses. Interestingly, these cell-to-cell fusion processes result in the formation of infected MGCs able to produce fully infectious virus particles. Together, our results reveal original mechanisms for viral transfer and dissemination in HIV-1 myeloid cell targets and for the formation of the MGCs observed in vivo in lymphoid and non-lymphoid tissues of HIV-1-infected patients. Thus far, numerous studies on HIV-1 co-receptor usage and cellular tropism have been performed using cell-free virus particles only, however, our data strongly indicate that the relationship between co-receptor usage and cellular tropism should be revisited in the context of HIV-1 cell-to-cell transfer. They contribute to a better understanding of the cellular processes involved in virus transmission, dissemination, and formation of viral reservoir during HIV-1 infection.
Single-cell transcriptomics reveals striking heterogeneity and functional organization of dendritic and monocytic cells in the bovine mesenteric lymph node
Preprint
Full-text available
Oct 2022
Güliz Tuba Barut
Marco Kreuzer
Rémy Bruggmann
Stephanie C. Talker
Dendritic and monocytic cells co-operate to initiate and shape adaptive immune responses in secondary lymphoid tissue. The complexity of this system is poorly understood, also because of the high phenotypic and functional plasticity of monocytic cells. We have sequenced mononuclear phagocytes in mesenteric lymph nodes (LN) of three adult cows at the single-cell level, revealing ten dendritic-cell (DC) clusters and seven monocyte/macrophage clusters with clearly distinct transcriptomic profiles. Among DC, we defined LN-resident subsets and their progenitors, as well as subsets of highly activated migratory DC differing in transcript levels for T-cell attracting chemokines. Our analyses also revealed a potential differentiation path for cDC2, resulting in a cluster of inflammatory cDC2 with close transcriptional similarity to putative DC3 and monocyte-derived DC. Monocytes and macrophages displayed sub-clustering mainly driven by pro- or anti-inflammatory expression signatures, including a small cluster of cycling, presumably self-renewing, macrophages.
With this transcriptomic snapshot of LN-derived mononuclear phagocytes, we reveal functional properties and differentiation trajectories in a “command center of immunity” that are likely to be conserved across species.
Mouse Dendritic Cells and other Myeloid Subtypes in Healthy Lymph Nodes and Skin: 26‐Color Flow Cytometry Panel for Immune Phenotyping
Article
Full-text available
Aug 2022
EUR J IMMUNOL
Florian Hornsteiner
Martina Sykora
Christoph H Tripp
Patrizia Stoitzner
This novel 26‐color flow cytometry panel allows the detailed immune phenotyping of the complex network of myeloid cells in murine lymph nodes and skin. With the optimized panel the different murine DC‐subsets and other myeloid cell types can be identified and further characterized for co‐stimulatory and inhibitory surface molecules. image
Type 2 cytokines in the thymus activate Sirpα+ dendritic cells to promote clonal deletion
Article
Full-text available
May 2022
NAT IMMUNOL
Elise Breed
Matouš Vobořil
Katherine Maude Ashby
Kristin A Hogquist
The thymus contains a diversity of dendritic cells (DCs) that exist in defined locations and have different antigen-processing and -presenting features. This suggests that they play nonredundant roles in mediating thymocyte selection. In an effort to eliminate SIRPα+ classic DC2 subsets, we discovered that a substantial proportion expresses the surface lectin, CD301b, in the thymus. These cells resemble the CD301b+ type 2 immune response promoting DCs that are present in the skin-draining lymph nodes. Transcriptional and phenotypic comparison to other DC subsets in the thymus revealed that thymic CD301b+ cDCs represent an activated state that exhibits enhanced antigen processing and presentation. Furthermore, a CD301b+ cDC2 subset demonstrated a type 2 cytokine signature and required steady-state interleukin-4 receptor signaling. Selective ablation of CD301b+ cDC2 subsets impaired clonal deletion without affecting regulatory T cells (Treg cells). The T cell receptor α repertoire sequencing confirmed that a cDC2 subset promotes deletion of conventional T cells with minimal effect on Treg cell selection. Together, these findings suggest that cytokine-induced activation of DCs in the thymus substantially enforces central tolerance. Breed et al. identify a subset of thymic SIRPα+ cDC2 dendritic cells that express CD301b, induced by type II cytokines, and high amounts of MHC-II. They find that the deletion of these cells can alter thymic CD4-single-positive repertoires, suggesting that they contribute to thymic tolerance.
Type I Conventional Dendritic Cells Relate to Disease Severity in Virus‐Induced Asthma Exacerbations
Article
Full-text available
Feb 2022
Aoife Cameron
Jaideep Dhariwal
Nadine Upton
the MRC‐GSK Strategic Alliance Consortium
Rationale:
Rhinoviruses are the major precipitant of asthma exacerbations and individuals with asthma experience more severe/prolonged rhinovirus infections. Concurrent viral infection and allergen exposure synergistically increase exacerbation risk. Although dendritic cells orchestrate immune responses to both virus and allergen, little is known about their role in viral asthma exacerbations.
Objectives:
To characterise dendritic cell populations present in the lower airways, and to assess whether their numbers are altered in asthma compared to healthy subjects prior to infection and during rhinovirus-16 infection.
Methods:
Moderately-severe atopic asthmatic patients and healthy controls were experimentally infected with rhinovirus-16. Bronchoalveolar lavage was collected at baseline, day 3 and day 8 post infection and dendritic cells isolated using fluorescence activated cell sorting.
Measurements and main results:
Numbers of type I conventional dendritic cells, which cross prime CD8+ T helper cells and produce innate interferons, were significantly reduced in the lower airways of asthma patients compared to healthy controls at baseline. This reduction was associated serum IgE at baseline and with reduced numbers of CD8+ T helper cells and with increased viral replication, airway eosinophils, and reduced lung function during infection. IgE receptor expression on lower airway plasmacytoid dendritic cells was significantly increased in asthma, consistent with a reduced capacity to produce innate interferons.
Conclusions:
Reduced numbers of anti-viral type I conventional dendritic cells in asthma are associated with adverse outcomes during rhinovirus infection. This, with increased FcεR1α expression on lower airway plasmacytoid DCs could mediate the more permissive respiratory viral infection observed in asthma patients.
Robust temporal map of human in vitro myelopoiesis using single-cell genomics
Preprint
Full-text available
Nov 2021
Clara Alsinet
Maria Primo
Valentina Lorenzi
Roser Vento-Tormo
Myeloid cells have a central role in homeostasis and tissue defence. Characterising the current in vitro protocols of myelopoiesis is imperative for their use in research and immunotherapy as well as for understanding the early stages of myeloid differentiation in humans. Here, we profiled the transcriptome of more than 400k cells and generated a robust molecular map of the differentiation of human induced pluripotent stem cells (iPSC) into macrophages. By integrating our in vitro datasets with in vivo single-cell developmental atlases, we found that in vitro macrophage differentiation recapitulates features of in vivo yolk sac hematopoiesis, which happens prior to the appearance of definitive hematopoietic stem cells (HSC). During in vitro myelopoiesis, a wide range of myeloid cells are generated, including erythrocytes, mast cells and monocytes, suggesting that, during early human development, the HSC-independent immune wave gives rise to multiple myeloid cell lineages. We leveraged this model to characterize the transition of hemogenic endothelium into myeloid cells, uncovering poorly described myeloid progenitors and regulatory programs. Taking advantage of the variety of myeloid cells produced, we developed a new protocol to produce type 2 conventional dendritic cells (cDC2) in vitro. We found that the underlying regulatory networks coding for myeloid identity are conserved in vivo and in vitro. Using genetic engineering techniques, we validated the effects of key transcription factors important for cDC2 and macrophage identity and ontogeny. This roadmap of early myeloid differentiation will serve as an important resource for investigating the initial stages of hematopoiesis, which are largely unexplored in humans, and will open up new therapeutic opportunities.
| https://www.researchgate.net/publication/308917617_Unsupervised_High-Dimensional_Analysis_Aligns_Dendritic_Cells_across_Tissues_and_Species |
The Oxford Oratory
A sanctuary in the midst of the city
The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman.
Let us not lose sight of Jesus
The author of the Epistle to the Hebrews spoke of a ‘cloud of witnesses’, by which he meant the martyrs, both of the Old Testament and which his readers must also have understood to refer to those among them who were suffering for Christ. Those who have given witness by the shedding of blood for the Faith have been the constant glory of the Church, since the day Paul stood guard over the cloaks of those responsible for the stoning of the deacon Stephen.
Why have there always been martyrs? Why do they hate Christians so much? The message we preach is that God loves us, that he came to be one of us, that he remains present among us, in order that we can love one another. Why is that message simply not ‘Good News’ to so many, and why throughout the Church’s history have they felt it necessary to resort to such extreme violence to stop us believing this and sharing it with others?
The most savage of persecutions have been, and still are, against our teaching that the Lord loves the world so much that he became one of us — the Incarnation. Even in our own country, the persecution was largely around the idea that our Lord wants to remain among us, to be truly present in the Mass, coming to us in Holy Communion. The persecution of Catholicism in these isles was, I believe, the longest ongoing persecution of the faith, causing sad divisions among our countrymen in the sixteenth and seventeenth centuries. But it was the cause of much holiness too, since there were many men and women who clung to the true faith with amazing tenacity and equal charity. Among these people are the great names of souls like St Thomas More and John Fisher, Edmund Campion, Ralph Sherwin, Margaret Clitherow and Margaret Pole. But there were others also, whose names haven’t really made it to the history books, such as the men whose memory we keep today, the anniversary of their martyrdom in Oxford on 5 July 1589. These are: Blessed George Nichols and Richard Yaxley, both priests, who died together with Blessed Thomas Belson, a gentleman, and Humphrey Pritchard, a bartender. Unlike the others, Blessed Humphrey was not a ‘university man’, and when taunted during his trial in Oxford by some learned divines, who told him that he did not know what it was to be a Catholic, he replied that he knew what he was to believe and that he would willingly die for so good a cause. They were hanged, drawn and quartered.
Jesus did warn us that his coming would bring division and indeed it has. It is a tremendous pity that the Mass, which is the sacrament of Unity, has been — even in the household of faith — something around which the divisions have been most vehement, whether it be theological or liturgical differences of opinion, where truth is boiled down to personal preference. What happens at the Mass is what matters above all, that Christ comes to us, that we plead his sacrifice for the sin of the world and he is given to us in Holy Communion, the Bread of Angels and Food for the Journey. The writer of Hebrews tells us to fix our eyes upon Jesus, and never to lose sight of him. This is advice our martyrs adhered to as ‘they ran with perseverance the race that was set before them’.
Although things look dark, we still have Our Lord. We have his presence in the Blessed Sacrament and we are able to come and pray each day in an open church. Moreover, we have the teaching of Christ, the Good News of God’s saving and merciful love, with a mission to pass it on to others, preaching as love knows how, by kindly words and virtuous life(Fr Faber).
It would be very easy to give in to the prevailing spirit and become discouraged, but we have the example of those men whose feast we keep today, our Oxford City Martyrs, whose perseverance and charity are a wonderful inspiration and example for us.
These reflections are sent out each Wednesday to all those on our mailing list.Click here to sign up to our mailing list, and receive our Sunday E-newsletter and these reflections straight to your inbox.
Saturday 1 July 2023
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Congratulations to Dom Stanislaus on his ordination to the priesthood yesterday at St Michael’s Abbey, Farnborough!
We look forward to welcoming him back to celebrate the Solemn Mass in our church on Sunday 9 July at 11am.
#oxfordoratory
Thursday 29 June 2023
July Music
Sunday 2 JulySolemn Mass 11:00
13th Sunday of the Year
Missa Tu es Petrus Palestrina
Sicut in holocaustis Palestrina
Laudibus in sanctis Byrd
Final from Organ Symphony No. 6 Widor
Sunday 9 JulySolemn Mass 11:00
14th Sunday of the Year
Missa Octavi toni Lassus
Simile est regnum caelorum Guerrero
Beati omnes qui timent Dominum Purcell
Prelude in A minor BWV 543i Bach
Sunday 16 JulySolemn Mass 11:00
15th Sunday of the Year
Mass for Four Voices Byrd
Ad te Domine levavi de Monte
Ave verum Byrd
A fancy Byrd
Sunday 23 JulySolemn Mass 11:00
16th Sunday of the Year
Missa simile est regnum caelorum Victoria
Tota pulchra es Vals
Salve Regina Palestrina
Fugue sur le nom d’Alain Op. 7ii Duruflé
Sunday 30 JulySolemn Mass 11:00
17th Sunday of the Year
Missa Quarti toni Victoria
Exaltabo te Domine Lassus
Tantum ergo de Severac
Prelude and Fugue in C BWV 547 Bach
Wednesday 28 June 2023
Two different men, one same Faith
Tomorrow we celebrate the feast of the two great pillars of the church, Peter and Paul. They were very different men from very different backgrounds. Peter was a fisherman from rural Galilee. Paul was a learned Pharisee from the university city of Tarsus. Peter’s first language was Aramaic; Paul’s first language was Greek. Peter knew Jesus from the time of his baptism and was with Jesus until the time of the Lord’s passion and death; Paul only ever met the risen Lord, in that famous incident, his conversion, on the road to Damascus.
For all their differences, they had that which is most important in common. Both of these men found themselves at odds with the Lord. Jesus called Peter “satan”, an obstacle in his path, when the Apostle tried to persuade the Lord away from his cross and passion — and then Peter would go on to deny his Master publicly three times. Paul had a hand in the death of the first Christian martyr, St Stephen, and violently persecuted Christ’s followers, and in doing that persecuted Christ himself.
And yet, in each case, it was Jesus who had the last word. Their resistance to the Lord did not prevent him from working powerfully through them. Peter was chosen to be the leader of the twelve, the rock on which Jesus would build his church. Paul was chosen to be the great apostle to the Gentiles, to take the faith out beyond Israel to the whole world.
They were very different people and the Lord worked through each of them in different ways. But they were united in one faith and in love for the Lord and for the little community of those who followed the Lord. They were certainly united in death: a very early tradition recalls that both were executed in Rome during the Emperor Nero’s persecution of Christians after the great fire of Rome.
The feast of Saints Peter and Paul reminds us that the way the Lord works through us is unique to each one of us. We each have our part in the great story of salvation, and each have our place in the great family of God which is the Church. The feast also reassures us that our many resistances to the Lord will not be a hindrance to his working through us. Peter, who denied the Lord, and Paul, who persecuted the Lord, would become his greatest servants and Apostles, and the very foundation of the Church. Our failings, even our greatest failings, do not define who we are. St Paul would go on to say, ‘the Lord’s grace toward me has not been in vain’. The Lord’s grace towards us in our weakness and frailty and our waywardness will never be in vain if we continue to open ourselves to the workings of that grace and the path that the Lord has prepared for us. May St Peter and St Paul pray for us, and for God’s church, as we each play our part in the preaching of the Gospel, the growth of the flock of Christ, and the building up of the kingdom.
These reflections are sent out each Wednesday to all those on our mailing list.Click here to sign up to our mailing list, and receive our Sunday E-newsletter and these reflections straight to your inbox.
Saturday 24 June 2023
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Congratulations to Andrew and Nina, baptised this morning!
Today, the birthday of St John the Baptist, is a fitting day to baptise, and not just because he is famous for baptising people. His birth marks the end of the Old Testament and the beginning of the New. Today is about looking forward to the future. Baptism can sometimes feel like an ending after the period of preparation and catechesis, but it is of course only the beginning of the Christian life. The big work lies before us. As St Philip used to say, “The great thing is to become saints.”
#oxfordoratory
Thursday 22 June 2023
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Yesterday we welcomed Fr William Pearsall of the Society of Jesus to preach for the feast of St Aloysius.
“What Aloysius did is what many saints have done — many who are condemned for not being useful. They explored the frontiers of the spiritual life. They were heroic in the sense that those who went to the North Pole or the South Pole or climbed the highest mountains, they were heroic… They were heroic because they were living with the discovery of God and how the limits between nature and grace will always be an expanding horizon.”
St Aloysius, pray for us!
#oxfordoratory
Wednesday 21 June 2023
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Happy feast of St Aloysius!
Two relics of his are displayed this month in our relic chapel, including a letter bearing his signature.
#oxfordoratory
Wednesday 21 June 2023
Flos paradisi
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Today we celebrate the great solemnity of the patron of our church: St Aloysius Gonzaga of the Society of Jesus. St Aloysius is, together with St Gabriel Possenti, patron of young people, students, and seminarians and thus was a natural choice as patron for our church in this university city. He is also the patron of our parish school and we entrust to his loving intercession all our children who are able to learn the love of God from his example. We have his shrine in the chapel of Our Lady of Oxford, his statue is there on the reredos, and his initials guide our eyes towards his heavenly home as we look up at the sanctuary ceiling. Our patrons are important — St Aloysius has been given to us in this parish by God, through his Church, to watch over us in a particular manner, to intercede for all those who live and worship here, and to encourage us in our own quest for holiness.
Born the eldest son of the Marquis of Castiglione, St Aloysius seemed destined for a life of political intrigue and secular affairs, but, as with St Ignatius before him, it was the lives of the saints that really captivated him and placed in his heart the desire to strive for something better. This was not some childish caprice; he had seen the reality of life at court with its violence, frivolity, and degradation of human dignity, and desired not only to turn his back on it, but to embrace with all his heart a life given wholly to God. He began in earnest, adopting severe penances and teaching the local children their catechism. Hearing about the missions of St Francis Xavier, he set his heart on becoming a Jesuit — much to the horror of his family.
Eventually, having not overcome family opposition but at least its concrete obstacles, and having renounced his rights of inheritance, he entered the Jesuit novitiate in Rome in 1585. He had much to learn and much to which to adapt himself, but whatever he had to do he simply did it with all his heart — trusting in the sure knowledge that God was at work. Would he have met St Philip in Rome? Concrete evidence is hard to find, though these two saints of Rome are often depicted in art. We know they had mutual friends and these no doubt would have told them of Rome’s Third Apostle and of the holy Jesuit novice. One can imagine St Aloysius on a novitiate walk popping in to the Chiesa Nuovato see Mister Father Philip whom all Rome spoke of and revered or of St Philip blessing a crowd of passing Jesuit novices and knowing the heart of one of them that would see them both in glory.
St Aloysius’ real work in Rome was that which St Philip had embarked upon at the beginning — the care of the sick and the destitute. When plague broke out he volunteered to go with the other novices to pick people off the streets, to wash them, to prepare them for the sacraments and care for their souls. At first, he admitted to his director St Robert Bellarmine, this revolted him, but he soon learnt to see the image of Christ in these people, and to love them, not only in caring for them, but in seeing Christ in them. Never one to enjoy good health, Aloysius himself fell ill of plague, and died at the age of 23 on 21 June 1591, just a few years before St Philip’s death.
When we look at images of St Aloysius we normally see a rather pale young man who looks like so many other sickly young saints, distinguished perhaps only by the great ruff that he wears about his neck. But he was more than that. He was a young man who bothered about God and thus about other people. He was not yet in his mid-twenties, when he had discovered that real freedom comes from serving God with all ones heart; that Christian love has to be lived in the real, strength-sapping, heart-breaking, service of others; that there is joy in taking people off the streets, washing them, bandaging their wounds and restoring them to the dignity that is theirs as children of God.
The image attached to these words is a depiction of St Aloysius in Milan in the Chiesa di Santa Maria presso San Satiro. The saint looks rather weak and malnourished, but what strength he has is used to hold up a man who is either dying or dead, with St Aloysius pressing the Cross to him and holding the man’s head up with his hands. The look on St Aloysius’ face is one, simply, of love — of love for God and neighbour, and of joy found in bringing the love of God to others. How much this young man, St Aloysius, still has left to teach us…
Friday 16 June 2023
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Heart of Jesus, all-holy! Fountain of all blessings, I adore thee, I love thee, and with a lively sorrow for my sins, I offer thee this poor heart of mine. Make me humble, patient, pure, and wholly obedient to thy will. Good Jesus, grant that I may live in thee and for thee. Protect me in the midst of danger; comfort me in my afflictions; give me health of body, assistance in my temporal needs, thy blessing on all that I do, and the grace of a holy death. Amen.
#oxfordoratory
Thursday 15 June 2023
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A photo from Sunday’s Solemn Mass for Corpus Christi.
#oxfordoratory
Thursday 15 June 2023
June Music
Sunday 4 JuneSolemn Mass 11:00
The Most Holy Trinity
Kyrie Mundy
Missa Euge bone Tye
Libera nos Sheppard
Honor, virtus et potestas Tallis
Sunday 11 JuneSolemn Mass 11:00
Corpus Christi
Missa Pange lingua Josquin
Lauda Sion Palestrina
Oculi omnium Byrd
Friday 16 JuneSolemn Mass 18:00
The Most Sacred Heart of Jesus
Missa Dormendo un giorno Guerrero
Improperium Palestrina
Sancte Deus Tallis
Sunday 18 JuneSolemn Mass 11:00
11th Sunday of the Year
Missa Brevis in F Op.117 Rheinberger
Benedicam Dominum Victoria
Salve Regina Poulenc
Wednesday 21 JuneSolemn Mass 18:00
St Aloysius Gonzaga
Missa O quam gloriosum Victoria
Justitiae Domini A Scarlatti
O bone Jesu Anchieta
Sunday 25 JuneSolemn Mass 11:00
12th Sunday of the Year
Missa Repleatur os meum Palestrina
Perfice gressus meos Lassus
Homo quidam fecit coenam magnam Mouton
Thursday 29 JuneSolemn Mass 18:00
St Peter and St Paul
Missa Petre ego pro te rogavi Lobo
Petre ego pro te rogavi Guerrero
Janitor caeli Ortiz
Wednesday 14 June 2023
The Sacred Heart
Love is a funny thing. Materialists will tell us that it is purely the result of a series of electro-chemical responses in the brain, and yet others will tell us that it is the result of fate, the conspiracy of the alignment of the planets or the times we find ourselves in. The heart has long been understood as the centre of a person, a place of knowledge as much as will. It makes us do unreasonable things like acts of unwarranted kindness and altruism and by the edge of its blade we can be hurt in ways that we just can’t speak about. And yet none of these express what love is in itself — only God does that.
On Friday we venerate the Heart of our Lord as the symbol of his human love in which God’s divine love is revealed to us. In most of the prayers to or the meditations on the Sacred Heart, even those very ancient prayers, the woundedness of our Lord’s heart comes to the fore. That heart pierced with a lance and bruised with outrages and blasphemies is a stark and realistic image of the extent to which Christ loves us. Christ, who is the image of the unseen God, the Icon of the Father, shows us precisely what God’s love for us looks like. And it looks like a heart pierced and bruised on account of our sins, yet burning with ardent love for you and for me. This divine love is not for softies.
The time when we celebrate this feast is very fitting. We have come to the end of the Church’s celebration of the mysteries of our redemption: the Passion, the Cross, the Resurrection, the Ascension, Pentecost, the Feast of the Blessed Trinity and Corpus Christi. But today we commemorate the divine-human love which motivated them all. In adoring the Sacred Heart, we adore the totality of Christ’s saving work — it represents the way in which God holds nothing back from us. And in order to share his divine life with us, he reaches down into the very depths of our life, even — and especially — where it is painful, difficult to speak of, hidden. By taking it all and joining it to himself, he scoops us up, he enables us to become like him. By sharing our life, and by sharing our pains, he heals us, he sanctifies us, and he strengthens us.
It is also true that his heart welcomes us precisely so that we might become like it. The whole thrust of our Christian life is that we might be conformed to our Saviour, that we might resemble him, and in this sense, in the life of faith, we should ask ourselves continually whether our heart resembles his. His Sacred Heart is both the example and the cause of our becoming like him. His love is attractive. The more we consider the love with which Jesus acted, and spoke and gave of himself for us, the more we can begin, by his grace, to imitate him — it is truly the school of Christian perfection.
And we begin in that school by prayer. When St John Henry Newman, our Cardinal, chose his motto, he looked to St Francis de Sales’ Treatise on the Love of God. The phrase he chose and paraphrased, Cor ad Cor loquiturrepresents for us the central mystery of the prayer that can begin to transform us. St Francis de Sales wrote:
Truly the chief exercise in mystical theology is to speak to God and to hear God speak in the bottom of the heart; and because this discourse passes in most secret aspirations and inspirations, we term it a silent conversing. Eyes speak to eyes, and heart to heart, and none understand what passes save those who speak.
We may be no great shakes at the spiritual life, or prayer, or we may feel that excelling in virtue is beyond us, but if we can in the simplest of ways open our poor heart to his Sacred Heart, and speak to him as to a friend, if we can entrust our lives to him and ask him devoutly and sincerely to shape us after the model of his Heart, then our Christian life will be all the more graced.
Tuesday 13 June 2023
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The Corpus Christi procession concluded with Benediction at the University Chaplaincy. #oxfordoratory
Tuesday 13 June 2023
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The procession finished at the University’s Catholic Chaplaincy. #oxfordoratory
Tuesday 13 June 2023
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The numbers caught the attention of the local media:
https://www.oxfordmail.co.uk/news/23582016.oxfords-catholic-congregations-take-part-corpus-christi-procession/
#oxfordoratory
Tuesday 13 June 2023
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Children scattered flower petals before the Blessed Sacrament all the way. #oxfordoratory
Tuesday 13 June 2023
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Our route now passes through the city in a straight line, taking us directly through the busiest shopping areas. #oxfordoratory
Tuesday 13 June 2023
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The canopy was carried by members of the University of Oxford wearing their academic dress. #oxfordoratory
Tuesday 13 June 2023
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Fr Robert Ombres OP preached a sermon. #oxfordoratory
Tuesday 13 June 2023
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We paused at Blackfriars. #oxfordoratory
| https://www.oxfordoratory.org.uk/publications/blog/post/10030-10030/blog/post/10038-10038/care-of-the-sick.php |
Facts about "Casablanca" : Classic Movie Hub (CMH)
Browse Fun Facts and Trivia about at Classic Movie Hub (CMH).
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Casablanca
"As Time Goes By" was written by lifelong bachelorHerman Hupfeldand debuted in 1931's Broadway show "Everybody's Welcome", sung byFrances Williams, It had been a personal favorite of playwright and high school teacherMurray Burnettwho, seven years later, visited Vienna just after the Nazis had entered. Later, after visiting a café in south France where a black pianist had entertained a mixed crowd of Nazis, French and refugees, Burnett was inspired to write the melodrama "Everybody Comes to Rick's", which was optioned for production byMartin GabelandCarly Wharton, and later, Warners. After the film's release, "As Time Goes By" stayed on radio's "Hit Parade" for 21 weeks. However, because of the coincidental musicians' union recording ban, the 1931Rudy Valleeversion became the smash hit. (It contains the rarely-sung introductory verse, not heard in the film.)Max Steiner, in a 1943 interview, admitted that the song "must have had something to attract so much attention".
"Here's looking at you, kid" was improvised by
Humphrey Bogart
in the Parisian scenes and worked so well that it was used later on again in the film. He originally used the same line in
Midnight
. It is also rumored that during breaks,
Ingrid Bergman
would play poker with other cast members. Since she was still learning English, Bogart would occasionally watch the game, and he added "Here's looking at you" to her poker repertoire.
"Rick's Café Américain" was modeled after Hotel El Minzah in Tangiers.
Humphrey Bogarthad to wear platform shoes to play alongsideIngrid Bergman.
Humphrey Bogart
,
Ingrid Bergman
and
Paul Henreid
later reprised their roles for a radio performance of on the CBS radio program "The Screen Guild Players", a war benefit show on April 26, 1943.
Humphrey Bogart
's wife
Mayo Methot
continually accused him of having an affair with
Ingrid Bergman
, often confronting him in his dressing room before a shot. Bogart would come onto the set in a rage. In fact, despite the undeniable on-screen chemistry between Bogart and Bergman, they hardly spoke, and the only time they bonded was when the two had lunch with
Geraldine Fitzgerald
. According to Fitzgerald, "the whole subject at lunch was how they could get out of that movie. They thought the dialogue was ridiculous and the situations were unbelievable... I knew Bogart very well, and I think he wanted to join forces with Bergman, to make sure they both said the same things." For whatever reasons, Bogart and Bergman rarely spoke after that.
S.Z. Sakall, who plays the maitre d' at Rick's Cafe, actually has more screen time thanPeter LorreorSydney Greenstreet.
Madeleine Lebeau
, who plays Yvonne, and
Marcel Dalio
, who plays croupier Emil, were husband and wife at the time of filming. They had not long before escaped the Nazis by fleeing their native France.
Dooley Wilson
(Sam) was a professional drummer who faked playing the piano. As the music was recorded at the same time as the film, the piano playing was actually a recording of a performance by
Elliot Carpenter
who was playing behind a curtain but who was positioned such that Dooley could watch, and copy, his hand movements.
Dooley Wilsonwas borrowed from Paramount at $500 a week.
Dooley Wilsonwas, in fact, the only member of the cast to have ever actually visited the city of Casablanca.
Joy Page
, who played the young Bulgarian wife, was the stepdaughter of studio head
Jack L. Warner
. She,
Humphrey Bogart
and
Dooley Wilson
were the only American-born people in the credited cast. This film was her debut.
Hal B. Wallisdidn't wantHumphrey Bogartwearing a hat too often in the film, as he thought it made Bogart look like a gangster.
Hal B. Wallis's first choice for director wasWilliam Wyler.
Sydney Greenstreet
wanted to wear something more ethnic to show that his character had assimilated into the Moroccan lifestyle. This idea was nixed by producer
Hal B. Wallis
who insisted that he wear his now-iconic white suit.
Ingrid BergmanandPaul Henreidmake their first appearance 24 minutes into the film.
Ingrid Bergman
considered her left side as her better side, and to the extent possible that was the side photographed throughout the film, so she is almost always on the right side of the screen looking towards the left regardless of who is in the shot with her. However, there are several shots where she is to the left and
Humphrey Bogart
is on the right, including the flashbacks to the street scene in Paris (0:41:50) and the scene at the window (0:43:40). There are also several scenes where Bergman is centered between
Paul Henreid
and Bogart, suggesting the triangle nature of their relationship; in these shots Henreid is usually to the left and Bogart is usually on the right, including the scene where she and Henreid enter the café at just before the famous "Battle of the Anthems" (1:07:40); the scene where Captain Renault arrests Victor Laszlo (1:34:00); and at the end of the final airport scene (1:39:00).
Ingrid Bergman's contract was owned by producerDavid O. Selznick, and producerHal B. Wallissent the film's writers,Philip G. EpsteinandJulius J. Epstein, to persuade Selznick to loan her to Warner Bros. for the picture. After 20 minutes of describing the plot to Selznick, Julius gave up and said, "Oh, what the hell! It's a lot of shit likeAlgiers!" Selznick nodded and agreed to the loan.
Ingrid Bergman
's line "Victor Laszlo is my husband, and was, even when I knew you in Paris" was almost cut from the film because during that time it was deemed inappropriate for a film to depict or suggest a woman romancing with another man if she were already married. However, it was pointed out that later in the film she explains that she had thought Laszlo was dead at the time, and the censors allowed the line to stay in.
Howard Hawks
had said in interviews that he was supposed to direct
Casablanca
and
Michael Curtiz
was supposed to direct
Sergeant York
. The directors had lunch together, where Hawks said he didn't know how to make this "musical comedy", while Curtiz didn't know anything about "those hill people." They switched projects. Hawks struggled on how to direct the scenes that involved singing, namely the "La Marseillaise" scene. It is ironic to note that most of his other films involved at least one singing scene.
| https://www.classicmoviehub.com/facts-and-trivia/film/casablanca-1942/?lv=true%2Fpage%2F5%2F%2Fpage%2F1%2F%2Fpage%2F4%2F%2Fpage%2F6%2F%2Fpage%2F5%2F%2Fpage%2F6%2F%2Fpage%2F4%2F%2Fpage%2F3%2F%2Fpage%2F4%2F |
Microorganisms | Free Full-Text | Danofloxacin Treatment Alters the Diversity and Resistome Profile of Gut Microbiota in Calves
Fluoroquinolones, such as danofloxacin, are used to control bovine respiratory disease complex in beef cattle; however, little is known about their effects on gut microbiota and resistome. The objectives were to evaluate the effect of subcutaneously administered danofloxacin on gut microbiota and resistome, and the composition of Campylobacter in calves. Twenty calves were injected with a single dose of danofloxacin, and ten calves were kept as a control. The effects of danofloxacin on microbiota and the resistome were assessed using 16S rRNA sequencing, quantitative real-time PCR, and metagenomic Hi-C ProxiMeta. Alpha and beta diversities were significantly different (p < 0.05) between pre-and post-treatment samples, and the compositions of several bacterial taxa shifted. The patterns of association between the compositions of Campylobacter and other genera were affected by danofloxacin. Antimicrobial resistance genes (ARGs) conferring resistance to five antibiotics were identified with their respective reservoirs. Following the treatment, some ARGs (e.g., ant9, tet40, tetW) increased in frequencies and host ranges, suggesting initiation of horizontal gene transfer, and new ARGs (aac6, ermF, tetL, tetX) were detected in the post-treatment samples. In conclusion, danofloxacin induced alterations of gut microbiota and selection and enrichment of resistance genes even against antibiotics that are unrelated to danofloxacin.
Danofloxacin Treatment Alters the Diversity and Resistome Profile of Gut Microbiota in Calves
Alan Hassall 3 ,
Renee Dewell 4 ,
Grant Dewell 3 ,
Orhan Sahin 3 ,
Qijing Zhang 1 and
Paul J. Plummer 1,3,5,*
1
Department of Veterinary Microbiology and Preventative Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA
2
College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA
3
Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA
4
Center for Food Security and Public Health, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA
5
National Institute of Antimicrobial Resistance Research and Education, Iowa State University, Ames, IA 50010, USA
*
Author to whom correspondence should be addressed.
Microorganisms 2021 , 9 (10), 2023; https://doi.org/10.3390/microorganisms9102023
Received: 8 September 2021 / Revised: 18 September 2021 / Accepted: 23 September 2021 / Published: 24 September 2021
(This article belongs to the Special Issue Antimicrobial Stewardship in Food-Producing Animals )
Abstract
:
Fluoroquinolones, such as danofloxacin, are used to control bovine respiratory disease complex in beef cattle; however, little is known about their effects on gut microbiota and resistome. The objectives were to evaluate the effect of subcutaneously administered danofloxacin on gut microbiota and resistome, and the composition of
Campylobacter
in calves. Twenty calves were injected with a single dose of danofloxacin, and ten calves were kept as a control. The effects of danofloxacin on microbiota and the resistome were assessed using 16S rRNA sequencing, quantitative real-time PCR, and metagenomic Hi-C ProxiMeta. Alpha and beta diversities were significantly different (
p
< 0.05) between pre-and post-treatment samples, and the compositions of several bacterial taxa shifted. The patterns of association between the compositions of
Campylobacter
and other genera were affected by danofloxacin. Antimicrobial resistance genes (ARGs) conferring resistance to five antibiotics were identified with their respective reservoirs. Following the treatment, some ARGs (e.g.,
ant
9,
tet
40,
tet
W) increased in frequencies and host ranges, suggesting initiation of horizontal gene transfer, and new ARGs (
aac
6,
erm
F,
tet
L,
tet
X) were detected in the post-treatment samples. In conclusion, danofloxacin induced alterations of gut microbiota and selection and enrichment of resistance genes even against antibiotics that are unrelated to danofloxacin.
Keywords:
antimicrobial resistance genes (ARGs)
;
bovine calves
;
bovine respiratory disease
;
Campylobacter
;
danofloxacin/fluoroquinolones
;
fecal microbiota
;
resistome
1. Introduction
The rise in the incidence of antimicrobial resistance has become the intractable challenge of public health in the 21st century [ 1 ]. Use of antimicrobials in the agricultural sector, especially in the livestock industries, has been identified as a contributor toward the acceleration of the selection and spread of antimicrobial-resistant bacterial strains. This makes livestock farms a potential source of resistant strains and antimicrobial resistance genes (ARGs) [ 2 , 3 , 4 ]. Gut microbiota is considered an additional “organ” for animals because of its beneficial effects on the physiology, metabolism, immunology, digestion, and nutrient uptake of the host [ 5 , 6 ]. However, it can also harbor ARGs, which may spread to humans through the food chain or environmental contamination [ 1 , 4 , 7 , 8 ]. This situation demands a clear understanding of the variables involved in the emergence and maintenance of antimicrobial-resistant bacterial strains and genes in livestock farms and a “One Health” approach to curb their spread to environments and humans.
Fluoroquinolone drugs, such as danofloxacin and enrofloxacin, are frequently used to prevent and control the Bovine Respiratory Disease (BRD) complex in U.S. cattle populations [ 9 , 10 , 11 ]. BRD is the most significant disease of young cattle in North America. Furthermore, it accounts for 70% to 80% of all feedlot morbidity and 40% to 50% of all mortality in the U.S. feedlots [ 11 ]. In 2011, a feedlot survey conducted by the National Animal Health Monitoring System (NAHMS) estimated 16.2% of cattle placed in feedlots showed signs of respiratory disease at some point during their stay on feedlots. Most of these animals (87.5%) were treated with antibiotics, of which 99.0% of the treated calves were injected with antibiotics [ 12 ]. Metaphylaxis, mass medication to reduce the incidence of a disease in a group of animals, has also been a well-documented, widely practiced strategy to decrease morbidity and mortality associated with BRD in high-risk cattle [ 11 ]. A survey conducted on feedlots by NAHMS in 2011 estimated that 21.3% of all animals entering the feedlot underwent metaphylaxis [ 12 ]. BRD is a significant health problem for dairy cattle as well. In 2007, NAHMS surveyed dairies in 17 states and estimated that 12.4% of pre-weaned heifer calves had been diagnosed with respiratory disease, and 5.5% were administered antibiotics [ 13 , 14 ]. BRD incidence has demonstrated seasonal variations and is typically increased in the fall season, which often coincides with the shipping of calves from their farm/ranch origin to the feedlot as well as inclement weather [ 15 ]. The Food and Drug Administration (FDA) reports that sales and distribution of fluoroquinolones as well as other medically important drugs have increased in recent years [ 16 ]. Fluoroquinolones, used for the control of BRD and individual animal treatment, accounted for 1.8% of the total regimens of antimicrobial drugs used in 22 U.S. beef feedyards in the years 2016 and 2017, which was moderately high compared to some other antimicrobials used for the same purposes (ranging from 0.11% (sulfonamide) to 9.9% (macrolide)) [ 17 ].
Ciprofloxacin, a fluoroquinolone antibiotic with the same principal agent as that of animal formulations, is commonly used to treat various human infections, including gastroenteritis caused by Campylobacter infection [ 18 , 19 ]. The increased incidence of ciprofloxacin resistance among foodborne pathogens has become a serious threat to public health, which has led to the first removal of fluoroquinolones from use on poultry farms in the U.S. in 2005 [ 20 ]. Despite the withdrawal, the trend of fluoroquinolone resistance in Campylobacter species has continued to increase in the last two decades ( https://www.cdc.gov/DrugResistance/Biggest-Threats.html#cam , accessed on 14 August 2020). It has been suggested that the rise in ciprofloxacin resistance in Campylobacter in humans may, at least in part, be associated with use of danofloxacin and enrofloxacin in other livestock [ 21 , 22 ]. Beyond inducing antibiotic resistance in specific bacterial pathogens, these antibiotics exert selection pressure on gut microbiota that may lead to its alteration and enhance the spread of ARGs within bacterial communities [ 23 , 24 , 25 ].
Perturbation of gut microbiota following exposure to antibiotics has been a well-recorded phenomenon in monogastric animals, including humans [ 26 , 27 , 28 , 29 , 30 , 31 ]. However, only limited information is available in cattle, and the available data demonstrate inconsistent results and conclusions among studies. In one study, intramuscularly administered penicillin modified the structure of fecal microbiota in calves [ 32 ]. Conversely, another group of researchers reported only minor alterations in community structure and the absence of changes in fecal microbial diversity in steers that received single and multiple doses of enrofloxacin subcutaneously [ 33 ]. In agreement with the 2018 study, comparisons of the fecal microbiota of calves with and without a history of antimicrobial exposure on beef farms were not different [ 34 ]. However, E. coli, used as an indicator organism for the impacts of antibiotics on gut bacteria, showed transient resistance (i.e., a temporary increase in minimum inhibitory concentration) [ 33 ], and increased resistance to multiple unrelated antimicrobial agents [ 32 ]. In general, the inconsistency among the studies could partly be attributed to differences in their study designs and methods as well as the inherent complexity within the gut microbiota [ 35 ].
The objective of this study was to assess the impacts of danofloxacin administered subcutaneously to bovine calves on the fecal microbiota,
Campylobacter
, and resistome (i.e., all detectable ARGs within a given sample). We hypothesized that infusion of danofloxacin and its metabolite, ciprofloxacin, from plasma into the intestine following a single-dose subcutaneous injection of danofloxacin will exert selective pressure on gut microbiota and alter its diversity and the resistome profile. In this study, we sequenced the 16S rRNA gene to compare the compositions and structures of fecal microbiota before and after the treatment and to assess changes in the compositions of
Campylobacter
. Additionally, we employed a novel proximity ligation-guided metagenomics approach (ProxiMeta) that has the advantage of linking the ARGs with their microbial reservoirs over other metagenomic methods [
36
], which enabled us to track changes in antibiotic-resistant determinants as driven by danofloxacin administration. Quantitative real-time PCR (qPCR) was employed to assess the impacts of danofloxacin on the dynamics of selected ARGs.
2. Results
2.1. Results of 16S rRNA Gene Analysis
The total number of reads in our samples was 10,999,180, with an average of 52,377 reads per sample (SD 12,721, range 5179–124,738, and median 51,698 reads per sample). A total of 6628 bacterial Operational Taxonomic Units (OTUs) were identified in 210 samples, which were classified into 298 genera (mean = 91 genera, SD = 7, and range = 68–116 per sample), 35 classes (mean = 23 classes, SD = 2, and range = 16–28 per sample), and 19 phyla (mean = 13 phyla, SD = 1, and range = 9–17). A random subsample of 11,500 reads per sample was used to normalize sequence numbers for the computation of alpha and beta diversity metrics; one sample with 5179 reads was excluded from the analyses due to insufficient depth.
2.1.1. Bacterial Phyla by Sampling Days
The relative abundances of phyla detected in this study were compared by the sampling days ( Supplementary Materials Table S1 ). Phyla with the highest relative abundance in the first sampling day, two days after the calves arrived at the animal study facility, included Firmicutes (relative abundance = 51.93%), Bacteroidetes (36.13%), Proteobacteria (3.00%), Tenericutes (2.18%), Spirochaetes (1.94%), Actinobacteria (1.33%), and Verrucomicrobia (1.03%). The relative abundances of the phyla varied over the subsequent sampling days during the four weeks of the study period; however, Firmicutes and Bacteroidetes remained dominant phyla throughout that time.
2.1.2. Alpha Diversities
The sequencing depth was evaluated using alpha rarefaction curves (figures not shown); for all considered alpha diversity metrics, the sequencing depth was sufficient to reveal rare microbes in the samples. Calves in group C that were challenged with
Mannheimia haemolytica
exhibited mild to moderate signs of BRD. However, microbial compositions and diversities were not significantly different from group B, the group that was not challenged with
M. haemolytica
but injected with danofloxacin subcutaneously. Thus, these two groups that received danofloxacin were collapsed together into one group, named the treatment group, for the comparison of microbial evenness and richness before and after the treatment. Based on the analyses, observed OTUs measuring the microbiota richness showed a significant change between pre- and post-treatment samples (
p
< 0.05). Similarly, microbiota evenness measured by the Shannon index was different between pre- and post-treatment samples (
p
< 0.05,
Figure 1
). Strikingly, both microbial richness and evenness significantly increased following danofloxacin administration, as shown in
Figure 1
.
Since the fecal samples were collected from the study calves over 28 days, there was an anticipation that the fecal microbiota would change over time because the calves were around two months old at the beginning of the study, the age at which microbial diversity and structure alter fast. Thus, linear mixed-effects models were run using QIIME2 to discriminate between microbial changes attributed to age from those due to danofloxacin exposure. Accordingly, the effect of time was not significant for either measure in the control group. In contrast, the time had a marginally significant influence (observed OTUs,
p
= 0.064 and Shannon,
p
= 0.091) in the treatment group, indicating the influence of danofloxacin on the microbial compositions and diversities was more prominent than the impact of the time in this study.
2.1.3. Beta Diversities
Beta-diversity was measured by the Bray–Curtis dissimilarity index, which can be visualized in the NMDS plot displayed in Figure 2 . Gut microbiota shifted after the treatment, as shown in the figure by a clustering difference between pre- and post-treatment microbial communities, and the community structures were significantly different ( p < 0.05).
2.1.4. Comparisons of Compositions of Bacterial Classes among Study Calf Groups
The relative abundances of bacterial taxa were compared among the calf groups using the Kruskal–Wallis and pairwise Dunn tests ( Table S2 ). For many of the bacterial classes, a significant difference ( p < 0.05) was observed between the control group (Group A) and the treatment groups (Group B or C, or both). For instance, Methanobacteria, Thermoplasmata, Betaproteobacteria, Epsilonproteobacteria, and Mollicutes significantly increased in the treatment groups, whereas Bacilli, Planctomycetia, and Synergistia decreased. Some bacterial classes, such as Bacteroidia, Cyanobacteria-4C0d-2, and Clostridia did not show significant changes. Comparisons between the treatment groups, which were BRD-induced Group C against non-BRD-induced Group B, had shown significant differences for certain bacterial classes such as Actinobacteria, Planctomycetia, Betaproteobacteria, and Tenericutes- RF3 .
2.1.5. Comparisons of Relative Abundance of Bacterial Genera between Pre- and Post-Treatment Communities
After the classification of the reads at a minimum of 97% similarity into OTUs using QIIME 1.9, a total of 4770 OTUs were obtained. Two hundred and sixty-five of the OTUs in the treatment group increased, and 211 of them decreased after danofloxacin injection at FDR
p
≤ 0.01 (379 and 319 at FDR
p
≤ 0.05, respectively). Furthermore, the relative abundance of genera in pre- and post-treatment samples were compared using the Wilcoxon signed-rank test and Boruta algorithm/random forest models. Out of 228 genera with relative abundance ≥ 0.01%, 66 of them had significantly shifted after the treatment as indicated by the Wilcoxon signed-rank test (
p
< 0.05,
Table 1
) and 57 genera after the
p
-value was adjusted by FDR (
p
< 0.05). These genera fell into 12 phyla, with 31 of them in
Firmicutes
, 13 in
Proteobacteria
, 8 in
Bacteroidetes
, 3 in
Actinobacteria
, 3 in
Spirochaetes
, 2 in
Elusimicrobia
, and the rest in the other six phyla.
For the classification of the microbial communities into pre- and post-treatment, out of 298 genera, 44 of them were confirmed as important attributes by the Boruta algorithm, meaning the treatment affected the proportions of these genera significantly. The feeding of these important genera to the random forest model resulted in an out of bag error of 2.06%, accuracy for the training sub-data of 100% (95% CI: 96.27–100 %), and an accuracy rate for the test sub-data of 100% (95% CI: 91.59–100 %). These 44 genera, classifying the microbial communities into pre- and post-treatment communities, were ranked by the random forest model based on their importance, as depicted in
Figure 3
. Four
Proteobacteria
genera (
Succinivibrio
, RF32_g_unclassified,
Gallibacterium
,
Enterobacteriaceae
_g_unclassified) and
Bacteriaodetes
_g_5.7N15 were the most important. Interestingly, 37 genera were identified as having a significant association with or predictors of pre/post-treatment status by both the Wilcoxon signed-rank test and the Boruta/random forest method.
Furthermore, the number of genera per sample 24 h after the treatment was significantly lower ( p < 0.05) in the treatment group than in the control group ( Figure 4 ). For groups B and C, the counts were significantly reduced at 24 h after the treatment compared with one day earlier sampling or four or seven days after the treatment (i.e., sampling days 19 vs. 18, 19 vs. 22, 19 vs. 28, p < 0.05; day 18 was the treatment day). In contrast, none of them were significant in the control group.
2.2. The Compositions of Campylobacter
2.2.1. Comparison by Sampling Days
The relative abundances of
Campylobacter
in samples collected on Day 2 through Day 28 were 0.03%, 0.03%, 0.35%, 0.72%, 0.04%, 0.31%, and 0.76% in the pooled data of the combined treatment groups (groups C and B), respectively. Its composition on Day 19 (24 h after danofloxacin administration) was significantly lower than the composition on Day 18, as well as than those on the last two sampling days.
Figure 5
depicts the proportions of
Campylobacter
in the samples collected at seven sampling times compared by the Kruskal–Wallis non-parametric and its post hoc tests.
Campylobacter
level dropped sharply and significantly 24 h after the treatment; however, it returned to the pre-treatment baseline after three days (i.e., no significant difference between the proportions on Day 18 and Day 22,
p
> 0.05). In contrast, the proportions of
Campylobacter
did not show significant variations among sampling days except for a slight rise in the last sampling day in the control group (results not shown).
2.2.2. Correlation with Other Genera
The relative abundance of Campylobacter was compared with other genera using the Spearman rank correlation test ( Tables S3 and S4 ). Twenty-one genera had a significant correlation with Campylobacter in the pooled data (all groups combined), of which ten of them had a negative correlation. Seven of the eight Bacteroidetes genera that significantly correlated with Campylobacter had negative correlation coefficients. In contrast, most of the genera in Firmicutes and Proteobacteria had a positive association with the relative abundance of Campylobacter .
On the other hand, pre- and post-treatment data were separately analyzed to assess if the treatment had an effect on the pattern of correlation between
Campylobacter
and other genera. Seven and eleven genera in pre- and post-treatment samples had a significant correlation with
Campylobacter
, respectively. Interestingly, pre- and post-treatment samples shared only one genus in common that had a significant association with
Campylobacter
, which was an unclassified genus in the family of
Desulfovibrionaceae
. This result suggests that danofloxacin exposure altered the correlation pattern between bacterial taxa.
2.2.3. Prediction of Important Genera by Random Forests
Using the Boruta algorithm, out of 298 genera, nine of them were confirmed as important attributes in the combined data of all groups. Based on the random forest model, these nine genera explained 46.01% of the variability in the relative abundance of
Campylobacter
with a very low mean squared error (i.e., 0.059), indicating the best model fitness. Except for two, these genera had significant Spearman rank correlation coefficients as well. Furthermore, genera ranked as very important by the random forest model had the highest Spearman correlation coefficients. Additional analyses were performed by dividing data as pre-treatment, post-treatment, and control to check if the treatment would have changed the association patterns between genera. In agreement with the Spearman rank correlation test, there was a difference between pre- and post-treatment samples in both the types and numbers of genera correlated with the compositions of
Campylobacter
in the fecal samples.
Figure 6
presents genera that predict the relative abundance of
Campylobacter
in the total, the pre- and post-treatment, and the control samples separately.
2.3. Results of Metagenomic Hi-C (ProxiMeta)
To assess the influence of danofloxacin injection on fecal resistome profiles, pooled samples from pre- and post-treatment samples were sequenced using metagenomic Hi-C. Accordingly, genes conferring resistance to tetracycline, aminoglycosides, β-lactams, macrolides, and phenicol were detected in both pre- and post-treatment samples (
Table 2
). The abundance of tetracycline resistance determinants was the highest with eight and nine different ARG types in pre-and post-treatment pooled samples, respectively.
tet
Q,
tet
W, and
tet
40 showed a dramatic increase both in number of hits and host ranges following the treatment;
tet
B was detected only in the pre-treatment sample, while
tet
L and
tet
X were identified after the treatment samples only.
tet
32 and
tet
O were carried on the same contig. Six unique aminoglycoside ARG types were detected in the samples with
aac
6 only observed in the post-treatment sample. The number of
ant
9 copies increased dramatically following the treatment from 39 to 189 with host range increase from 12 to 23. The rest of the aminoglycoside ARGs showed minor variations between pre-and post-treatment pooled samples. Two or more ARG types were carried on the same contig. Four unique macrolide ARGs were identified,
erm
B being undetected in the post-treatment sample, while the rest of them did not fluctuate both in copy numbers and host ranges between the two sampling time points.
aci
and
cf
X β-lactam ARGs were reported in this study with the latter ARG emerged after the treatment. Only one phenicol resistance gene (
cfr
) was observed, which significantly increased both in the number of hits and reservoirs following the treatment.
Using proximity ligation, the linkage of ARGs with their respective bacterial hosts was also established in the present study. Phyla associated with the current ARGs are presented in
Table 3
.
Firmicutes
was the leading phylum associated with these ARGs, whereas
Bacteroidetes
appeared to acquire the ARGs following the treatment. At lower bacterial classification level, most of these resistance genes were hosted by class
Clostridium
species,
Eubacterium
species, and
Sharpea azabuensis
DSM_18934 in the pre-treatment samples, and
Clostridium, Eubacterium
,
Prevotella,
and
Ruminococcus
species in the post-treatment samples (
Table S5
). Most of the identified ARGs were carried by more than one clusters of bacterial taxa having ≥ 80 % complete genomes; for instance,
tet
W was detected in 12 and 49 clusters in pre-and post-treatment samples, indicating a wide range of distribution.
Table S5
presents copy numbers and bacterial taxa (at a lower classification level) associated with each ARG.
2.4. Results of qPCR
To validate the Hi-C results, a subset of genes was selected for qPCR testing. Primers targeting tet W, tet O, tet X, erm B, and erm F were used to compare the changes in their quantity following danofloxacin administration. Comparison of the treatment groups (B and C) with the control group using the non-parametric pairwise Dunn test has revealed that tet W increased significantly (adj. p < 0.05) in the post-treatment pooled samples from group B compared the control. In contrast, tet O was significantly reduced (adj. p < 0.05) in group C compared to the control while erm F increased significantly in the same group. The change in the quantity of erm B was significantly lower in group B than the control group ( Table 4 ).
3. Discussion
Danofloxacin is frequently administered to beef calves as prophylaxis and metaphylaxis to prevent and control BRD in beef cattle in the U.S. Having a short meat withdrawal time makes it one of the preferred antibiotics used by producers [
37
]. However, little is known about its unintended side effects on gut microbial compositions, diversities, and resistome. In this study, we investigated the impacts of a single dose of subcutaneously administered danofloxacin on the fecal microbiota, the compositions of
Campylobacter
, and the resistome in calves. Compared to the control group, fecal microbiota was shifted in the treatment groups following danofloxacin injection, as indicated by significant changes in alpha and beta diversities as well as the shift in the relative abundance of bacterial taxa. Additionally, the abundance of
Campylobacter
has been altered in the treatment groups, likely due to the emergence of antibiotic resistance in this genus (data being prepared under a separate manuscript). Furthermore, our study showed enrichment of antibiotic determinants, which suggests that danofloxacin created an environment that might have favored the dominance of resistant strains and/or transfer of ARGs among bacteria. Given that antibiotic use exerts selective pressure on bacteria for the emergence of resistance, these findings are consistent with evidence by many other studies. The emergence of resistant strains and genes in livestock is worrisome since they shed them with feces and contaminate the farm environments, which may eventually reach the human food chain or drinking water. This necessitates capturing the “One health” paradigm to study AMR and minimizing its economic and public health impacts [
7
,
8
].
The effect of danofloxacin on bovine gut microbiota has not been previously studied despite being one of the commonly used fluoroquinolone drugs on beef farms. Fluoroquinolones have a bactericidal effect on bacteria by interfering with the DNA coiling during replication [ 37 ]. Their mechanisms involve inhibition of bacterial enzyme topoisomerases, such as topoisomerase II (DNA gyrase) in Gram-negative bacteria and topoisomerase IV in Gram-positive bacteria. Danofloxacin is a third-generation fluoroquinolone drug used for the treatment of respiratory disease in pigs and cattle [ 38 ]. Parenteral administration of this drug results in a high concentration in the digestive tract, which increases antibiotic exposures of gut microbiota. According to a study performed on dairy cows, the concentration of danofloxacin in tissue samples from the digestive tract of cattle was high. It was more than five times and 19 times the plasma concentration in the colon and mesenteric lymph nodes at 8 h and 12 h post-administration, respectively [ 38 ]. The same study indicated a high volume of distribution and prolonged elimination half-life of danofloxacin. Other researchers also demonstrated that marbofloxacin (another fluoroquinolone) doses used to target pathogens in the lungs had a similar effect on the bacterial population in the small intestine [ 39 ]. These authors reported 2- to 8-fold higher levels in total marbofloxacin concentrations in the digestive tract than in plasma for over 24 h following intramuscular injection of this drug to young pigs [ 39 ]. However, the bactericidal effect of fluoroquinolones in the intestine is diminished because they are highly bound in the intestines/feces, as demonstrated in pigs [ 39 ], rats [ 40 ], and humans [ 41 ]. Despite the reduced bactericidal effect, available evidence shows that fluoroquinolones create selective pressure in the intestine [ 18 ]. One such example is the emergence of fluoroquinolone resistance in Enterobacteriaceae strains following intramuscular injection of enrofloxacin in pigs [ 42 ]. The same study revealed that both orally and parenterally administered enrofloxacin induced development of AMR in selected bacterial species with different levels in pigs [ 42 ]; however, the difference in the impacts of fluoroquinolone drugs administered via oral and parenteral routes on gut microbiota needs to be investigated in calves. Nevertheless, there is enough evidence from the literature that complements our findings and shows parenterally administered danofloxacin is capable of enhancing selective pressure on gut microbiota and inducing its perturbation.
The major bacterial phyla identified from the fecal samples collected after two days of the beginning of the study (i.e., baseline data) were Firmicutes (51.93%), Bacteroidetes (36.13%), Proteobacteria (3.00%), Tenericutes (2.18%), Spirochaetes (1.94%), Actinobacteria (1.33%), and Verrucomicrobia (1.03%). These findings agree with previous studies in beef cattle [ 43 , 44 , 45 , 46 ]. A study conducted in Canada, however, indicated a variation between beef farms with regard to bacterial dominance; some of the farms were characterized by the dominance of Actinobacteria and Proteobacteria, while the other farms by the dominance of Firmicutes [ 34 ]. Several factors, such as diets, antibiotic exposure, genetics, management, and environment, contribute to the variation in microbial compositions and diversities between and within farms [ 28 , 30 , 47 , 48 ]. In the current study, the calves were originated from the same farm, fed the same diets, and managed the same way under similar environment; and none of them had a history of antibiotic exposure prior the study. Thus, microbial variations attributed to these factors were minimal.
In the present study, danofloxacin increased microbial richness (median OTUs rose from 293 to 313) and diversity (median Shannon index rose from 6.98 to 7.08). These findings contrast with our initial hypothesis that the higher concentration of danofloxacin diffusing into the intestine reduces microbial richness and diversity. Consistent with our original hypothesis, a two-week tetracycline administration reduced gut microbial diversity, changed the abundance of some bacterial taxa, and enhanced the abundance of ARGs, plasmids, and integrons in mouse guts [ 24 ]. In agreement with our current finding, other authors reported that diversity of microbiota increased in the piglets that received a single injectable dose of tulathromycin compared to the control, which they considered as “more chaotic” [ 30 ]. On the other hand, the numbers of genera in the treatment groups dramatically and significantly reduced 24 h after danofloxacin injection compared to the control group in this study. However, these numbers returned to the pre-treatment level three days later, which may indicate a transient effect of danofloxacin on microbial richness. Furthermore, a significant clustering difference between pre- and post-treatment microbial communities depicted in the NMDS plot ( Figure 2 ) demonstrated the impact of danofloxacin on the structures of microbial communities. In contrast to the present study, Ferguson and colleagues [ 33 ] reported only minor changes in community structure and the absence of changes in microbial diversity following enrofloxacin administration in steers. The discrepancy between these two studies could be partly attributed to the difference in the study designs, where we used ten calves per group under a controlled study setup, and they employed six animals per group. However, it is worthwhile to investigate if the pharmacokinetic differences that exist between danofloxacin and enrofloxacin might have contributed to the variations between these two studies [ 49 ].
In the present study, we assessed the effect of danofloxacin on the composition of
Campylobacter
and its association with the other genera. We were particularly interested in this genus because of the public health significance that some species belonging to
Campylobacter
have and the rising of antibiotic resistance among them [
50
]. Twenty-six of the thirty study calves were colonized by
Campylobacter
species that have public health importance (i.e.,
C. jejuni
) when they were first enrolled in this study, as indicated by bacterial culture (data not shown). Following the inoculation of the laboratory strains, the proportion of
Campylobacter
(i.e., based on the 16S study) continued to rise until the day danofloxacin was administered to the calves in the treatment groups. The increase in the abundance was not quick as there was no significant difference between the sampling time points 1 and 2 (Day 2 and Day 6, the laboratory strains were administered on Day 4 after the start of the study), and the absence of a difference between the two sampling points could be due to the delay in
Campylobacter
colonization arising from fighting for niches with other microbes [
51
]. After danofloxacin injection to the treatment calves, the relative abundance of
Campylobacter
sharply reduced in the samples collected after 24 h; however, it rebounded to the pre-treatment baseline after three days (
Figure 5
), suggesting that resistant strains emerged as a result of the antibiotic exposure. In agreement with this finding, previous studies conducted by our research team reported the emergence of fluoroquinolone resistance in
Campylobacter
strains in chicken intestine as early as 24 h after the initiation of oral enrofloxacin treatment. The proportion of this genus remained unaltered in the control group except for a slight rise in the last sampling day, which strongly suggests that the changes that observed in the treatment groups were driven by danofloxacin administration.
Furthermore, in the current study, we identified 21 genera that had a significant correlation ( p < 0.05) with Campylobacter . Most of them were confirmed to have a correlation with Campylobacter by the Boruta important variable selection algorithm and the random forest models, which are robust methods to identify correlation between variables [ 52 , 53 , 54 ]. Consistent with previous studies, most of the genera in Bacteroidetes phylum had a negative correlation and genera in Firmicutes and Proteobacteria phyla had a positive correlation with Campylobacter in the present study [ 55 , 56 , 57 ]. However, there are some variations with those studies; for instance, we found a negative correlation between Campylobacter and Prevotella in contrast to the report by Dicksved and colleagues [ 57 ]. Understanding the association between gut bacterial taxa has public health implications because gut microbial compositions affect colonization resistance to enteric bacterial infections, including Campylobacter [ 50 , 56 ]. For instance, 12 bacterial taxa were shown to have a significant impact on the prevalence and enumeration of E. coli O157:H7 in cattle feces [ 58 ]. We also found that the genera that had a correlation with Campylobacter were different before and after danofloxacin injection, except for one genus ( Table S4 ). The change in the patterns of association between gut microbiota may have to do with the way different bacterial taxa respond to antibiotics. As indicated in Table 2 and Table 3 , some of the bacterial taxa significantly increased or decreased in their compositions following danofloxacin injection, while the other remained unaltered.
The mechanisms by which gut microbiota affect the compositions of Campylobacter include direct inhibition, altering the intraluminal milieu, and production of metabolites [ 50 , 57 , 59 ]. Exploring the relationship between Campylobacter and gut microbial compositions can give an insight into how to mitigate the spreading and transmission of this foodborne pathogen to humans. Deliberate alteration of gut microbial composition could help to control the amount of Campylobacter shed in cattle feces [ 58 ]. Our findings call for further investigation of the identified bacterial taxa with a negative correlation with Campylobacter, particularly those genera with high correlation coefficients or high importance in the random forest plots, which could be used as probiotics to curtail the fecal shedding in cattle or other food animals. Several bacteria, mainly Lactobacillus species, have been shown to reduce colonization and shedding of C. jejuni in poultry [ 60 , 61 , 62 ]. Brooks and colleagues observed that antibiotic-driven depletion of gut microbiota in a mouse model increased C. jejuni colonization, invasion, and severity of gastroenteritis, which may require administration of probiotics following C. jejuni infection to ameliorate inflammation and autoimmune disease [ 63 ].
In the current study, the metagenomic Hi-C ProxiMeta predicted the presence of ARGs that confer resistance to tetracycline, aminoglycoside, β-lactams, and erythromycin in the fecal samples. The presence of ARGs of these antibiotics in the samples is not a surprise because they are among the most frequently used antibiotics on beef farms for the control and prevention of diseases and as feed additives [ 17 ]. According to the FDA report, these antibiotics accounted for 67% (tetracyclines), 12% (β-lactam penicillin), 8% (macrolides including erythromycin), and 5% (aminoglycoside) of the total medically important antibiotics approved for use in food-producing animals and actively marketed in 2019 [ 64 ]. Furthermore, based on a recently conducted study on 22 U.S. beef farms, macrolide and tetracycline in-feed use accounted for 59.7% and 19.4% of the total regimens used in 2016 and 2017, respectively [ 17 ]. The in-feed ingredient use of these antibiotics in the feedlot production system contributes toward the emergence and spread of resistance; even, in those farms that stopped using these drugs a long time ago, detection of their resistance genes is a common phenomenon [ 65 ]. In agreement with our findings, Zaheer and colleagues [ 43 ] documented a high prevalence of tetracycline resistance (82%), followed by macrolide (14%) and aminoglycoside resistance (2.2%) in fecal samples from beef cattle.
Fluoroquinolone (in this case danofloxacin) resistance is primarily conferred through a single mutation in
gyr
A gene that is involved in DNA supercoiling [
66
]. The method we employed in the current study does not detect a single nucleotide change, despite the rebound of
Campylobacter
four days post-treatment, suggesting the emergence of resistant strains, which also complemented by previous trials in our laboratory and in the literature [
18
,
25
]. Genes that have been shown to be associated with fluoroquinolone resistance in other bacteria (e.g.,
qnr
A,
qnr
B,
qnr
S, etc.) were not detected in the current study. In a previous study that assessed the effect of danofloxacin treatment (IM, for three days) in pigs on the
Campylobacter coli
resistance profile, the MIC of the isolates increased after the treatment and attributed to the mutation of the
gyr
A gene [
18
].
In this study, antibiotic resistance determinants have increased both in number and types after danofloxacin administration. The detection of new types of ARGs (i.e., erm F, sat , tet L, and tet X; Table 2 ) that were not detected in the pre-treatment samples might trigger a question of why resistance genes unrelated to danofloxacin had emerged after the treatment. We propose two hypotheses supported by literature. (1) An enrichment of bacterial strains resistant to these antibiotics: danofloxacin might have wiped out or weakened susceptible bacterial strains and selected for resistance strains to predominate others. The identified resistance genes might have been present before the treatment at a level below the detection limit; however, the treatment might have enriched the bacterial strains hosting these ARGs to the level where our method was capable of detecting them. Parallel to our observation, the sulfonamide resistance gene ( sulf 2) was enriched following the administration of unassociated antibiotics such as macrolides and tetracycline in cattle [ 67 ]. (2) These ARGs might be available at an undetected level before the treatment; however, danofloxacin administration might have favored horizontal gene transfer among genetically related and, probably, unrelated bacteria. Horizontal gene transfer is a common way of acquiring ARGs by bacteria in complex environments, such as in the gut [ 27 , 68 , 69 ]. Co-transfer of erm B and tet M in Streptococcus pyogenes was reported, which suggested their linkage in individual genetic elements [ 70 ]. Colocalization of many ARGs on microbial genomes was found in swine feces and manure; they confer multi-drug resistance to bacteria within a community [ 71 ]. In the current study, the exposure to danofloxacin might have enhanced both the dominance of resistant bacteria as well as the transfer of the resistance genes among the microbes in the bacterial communities horizontally [ 72 ]. In one study, it was shown that danofloxacin treatment decreased the susceptibility of C. jejuni to macrolide (tylosin) [ 18 ]. Meanwhile, in the mouse intestinal microbiota, tetracycline treatment enhanced the abundance of antibiotic ARGs (from 307.3 to 1492.7 ppm), plasmids (from 425.4 to 3235.1 ppm), and integrons (from 0.8 to 179.6 ppm) [ 24 ].
The ProxiMeta Hi-C metagenomic deconvolution also enabled us to predict bacterial taxa that hosted the ARGs. Previously, using the metagenome-assembled genomes reconstructed by this method, Stalder and colleagues detected an association between ARGs, mobile genetic elements, and host genomes from wastewater samples [ 36 ]. In our study, the order Clostridiales in class Clostridia hosted the largest number of ARGs, where ant 6, ant 9, aph 2, sat , tet O, tet W, tet 32, tet W40, and tet 44 were hosted by this bacterium. Sharpea azabuensis DSM_18934 (in the phylum Firmicutes , class Erysipelotrichia , and family Coprobacillaceae ) identified in the pre-treatment samples was found to host ant 6, ant 9, cfr , and tet W. The genus Sharpea was detected in 78 of 80 pre-treatment and 59 of 60 post-treatment samples using the 16S rRNA analysis, but it was not identified by the Hi-C metagenomics in the post-treatment samples. Sharpea azabuensis is a ruminal bacterium that produces trans -11 intermediates from linoleic and linolenic acid [ 73 ]. Information about the antimicrobial resistance status or acting as a reservoir of resistant genes is not available for this species. In general, the Hi-C findings are consistent with a longitudinal study conducted in China, where they quantified resistance genes in manure from pigs using real-time PCR (i.e., qPCR) and 16S gene sequencing [ 68 ]. The authors reported a strong positive correlation between the dynamics of tetracycline resistance genes (i.e., tet M, tet O, tet Q, and tet W) and the relative abundances of certain OTUs of gut associated Clostridiales . Furthermore, higher levels of tet W and tet 40 were detected in Bacteroidetes following danofloxacin treatment, suggesting the occurrence of ARG transfer horizontally between these Clostridiales in this phylum and other bacteria. Previous studies show that bacterial species in this family acquire resistance genes from other bacteria through transposons and plasmids [ 74 , 75 ]. It appears that danofloxacin administration favors expansion of the ARG host ranges. In this study, 11 and 6 ARG types increased and decreased in copy numbers following the treatment, while 12 and 7 of them had their host range increased and decreased, respectively.
Selected ARGs identified by the metagenomic Hi-C method were further quantified using qPCR in the current study. The results of the latter method were consistent with the Hi-C results in that the quantity of
tet
W and
erm
B were altered significantly, while that of
tet
O,
tet
X, and
erm
F were not affected in the post-treatment fecal samples in group B. However, the dramatic increase in
tet
W predicted by the Hi-C method was not measured by qPCR, which might be attributed to one or both of the following reasons: the fecal samples used in the case of Hi-C ProxiMeta was a pooled sample from two calves on the danofloxacin injection day (i.e., Day 18) for pre-treatment sample and four days later (i.e., Day 22) for the post-treatment sample. In the case of qPCR testing, however, DNA extracts from all calves (ten) in group B were pooled together with a different post-treatment day. The pre-treatment sampling day was the same (i.e., Day 18) but the post-treatment sampling day was different (i.e., Day 28). Nevertheless, the prediction of the trends of ARG changes between the well-established gene quantification method (qPCR) and the novel metagenomic Hi-C method is similar, suggesting the robustness of this novel method in predicting the dynamics of antibiotic determinants in complex microbial communities, such as gut or fecal microbiota.
4. Materials and Methods
4.1. Study Design and Animals
For this study, 30 dairy calves (26 male; 4 female) with predominantly Holstein genetics and no prior history of antibiotic exposure were acquired from a dairy farm located in the state of Iowa. Calves were approximately 8 weeks old at the time of procurement and weighed between 54 kg to 93 kg. Following purchase, they were group-housed in three rooms (ten calves in each room) at the Livestock Infectious Disease Isolation Facility (LIDIF) at Iowa State University (Biosafety level 2) for 28 days. The rooms were maintained at 20–21 °C (68–70 °F), and each of them had an independent airflow system. Upon arrival at the facility, calves were visually examined by veterinarians for signs of disease such as lameness, nasal discharge, dyspnea, obtundation, ophthalmic abnormalities, bloat, or diarrhea. Only calves that appeared healthy were enrolled in the study. Following visual examination, calves were weighed and then randomly assigned to one of three study groups after blocking by their weight. Study groups included: Group A—control, oral inoculation with
C. jejuni
; Group B—oral inoculation with
C. jejuni
and subcutaneous administration of a single dose of danofloxacin; and Group C—oral inoculation with
C. jejuni
, trans-tracheal inoculation with
Mannheimia haemolytica
, and subcutaneous administration of single dose of danofloxacin. Throughout the study course, calves were fed mixed grass hay and a pre-mixed calf starter (Heartland Co-op, Des Moines, IA, USA) and provided with
ad libitum
water. None of these calves showed serious health problems that required additional antibiotic administration during the study period. The procedures in this study were undertaken following prior approved Institutional Animal Care and Use Committee requirements for Iowa State University.
Following a four-day acclimatization period, all calves were orally inoculated with
C. jejuni
(a cocktail of laboratory strains obtained from Texas, Missouri, and Colorado). The inoculum was prepared by combining fresh colonies of
C. jejuni
with Mueller–Hinton (MH) broth. For each calf, 60 mL of
C. jejuni
suspension (~10 × 10
9
CFU/mL) was administered using a calf esophageal tube. Six days following the administration, calves in group C were inoculated with
M. haemolytica
(10 mL per calf, ~3 × 10
9
CFU/mL) by trans-trachea injection using a catheter to induce BRD according to the protocol described in our publication [
76
]. In the subsequent days, the calves were monitored for signs of BRD, such as elevated body temperature, eye and nasal discharges, ear droop or head tilting, cough, and changes in breathing, eating, and ambulation. Eight days after trans-tracheal inoculation of
M. haemolytica,
calves in groups B and C were subcutaneously injected with a single dose of danofloxacin (ADVOCIN™,
danofloxacin mesylate
, Pfizer Animal Health; 8 mg/kg body weight) in the neck. Fecal samples were collected to a 50 mL screw-cap tube directly from the rectum from all study calves on days 2, 6, 14, 18, 19, 22, and 28; four times before the treatment (i.e., danofloxacin injection) and three times after the treatment. The calves were euthanized with a penetrating captive bolt gun at the end of the study, as per AVMA Guidelines on Euthanasia [
77
].
4.2. DNA Extraction, Library Preparation, and Sequencing
16S rRNA : To determine the effects of danofloxacin on gut microbiota, 16S rRNA analysis was conducted. DNA extractions were performed following ZymoBIOMICS™ protocol from 210 fecal samples (10 calves per group and seven sampling time points). The V4-V5 hypervariable regions of the bacterial 16S rRNA gene were amplified using a universal 16S forward primer (515F: GTGYCAGCMGCCGCGGTAA) and a reverse primer (926R: CCGYCAATTYMTTTRAGTTT). Briefly, the fecal samples were thawed at room temperature for approximately 30 min. From each sample, 200 mg of feces was transferred to a 2 mL ZR BashingBead™ lysis tube and mixed with 250 µL deionized sterile water, 750 µL lysis solution, and 50 µL proteinase K. The samples were processed by a bead beater for 10 min followed by incubation for at least 30 min in a water bath at 55 °C. Then, the lysis tubes were centrifuged in a microcentrifuge at 10,000 × g for 3 min. The supernatant was harvested to columns and then washed with DNA Wash Buffer 1 and 2. The final product was eluted with DNase/RNase free water, and the concentration of eluted DNA was measured first by NanoDrop 3300 Fluorospectrophotometer (Nanodrop technologies, USA) and confirmed by Qubit fluorometer (Invitrogen). Following normalization of all the DNA extracts, they were transferred to 96-wells plates, and submitted for sequencing to the DNA Facility of Iowa State University. The Earth Microbiome Project protocol was followed for sequencing on the Illumina MiSeq platform (2 × 250 paired-ends) in a single flow cell lane. For control, two community standards were used.
Shotgun sequencing: To assess the effects of danofloxacin on gut microbial resistome, shotgun and ProxiMeta Hi-C metagenomics were performed. For shotgun library preparation, four samples (pooled two pre-treatment samples and pooled two post-treatment samples from calves in Group B) were selected based on the results of 16S analysis. Samples collected right before danofloxacin injection (i.e., Day 18) and four days later (i.e., Day 22) were used for this purpose. Like in the case of 16S rRNA gene, whole-genome DNA was extracted from the fecal samples according to ZymoBIOMICS™ instructions. The whole-genome extracts were submitted to the DNA Facility of Iowa State University, where a single flow cell lane Illumina HiSeq platform (2 × 150 bp) was used for sequencing.
Metagenomic Hi-C ProxiMeta DNA extraction and library preparation: The same samples used for the whole-genome shotgun DNA extraction were used for the Metagenomic ProxiMeta sequencing. The Hi-C library was created using a Phase Genomics (Seattle, WA, USA) ProxiMeta Hi-C Microbiome Kit, which is a commercially available version of the Hi-C protocol. Briefly, 100 mg of the fecal sample was washed with TBS, and then genetic material (both chromosomal and non-chromosomal) were crosslinked in vivo while the bacterial cells were still intact using a formaldehyde solution, simultaneously digested using restriction enzymes Sau3AI and MlucI. The genetic materials were proximity ligated with biotinylated nucleotides to create chimeric molecules composed of fragments from different regions of genomes that were physically proximal in vivo according to the manufacturer’s instructions for the kit. The chance of inter-cellular interactions of genetic materials was negligible. Molecules were pulled down with streptavidin beads and processed into an Illumina-compatible sequencing library according to the protocol. Sequencing was performed on an Illumina HiSeq instrument (2 × 150 bp). The bioinformatic analyses were described in our recent publication [ 78 ].
Quantitative real-time PCR ( qPCR ): To assess the dynamics of antimicrobial resistance genes following danofloxacin injection in the fecal samples, we ran qPCR using primers previously designed by Looft et al. [ 79 ] presented in Table 5 . The target resistance genes were selected based on the metagenomic Hi-C results; accordingly, primers were ordered from the ISU DNA facility for tet W, tet O, tet X, erm B, and erm F. The DNA extracts (described above) from fecal samples collected on Day 18 for the pre-treatment and Day 28 for the post-treatment, were pooled together for each group separately. PCR assays were run using the SsoAdvanced™ Universal SYBR ® Green Supermix (Bio-Rad, Hercules, CA, USA) and the CFX Maestro™ Real-Time PCR detection system (Bio-Rad). Dilutions of DNA template for both standards (16S and target genes) and all unknowns were run in triplicate with reaction volumes of 10 μL. Amplification of DNA occurred with 35 cycles of denaturation at 95 °C for 10 s and then annealing for each primer pair at 60 °C for 30 s. Both standard curves (16S and target genes) were experimentally validated to have high efficiency > 90% of amplification and precision R 2 ~ 0.98 prior the analysis. Relative expression was normalized using 16S detection levels. The relative fold change of detection between the control and treatment groups (B and C) were calculated using the ISU Gallup Method Equation [ 80 ]. Statistical analysis was performed using Dunn pair-wise comparison test in Rstudio to determine significance changes in ARG levels between the pre-and post-treatment pooled samples. An adjusted p -value of < 0.05 was considered significant.
4.3. Bioinformatics and Data Analysis of 16S Data
Bioinformatic analyses of the 16S rRNA sequence data were performed using the QIIME 1.9 and QIIME 2 pipeline. Alpha and beta diversity metrics were computed to evaluate the effects of the antibiotic on the richness and diversity of gut microbiota. The richness was estimated by using observed OTUs, and the evenness using the Shannon index. A non-metric multidimensional scaling plot (distance = bray, k = 3) was developed using the Vegan R package to visualize the clustering difference between pre- and post-treatment microbial communities.
We used R statistical software for statistical analyses and plotting of graphs. The Kruskal–Wallis test was used to compare the relative abundances of bacterial taxa among the three calf groups and Dunn test for pair-wise comparisons. Similarly, pre- and post-treatment bacterial OTUs were compared by the Wilcoxon signed-rank test. The association of the relative abundance of genus
Campylobacter
with other genera was explored using the Spearman rank correlation test, and multiple testing correction with a false discovery rate was performed [
5
]. A
p
-value < 0.05 was considered significant for all analyses, and for the false discovery rate,
p
adjusted < 0.05 was used unless specified otherwise.
Prediction Models Using Random Forest Models
In total, we obtained 298 genera in our samples; 70 of them with very low relative abundance (zero-inflated) were excluded from further analyses. Among 228 genera, important genera that might have a significant association with pre- and post-treatment status and the compositions of
Campylobacter
were selected using the Boruta algorithm. For the building of random forest models, the data were randomly divided into a training sub-data (70%) and a test sub-data (30%). The models were first trained using the training sub-data, and then its fitness was evaluated using the test sub-data. The genera selected by the Boruta algorithm were fed to the random forest models to rank the genera based their predictive importance and presented in graphs. The Boruta algorithm and random forest models have been used in the microbiota studies to select and rank important variables from high-dimensional data [
52
,
53
,
54
]. In this study, we used these methods to identify bacterial taxa that are capable of classifying the microbial communities into pre- and post-treatment, as well as predicting the relative abundance of
Campylobacter.
For the latter case, further analyses were performed by subsetting data as pre-treatment, post-treatment, and control to check if the treatment might have affected the association patterns between genera.
5. Conclusions
In summary, our data indicate that subcutaneous administration of danofloxacin significantly altered the compositions and structures of the fecal microbiota in calves. However, not all bacterial taxa were affected alike by the treatment. Several of them showed a reduction in relative abundances, a few other taxa were enriched, and many of them remained the same. The relative abundance of the genus with public health importance,
Campylobacter
, abruptly reduced 24 h after the treatment but was resilient after three days, which may imply that this bacterium developed resistance to danofloxacin and, thus, it entails a risk to the public health. The novel ProxiMeta Hi-C method revealed that several types of ARGs that confer resistance to commonly used antibiotics in cattle were enriched by danofloxacin. Additionally, using this method, the presumptive reservoirs of resistance genes have been predicted, and this will help to make further investigations to acquire a deeper understanding of the way resistance genes spread within microbial communities in general and the way they transmit to bacterial species that have public health significance in particular.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/microorganisms9102023/s1 , Table S1: the relative abundance of bacterial phyla of 30 study calves at seven sampling days over four weeks of the study period, Table S2: comparisons of the relative abundance of bacterial taxa between control (group A) and treatments (group B—non-BRD-induced and group C—BRD-induced) groups, Table S3: the Spearman rank correlation test between Campylobacter and other genera in the whole fecal samples (all groups combined), Table S4: the Spearman rank correlation test between Campylobacter and other genera in pre- and post-treatment samples (groups B and C combined), Table S5: summary of antimicrobial resistance genes detected in pre-and post-treatment fecal samples along with their respective bacterial reservoirs in calf group B.
Author Contributions
Conceptualization, Q.Z., P.J.P., O.S. and A.F.B.; methodology, P.J.P., Q.Z., O.S. and A.F.B.; Data collection: A.F.B., D.B.-G., T.H., C.S., R.D. and G.D.; Laboratory work, A.F.B., T.H., C.S., B.R., A.H. and D.B.-G.; formal analysis, P.J.P. and A.F.B.; writing—original draft preparation, A.F.B. and P.J.P.; writing—review and editing, all; supervision, G.D., R.D., P.J.P., O.S. and A.F.B.; project administration, Q.Z. and P.J.P.; funding acquisition, Q.Z., P.J.P., O.S. and G.D. All authors have read and agreed to the published version of the manuscript.
The procedures in this study were undertaken following prior approved Institutional Animal Care and Use Committee requirements for Iowa State University.
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Figure 1. Boxplots for alpha diversity metrics comparing pre- and post-treatment samples in the treatment group ( top ) and control group ( bottom ). The treatment group received a single subcutaneous injection of danofloxacin. Asterisks show significant differences (* p < 0.05, ** p < 0.01) between pre- and post-treatment microbial communities for the respective group. Note: the control group was divided into pre- and post-treatment to compare with the treatment group in a temporal manner; otherwise, the calves in the control group did not receive any antibiotic. The observed OTUs and Shannon index do not have units, but they measure microbial richness and evenness based on OTU counts and abundance.
Figure 1. Boxplots for alpha diversity metrics comparing pre- and post-treatment samples in the treatment group ( top ) and control group ( bottom ). The treatment group received a single subcutaneous injection of danofloxacin. Asterisks show significant differences (* p < 0.05, ** p < 0.01) between pre- and post-treatment microbial communities for the respective group. Note: the control group was divided into pre- and post-treatment to compare with the treatment group in a temporal manner; otherwise, the calves in the control group did not receive any antibiotic. The observed OTUs and Shannon index do not have units, but they measure microbial richness and evenness based on OTU counts and abundance.
Figure 2. Non-metric multidimensional scaling (NMDS) of the Bray-Curtis dissimilarity index showing clustering difference between pre- and post-treatment microbial communities, blue and red dots, respectively.
Figure 2. Non-metric multidimensional scaling (NMDS) of the Bray-Curtis dissimilarity index showing clustering difference between pre- and post-treatment microbial communities, blue and red dots, respectively.
Figure 3. Bacterial genera that classify pre- and post-treatment communities based on the Boruta important variable selection algorithm and ranking by the random forest model. The length of the horizontal bars corresponds to its predictive importance.
Figure 3. Bacterial genera that classify pre- and post-treatment communities based on the Boruta important variable selection algorithm and ranking by the random forest model. The length of the horizontal bars corresponds to its predictive importance.
Figure 4. Number of genera per sample for three calf groups by sampling time point. Genus count at sampling Day 19 were significantly lower in both treatment groups B and C than in the control group A. C. jejuni cocktail, M. haemolytica , and danofloxacin were administered on Days 4, 10 and 18, respectively. *** p = 0.001.
Figure 4. Number of genera per sample for three calf groups by sampling time point. Genus count at sampling Day 19 were significantly lower in both treatment groups B and C than in the control group A. C. jejuni cocktail, M. haemolytica , and danofloxacin were administered on Days 4, 10 and 18, respectively. *** p = 0.001.
Figure 5. Comparisons of the relative abundance of Campylobacter in samples collected from the calves in the combined treatment groups (B and C) by sampling days. Danofloxacin was injected on Day 18 right after fecal sample collection. **** relative abundance of Campylobacter on Day 19 was significantly different from those on the sampling Day 14, Day 18, Day 22, and Day 28. The abundance rates were significantly different from each other on sampling Day 22 and Day 28 ( p = 0.000).
Figure 5. Comparisons of the relative abundance of Campylobacter in samples collected from the calves in the combined treatment groups (B and C) by sampling days. Danofloxacin was injected on Day 18 right after fecal sample collection. **** relative abundance of Campylobacter on Day 19 was significantly different from those on the sampling Day 14, Day 18, Day 22, and Day 28. The abundance rates were significantly different from each other on sampling Day 22 and Day 28 ( p = 0.000).
Figure 6. Genera associated with the relative abundance of Campylobacter selected by the Boruta algorithm and ranked by the random forest models. Control ( top left ), pre-treatment ( top right ), post-treatment ( bottom left ), and all data ( bottom right ). The length of the bar is proportional to the predictive importance of the genera; vimp—variable importance.
Figure 6. Genera associated with the relative abundance of Campylobacter selected by the Boruta algorithm and ranked by the random forest models. Control ( top left ), pre-treatment ( top right ), post-treatment ( bottom left ), and all data ( bottom right ). The length of the bar is proportional to the predictive importance of the genera; vimp—variable importance.
Table 1. Comparisons of the relative abundance of bacterial genera between fecal samples collected before and after danofloxacin injection in the treatment group by the Wilcoxon signed-rank test. Only significantly altered genera were shown in the table.
Table 1. Comparisons of the relative abundance of bacterial genera between fecal samples collected before and after danofloxacin injection in the treatment group by the Wilcoxon signed-rank test. Only significantly altered genera were shown in the table.
Genus Relative Abundance (%) p Genus Relative Abundance (%) p Pre Post Pre Post Succinivibrio 0.38 0.05 0.000 Erysipelotrichales_RFN20 0.04 0.03 0.000 Streptophyta_5-7N15 4.12 8.31 0.000 Desulfovibrio 0.51 0.27 0.000 Enterobacteriaceae_unclassified 0.08 0.01 0.000 Elusimicrobiaceae_unclassified 0.12 0.04 0.000 Peptococcaceae_unclassified 0.13 0.25 0.000 Bacteroidaceae_unclassified 1.53 2.54 0.000 Alphaproteobacteria_unclassified 0.38 0.14 0.000 Synergistes 0.03 0.01 0.000 Eubacterium 0.13 0.03 0.000 Methanosphaera 0.35 0.22 0.001 Coprobacillus 0.01 0.00 0.000 Sutterella 0.61 0.24 0.001 Erysipelotrichales_p-75-a5 0.10 0.00 0.000 Pseudoramibacter 0.05 0.02 0.001 Prevotella 2.29 0.93 0.000 Rikenellaceae_unclassified 5.57 3.44 0.003 Blautia 0.27 0.05 0.000 Epulopiscium 0.04 0.08 0.004 [Paraprevotellaceae]_unclassified 0.04 0.00 0.000 Treponema 1.98 1.45 0.005 Faecalibacterium 0.15 0.00 0.000 Clostridiales_unclassified 9.72 8.65 0.005 Phascolarctobacterium 0.51 0.36 0.000 [Barnesiellaceae]_unclassified 0.19 0.32 0.008 Anaerovibrio 0.10 0.03 0.000 Bifidobacterium 0.37 0.12 0.013 Mogibacteriaceae_unclassified 0.69 0.50 0.000 Desulfovibrionaceae_unclassified 0.20 0.28 0.014 Butyrivibrio 0.09 0.16 0.000 Akkermansia 2.94 4.72 0.018 Cyanobacteria_unclassified 1.16 0.75 0.000 Elusimicrobium 0.22 0.29 0.022 Veillonellaceae_unclassified 0.18 0.13 0.000 Peptostreptococcaceae_unclassified 1.61 2.33 0.023 Ruminococcaceae_unclassified 27.17 31.87 0.000 Bacteroides 1.83 0.23 0.042 Pirellulaceae_unclassified 0.05 0.14 0.000 Ruminobacter 0.01 0.02 0.046
Table 2. Summary of antimicrobial resistance genes in pooled fecal samples before and after danofloxacin injection in calves identified by Metagenomic Hi-C.
Table 2. Summary of antimicrobial resistance genes in pooled fecal samples before and after danofloxacin injection in calves identified by Metagenomic Hi-C.
Antibiotic Class Resistance Gene Number of Hits Number of Hosts Pre-trt a (165 *, 38 **) Post-trt b (200, 64) Pre-trt (165, 38) Post-trt (200, 64) Aminoglycoside aac 6 0 3 0 3 aph 2 61 58 14 16 aph 3 51 55 11 13 ant 6 75 84 22 29 ant 9 39 189 12 23 sat 51 56 11 12 Beta-lactams aci 1 4 1 2 cf X 5 8 5 3 Macrolides erm B 8 0 3 0 erm F 0 1 0 1 erm G 24 5 3 3 erm Q 1 0 1 0 mef E 3 1 2 1 Phenicol cf R 15 24 3 14 Tetracyclines tet 32 20 16 9 7 tet 40 112 1484 44 91 tet 44 15 6 10 5 tet A 8 4 5 3 tet B 1 0 1 0 tet L 0 69 0 5 tet O 78 75 27 21 tet Q 25 483 10 19 tet W 178 2836 79 105 tet X 0 1 0 1
a Pre-treatment samples, pooled individual samples collected right before danofloxacin injection (Day 18); b Post-treatment samples, pooled individual samples collected four days after danofloxacin injection (Day 22). * Total number of clusters in the pooled samples, and ** number of clusters with ≥ 80% complete genomes.
Table 3. Summary of phyla associated with antimicrobial resistance genes detected in pooled fecal samples before and after danofloxacin administration.
Table 3. Summary of phyla associated with antimicrobial resistance genes detected in pooled fecal samples before and after danofloxacin administration.
Phylum Pre-Treatment Post-Treatment Actinobacteria ermB, ermG, tetW ant9, tet40, tetQ, tetW Bacteroidetes tetQ aph2, aph3, ant6, cfX, ermF, ermG, mefE, cfR, tet40, tetQ, tetW Euryarchaeota ant9, tetA, tetO No ARGs Firmicutes aph2, aph3, ant6, ant9, sat, cfX, ermB, cfR, tet32, tet40, tet44, tetA, tetB, tetO, tetQ, tetW aac6, aph2, aph3, ant6, ant9, sat, ermG, cfR, tet32, tet40, tetA, tetL, tetO, tetQ, tetW Proteobacteria aph2, aph3, ant6, ant9, sat, tet32, tet40, tetO, tetW aac6, aph2, aph3, ant6, ant9, cfR, tet40, tetL, tetQ, tetW Spirochaetes NA ant6, sat, tet40, tet44, tetW Tenericutes tet40 No ARGs Verrucomicrobia tet40 ant6, sat, tet40, tetW
Table 4. Changes in the quantity of selected antimicrobial resistance genes in pooled fecal samples following danofloxacin treatment measured by qPCR.
Table 4. Changes in the quantity of selected antimicrobial resistance genes in pooled fecal samples following danofloxacin treatment measured by qPCR.
Change Control Group B Group C tet W Mean (log2 *) −0.21 0.58 0.34 SD 0.017 0.065 0.015 p value ** NA 0.034 a 0.272 tet O Mean −0.01 −0.15 −0.32 SD 0.024 0.088 0.173 p value NA 0.272 0.0338 c tet X Mean −0.31 −0.92 0.02 SD 0.081 0.058 0.039 p value NA 0.267 0.264 erm B Mean 0.52 −0.76 −0.15 SD 0.081 0.064 0.174 p value NA 0.022 b 0.359 erm F Mean −0.68 −0.44 0.19 SD 0.054 0.095 0.173 p value NA 0.359 0.022 d
* The values obtained using Gallop method analysis was log2 transformed to compare the fold changes in gene abundance between calf groups. ** An adjusted p -value obtained from pairwise comparisons using the Dunn test. a tet W increased and b erm B decreased significantly in the group B post-treatment pooled sample compared to the control group post-treatment sample. c tet O decreased and d erm F increased significantly in group C compared to the control group.
Table 5. Primers used in quantitative real-time PCR tests to assess the dynamics of selected antimicrobial resistance genes in pooled fecal samples from calves.
Table 5. Primers used in quantitative real-time PCR tests to assess the dynamics of selected antimicrobial resistance genes in pooled fecal samples from calves.
ARGs Forward Primer Reverse Primer Reference erm B TGAAAGCCATGCGTCTGACA CCCTAGTGTTCGGTGAATATCCA [ 79 ] erm F TTTCAAAGTGGTGTCAAATATTCCTT GGACAATGGAACCTCCCAGAA tet O ATGTGGATACTACAACGCATGAGATT TGCCTCCACATGATATTTTTCCT tet W TCCTTCCAGTGGCACAGATGT GCCCCATCTAAAACAGCCAAA tet X AAATTTGTTACCGACACGGAAGTT CATAGCTGAAAAAATCCAGGACAGTT
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| https://www.mdpi.com/2076-2607/9/10/2023 |
The Plaintiffs' Perspective: Putting the Notion of "Woodshedding" to Rest
Defendants' attempts to restrict communications between plaintiffs' counsel and plaintiffs' physicians remain unsuccessful.
The Plaintiffs' Perspective: Putting the Notion of "Woodshedding" to Rest
A constant subject of motion practice in pharmaceutical and medical device multidistrict litigation (MDL) practice concerns ex parte contact with plaintiffs’ prescribing and treating physicians. Defendants consistently seek to limit the communication between plaintiffs’ counsel and plaintiffs’ physicians to a strict discussion of the physicians’ diagnosis and treatment and of the medical conditions of the plaintiffs, yet they request permission to engage in their own ex partecommunications with some of these very same doctors in the hope of retaining them as experts. In some cases, particularly with a limited expert pool, courts have granted defendants’ motions permitting them to retain a finite number of plaintiffs’ physicians as their own experts; however, defendants’ attempts to restrict communications between plaintiffs’ counsel and plaintiffs’ physicians remain unsuccessful.
Three recent decisions reinforce existing case law, which rejects the limitations defendants seek to impose on plaintiffs’ ex parte contacts with plaintiffs’ physicians and discredits defendants’ allegations that plaintiffs will use this as an opportunity to improperly influence physician testimony. In a recent one-month period, three different MDL courts addressed the issue of ex parte communications between plaintiffs’ counsel and plaintiffs’ prescribing and treating physicians. See generally In re Xarelto (Rivaroxaban) Prods. Liab. Litig., MDL No. 2592, 2016 WL 915288 (E.D. La. Mar. 9, 2016); In re Testosterone Replacement Therapy Prods. Liab. Litig., MDL No. 2545, 2016 WL 929343 (N.D. Ill. Mar. 7, 2016); In re Benicar (Olmesartan) Prods. Liab. Litig., MDL No. 2026, 2016 WL 1370998 (D.N.J. Apr. 6, 2016). In each litigation, defendants sought entry of a court order barring plaintiffs’ counsel from discussing liability issues or theories with plaintiffs’ physicians. In re Xarelto, 2016 WL 915288, at *2; In re Testosterone Replacement Therapy, 2016 WL 929343, at *2; In re Benicar, 2016 WL 1370998, at *1.
As discussed, this is not an issue of first impression for the courts. Defendants in three cases attempted to introduce new arguments; however, no court found good reason to depart substantially from the rationale of one of the earliest rulings on this issue. In re Xarelto, 2016 WL 915288, at *4 (discussing the Vioxxdecision; see below); In re Benicar, 2016 WL 1370998, at *4 (same); In re Testosterone Replacement Therapy, 2016 WL 929343, at *3. In In re Vioxx Products Liability Litigation, 230 F.R.D. 473, 474 (E.D. La. July 22, 2005), Judge Eldon Fallon issued an order requiring plaintiffs’ counsel to provide notice to defense counsel five days in advance of an interview with the plaintiff’s prescribing physician, and opposing counsel would then be permitted to attend and participate in the interview. The plaintiffs sought modification of this order, arguing its effect resulted in several unintended consequences, including plaintiffs’ counsel’s inability to conduct proper pre-filing case evaluations. Id.at 475. In granting the plaintiffs’ motion, Judge Fallon determined the presence of defense counsel during these interviews, without the permission of the patient, would impair the sanctity of the confidential patient-physician relationship and potentially reduce the quality of medical care received by the plaintiffs. Id.at 477. Furthermore, because the defendants will receive each plaintiff’s medical records as well as a profile form detailing the plaintiff’s relevant medical history, and because they already have documentation of the information the company relayed to the treating physicians about Vioxx, Judge Fallon ruled that the defendants “do not need the doctors to tell them in ex parteconferences what they already know.” Id.
The defendants acknowledge a need to preserve the patient-physician relationship but contend that giving plaintiffs’ counsel unfettered access to the plaintiffs’ treating and prescribing physicians will result in “woodshedding.” In these so-called “woodshedding” motions, defendants use this term to describe a process by which plaintiff’s attorneys’ meetings with treating physicians result in impermissible coaching. In re Xarelto, 2016 WL 915288, at *1 n.1; In re Testosterone Replacement Therapy, 2016 WL 929343, at *2; In re Benicar, 2016 WL 1370998, at *1 n.2.
The defendants argued in these MDLs that if plaintiffs’ counsel are entitled to review internal documents and discuss theories of liability with plaintiffs’ physicians, this will undoubtedly have an improper influence on the physicians and could even deter physicians from prescribing the medication that is still on the market and known to have proven health benefits. In re Xarelto, 2016 WL 915288, at *3; In re Testosterone Replacement Therapy, 2016 WL 929343, at *2; In re Benicar, 2016 WL 1370998, at *3. In support of this notion, the defendants cited one purported example of “woodshedding” in the California ASRhip implant litigation. In re Xarelto, 2016 WL 915288, at *2, *6; In re Benicar, 2016 WL 1370998, at *3. In this anomalous situation, the plaintiff’s physician was a personal friend of the attorney for over 20 years. The physician admitted to incorporating specific language in the record (“reasonable degree of medical certainty,” etc.) at the request of plaintiff’s counsel, but did so to “support … eventually getting his total hip paid for, at least help in paying for it for him if he didn’t have other coverage.” Transcript of Hanson Deposition at 173 (lines 3–5), Kransky v. DePuy Inc., No. BC456086 (Cal. Super. Ct. Nov. 30, 2012) (transcript on file). When viewed in context, this instance involved a distinct set of facts and is in no way representative of plaintiffs’ counsel’s conduct in mass tort litigation generally.
Aside from this example, the courts found little authority in support of the defendants’ contentions. “The problem with defendant’s argument is that there is no credible evidence to support it.” In re Benicar,2016 WL 1370998, at *3. For instance, after four years of unregulated ex partecontacts between plaintiffs’ counsel and treating physicians in the Kugel Meshlitigation, the defendants in that litigation could not provide any substantial evidence of woodshedding to warrant imposition of additional restrictions. In re Xarelto, 2016 WL 915288, at *4, *6 (citing In re Kugel Mesh Hernia Repair, No. 07-184ML, slip. op. at 3 (D.R.I. Jan. 12, 2012). As the courts came to agree, not only was there insufficient proof of routine abuses, but this is a problem that cannot be easily patrolled:
The Court lacks the ability to surgically remove delicate insinuations from the individual sentences of Plaintiff’s counsel. . . . Simply put, the Defendants’ request to cleanse advocacy from Plaintiffs’ ex partephysician contacts may not be easily detectable and is not enforceable, and this Court will not issue a pretrial order which is impossible to police.
Id.at 5.
Moreover, the courts rejected the defendants’ implication that plaintiffs’ physicians, highly trained professionals, would be so easily influenced by plaintiffs’ counsel. “The Court is doubtful that plaintiff’s physicians can and will be duped, and they will defer to plaintiffs’ lawyers about what drugs to prescribe.” In re Benicar,2016 WL 1370998, at *4. The plaintiffs thus believe that the term “woodshedding” should be removed from the legal lexicon because it demeans the integrity of both attorneys and physicians by suggesting that improper conduct by counsel representing their clients will overcome the independent medical judgment of physicians. Indeed, if we continue to use this term in our everyday practice, it should then also be referenced every time sales representatives or corporate witnesses are prepped by defense counsel.
While defendants may interpret these rulings as giving plaintiffs free rein to pit physicians against the pharmaceutical companies, the courts did not leave the defendants without meaningful recourse. “The opposing party may question the witness about his contacts with the other side to shed light on improper attempts to influence or mislead; may, with some limitations, obtain discovery regarding those contacts; and may, if the circumstances warrant, seek sanctions.” In re Testosterone Replacement Therapy, 2016 WL 929343, at *1. Furthermore, each court implemented a strict deposition protocol that guarantees that the defendants receive adequate protections from the perceived ills of allowing plaintiffs’ counsel to discuss topics outside plaintiff-specific treatment with the physician. Accordingly, prior to each physician’s deposition, plaintiff’s counsel must produce the following information concerning pre-deposition contacts: the date, approximate duration, the means (e.g., in person, by telephone), the participants, and the identity of the documents or any electronically stored information provided or described to the physician in connection with the communication. In re Xarelto, 2016 WL 915288, at *6; In re Testosterone Replacement Therapy, 2016 WL 929343, at *3; In re Benicar,2016 WL 1370998, at *6. The remedy of disclosure of this information and the opportunity for cross-examination ameliorates the expressed concern for so-called woodshedding. The courts have achieved a proper balance by permitting plaintiffs’ counsel to properly represent their clients in ex parte communications with physicians, while granting the defendants access to information about ex parte contacts.
These three decisions also touch on defendants’ ability to engage in ex parte communications with plaintiffs’ treating and prescribing physicians for the purpose of retaining their own experts. This practice began following the New Jersey Appellate Division’s ruling in the New Jersey Pelvic Meshlitigation. In In re Pelvic Mesh/Gynecare, 426 N.J. Super. 167, 174 (App. Div. 2012), the trial court prohibited the plaintiffs from consulting with or retaining any physician who had at any time treated any plaintiff in the litigation. The defendants argued that with the number of plaintiffs continuing to increase and the limited number of urogynecologists with experience in the use of pelvic mesh, the trial court’s ruling would prevent the defendants from retaining physician experts with the most specialized knowledge and expertise in the field. Id.at 175. The appellate court agreed, and we now see similar rulings in other MDL courts, each presiding over more than a thousand cases— Xarelto, Testosterone, and Benicar. In this regard, the number of cases in suit is quite significant. Courts should not readily grant similar motions in litigations involving fewer plaintiffs because defendants are more likely to find a qualified expert who has not treated a plaintiff.
The Xareltoparties subsequently proposed a joint pretrial order that was entered by the court.Pretrial Order No. 28, In re Xarelto (Rivaroxaban) Prods. Liab. Litig., MDL No. 2592 (E.D. La. Apr. 28, 2016), ECF No. 3156. The order establishes that defendants’ counsel will disclose to plaintiffs’ counsel the name of any testifying expert who has patients who are plaintiffs in the MDL on the previously agreed-upon date outlined in the bellwether scheduling order. Effectively, the physician is rid of any obligation to personally notify his or her patients of any potential involvement in the litigation. However, in an effort to balance the interests of the parties, the order further stipulates that the defendants are limited to engage in ex parte communications with up to 30 MDL plaintiffs’ prescribing or treating physicians and may only retain up to 15 of these physicians. Importantly for the plaintiffs and the efficacy of the bellwether process, the order prohibits the defendants from retaining any physician expert who served as a prescribing or treating physician of any current discovery pool plaintiff until after the trial or disposition of the first four bellwether trials. Plaintiffs will and should continue to oppose defendants’ request to retain plaintiffs’ physicians as their own experts, but they can have some solace if the courts continue to impose similar restrictions on defendants.
In sum, these recent decisions should put to rest defendants’ motions seeking to limit ex parte communications between plaintiffs’ counsel and plaintiffs’ physicians to case-specific medical treatment. No court was persuaded by defense allegations that plaintiffs’ counsel will abuse this ability. While the courts had been primarily concerned with implementing measures to preserve the patient-physician relationship, this new wave of analysis in which the courts appreciate the integral role that prescribing and treating physicians will play in the plaintiff’s case should, it is hoped, restore the long-standing legal principles of witness preparation and client advocacy.
Keywords:litigation, mass torts, woodshedding, ex parte communication, treating physician
| https://www.americanbar.org/groups/litigation/committees/mass-torts/articles/2016/fall2016-0916-ex-parte-contracts-woodshedding/ |
Meeting of the Parliament: EEFW/26/03/2019 | Scottish Parliament Website
Chamber and committees
Economy, Energy and Fair Work Committee
Meeting date: Tuesday, March 26, 2019
Official Report 627KB pdf
Agenda: Decision on Taking Business in Private, Construction and Scotland’s Economy, European Union (Withdrawal) Act 2018
Contents
Attendance
Decision on Taking Business in Private
Construction and Scotland’s Economy
European Union (Withdrawal) Act 2018
Construction and Scotland’s Economy
Agenda item 2 is evidence taking from a number of witnesses for our inquiry into construction and Scotland’s economy. I advise our witnesses that there is no need to press any buttons, because the microphones are operated from the sound desk. If you want to come into the discussion, please indicate as much by raising your hand.
I welcome to the meeting Graeme Dodds, director of operations, Jacobs; David Stewart, policy lead, Scottish Federation of Housing Associations; Mark Dickson, director of capital investment, Scottish Water; Peter Reekie, chief executive, Scottish Futures Trust; and Søren Kirk Jensen, senior policy and research adviser, CoST—the Infrastructure Transparency Initiative.
The deputy convener, John Mason, will start our questions.
The first area that I want to touch on is the project pipeline. As I understand it, the Government is giving an overview of the amount of money that is available and the number of projects that it is expecting in the coming years. How useful is that approach? Are there any gaps? Would you like that overview to go further ahead? Would you like more detail? Would you like other sectors to be covered that are not already being covered? Does anyone have any strong thoughts on that and want to start us off? I see that Mr Stewart looks interested.
I am happy to start off, but I should probably begin by saying that I am not an expert on infrastructure. I propose to talk more about planning programmes for housing, although I realise that infrastructure has a role to play in that.
We very much welcome the target of 50,000 affordable homes, and I would also note that grant planning targets have been set out for three years. I would therefore say that, as far as clients and contractors being able to plan out work is concerned, we are in a good situation over the current parliamentary session. That is extremely welcome, because we have not always been in that position.
Am I right in saying that housing is not included in the project pipeline that is produced by the Government, because the detail of that is decided by other bodies?
I believe that that is the case.
But we still have a pretty clear target for housing.
Yes.
The Scottish Government last published the infrastructure investment plan in 2015, with an update in April 2018. It included nearly £1 billion of project opportunities—high-value projects across all sectors that have Government involvement—that had not started construction at that stage. However, most infrastructure investment is done by local authorities and other bodies such as housing associations, as you have alluded to. The Government’s page has a click-through to the SFT’s pipeline; we publish the pipeline that looks ahead to the hub programme that we manage, which also does not cover everything that is being done by local authorities and others.
In 2016, Audit Scotland identified in its follow-up report on “Major capital investment in councils” that a third of local authorities published forward-looking investment plans—I do not know whether the proportion has changed since then—and it recommended that more information should be published by local authorities.
In summary, high-level plans are published by Government and different bodies publish their plans, but I agree with your premise that there is no single place to look for all investment across every body that procures infrastructure in the public sector across Scotland.
I suppose that not having a single place does not matter as long as everybody has access to all the information.
That is right.
Does the SFT have access to all the information that it needs? You are obviously closer to Government than some of the witnesses.
The plans that are published give a good look ahead, but many people in the industry have said that more pipeline information would be more useful. People will always want to be able to look further ahead to plan their resources. Industry witnesses will be better placed than I am on this point, but it is one thing to know what is coming but quite another to know that your organisation is going to be part of what is coming and win tenders and so on. There is good information on the overall volume of activity and pretty good information on which sectors it will come in, but organisations then have to start looking in different places for individual projects.
A tension that arises is that although, if all that information were published in a central place, every contractor from anywhere would be able to click on it and see what work was coming in every area of the country, if local authorities publish their own information, that arguably makes it easier for local contractors to view what is coming locally, which they might see as a good thing. Therefore, everyone would like to see more information published—with the challenge about how far ahead because of budgets and so forth—but there will be different views on where the best place is for it to be published and whether it should all be centralised.
I provide an outsider’s perspective here. From the international point of view, I agree with Peter Reekie about the different ways to make things transparent. Our case study on Scotland, which was published last year, found that it has a high level of infrastructure transparency for data that is disclosed throughout project delivery, in comparison with the United Kingdom and internationally. For large projects above £20 million, the level of transparency was 95 per cent when measured against the infrastructure data standard, and for projects between £4.5 million and £20 million, transparency was 70 per cent of the standard.
However, the drawback is that the information is fragmented and scattered across websites and reports, so considerable time is needed to find it, which lowers the value for contractors and for citizens who are interested.
As Peter Reekie mentioned, industry will always want the pipeline to be as detailed and as long as possible, because that gives us surety in our investments in our people. However, we understand that there is a practical limit as to how far that can go.
The existing pipeline is relatively good at telling us what is being constructed and what is about to be constructed, but it is less good at pointing out forthcoming construction, although there is a certain degree of probability about those projects, because some require funding decisions that still have to be made. There is tension between what can be said definitively and the advice that can be given to the industry on what may be coming up to allow it to make judgments. The industry understands that probability factor. Peter Reekie referred to the fact that we do not win everything, but we look at our forward order book all the time and at probabilities of what we might win.
Other speakers were right about the fragmentation that exists once we move away from the infrastructure plan. Relative accuracy is important for industry. Therefore, we would not want to see an expansion of the plan that degrades that accuracy. It is important that there is either a degree of governance of what goes into any published plan—which we have with the current infrastructure plan—or an understanding of a threshold of certainty that agencies at national or local level need to meet, in order to give the industry surety about what is coming forward.
To take the A9, which is quite a long-term plan, you could sit down on day 1 and say, “This is what we are going to do this year, and in years 2, 3 and 20,” but year 20 would change in all likelihood. I am struggling to understand. Should we be trying to plan further ahead, even if we are uncertain about something?
I declare an interest in the A9, because we are involved in it.
The diagram for the process would feature a cone, in which the certainty decreases as one moves further out. However, it is also a conveyor belt in which, as we move forward in time, the certainty about where certain elements of a project lie increases. It would be useful for the industry to reflect on that. It would be difficult to say with any degree of accuracy what is going to happen in five years time on a project or to say that something is going to happen on April 14 2025—the only thing that we can say about that is that it is wrong. However, some indication of what is coming forward further out would be of use to the industry.
A forward pipeline of work is crucial. We are not included in the specific infrastructure plan that you referred to, but we work within a regulatory cycle that allows us to have a long-term, medium-term and short-term view of the work that is coming. We endeavour to share that as widely as we can with our whole supply chain to allow sufficient planning, first, to get the projects delivered efficiently and effectively, and secondly, to understand the capacity and capability that we might need in the medium to longer-term future.
How certain can you be? How far ahead can you be certain as to Scottish Water’s investments?
At the moment, we are in year 4 of a six-year plan, so we have reasonable certainty looking forward to 2021. As we go into the next regulatory cycle, we will have an understanding of the next two years of work in place by the back of this year, and will move into a rolling two-year plan thereafter.
To build on Graeme Dodds’s point, we can see out to 2021 with reasonable accuracy, but we can also understand the nature of the project work that is coming up in the following period, and some of the capacity and capability for which we need support from the industry. That allows us to talk to our supply chain extensively about the investment that is needed to grow that capacity and capability. The whole notion of a forward-looking pipeline that is as accurate as possible is very useful.
Thank you. I could ask more questions, but I think that that is enough.
I have a follow-up question for David Stewart. Would you agree that housing is infrastructure?
We would certainly argue that it is.
So you would say that both public housing and private housing are infrastructure.
Yes.
Right—I must have misunderstood something that you said earlier.
What more could be done to make the infrastructure investment plans useful beyond what you have already hinted at in relation to further forecasting?
I appreciate that it is difficult. Although there is a great deal of clarity about current funding—there is more than £3 billion in public money to support affordable housing, which will be match funded by investment by landlords—in the past, housing has suffered from changes over electoral cycles because there has not been long-term agreement on how much affordable housing or housing in general we need and how we can deliver that. I appreciate that there is not a lot of point in having a 20-year plan for the A9 because it will change, but if there could be consensus broadly about how we arrive at the level of housing need and how we will deliver housing through planning, infrastructure and land release, it would help the industry to invest in apprentices and move to digital and off-site delivery, so that it can attract different people into housing, such as more young people and women. Even if we accept that things change because of economics or political cycles, any horizon scan that looked to a longer-term target would be very helpful.
In the broadest sense, the industry is building construction, civil engineering and house building. Then there are the geographies in which people operate and scales of projects that different organisations get involved in and work on. It would be interesting if the Scottish Futures Trust or the Government could provide information that breaks things down into those broad categories—whether projects are in construction, civils or house building, the scale of the projects and where they are going to happen—so that they are of interest to different firms. We could create a perfect world in our minds where we can look at areas of the country, scales of projects and the nature of activity that will be going on, and then work back to what is possible and see which organisations own bits of data beyond that.
I echo most of what was just said. It is useful to understand whether something is a programme or a project within a programme. That is helpful for small and medium-sized enterprises when they engage with tier 1 contractors on programmes, so that they have an idea of what they need to do, how they need to get engaged and whether there are elements within programmes that will be split into projects that they could take on themselves.
The Australian and New Zealand system has six classifications, running from prospective to closed out. The ability to have such a classification system is useful in understanding the overall picture. That approach would not focus just on work that has all its permissions in place and is shovel ready but would also give the industry an indication of the types of projects that are coming up and therefore the kinds of skills that the industry will need to mobilise at that time to meet that need.
The question is whether it is possible to move from an infrastructure investment plan to a broader, overarching strategy. That is not our thinking, but it is something that was recommended by Audit Scotland in 2011. The infrastructure investment plan should be upgraded to become an overarching strategy, to identify some of
“the long-term investment needs and constraints for capital investment in Scotland.”
At that time, it was found that the IIP did not strategically assess
“the complex interrelationship between needs, affordability, political priorities and implementation capacity.”
It is quite encouraging that, since we concluded our research, the Government has created the infrastructure commission for Scotland, which will support the development of the next infrastructure investment plan. Our advice here would be that the Government goes back to the Audit Scotland recommendation and instructs the commission to work on something that is more strategic and visionary for the country, in order to guide priorities and decision making, which would also add value to the work of the infrastructure investment board.
I think that the Government is consulting on the infrastructure commission right now. Are all the panel members responding to the consultation?
I can help with the timescale for that. I wrote down the infrastructure commission’s remit before I came to the meeting. The commission has been asked to
“provide independent, informed advice on the vision, ambition and priorities for a long-term, 30-year, strategy for infrastructure in Scotland to meet our future economic growth and societal needs.”
I understand that the consultation is out at the minute. I clicked on the website last night, and the consultation closes on 3 May, if anyone is interested.
I think that someone else will cover the infrastructure commission.
I will ask about the Government’s plans to increase investment by £1.5 billion per year by 2025-26. Is that realistic? What should we be prioritising?
The question of realism is probably one for the Government. From an industry perspective, we will respond to whatever is required—industry will ramp up as necessary to meet that need.
However, I will make two points. First, we should not see concrete, steel and black top for roads as the first priority for the increased investment or for our infrastructure spend. We need to step back and look at emerging solutions. We are on the cusp of fourth industrial revolution digital solutions. We need to think better about how we address infrastructure, and when we do concrete and steel, which we will still do, we need to make sure that we have chosen the best schemes to take forward—schemes that are cross cutting and which deliver not only for single parts of the economy, but across the board.
My second point is also about how the investment is prioritised. At the moment, we have the Treasury rule book and we look at 60-year return periods on investment, but I am certainly not going to sit in front of the committee and tell you what the transport network will look like in 60 years. Not far from here, we have the legacy of a bridge that has been there for almost 120 years and is still performing an important role in getting trains across the Forth. The way in which we examine and test infrastructure has to take into account a lot more dimensions than simply the economic rate of return. It needs to reflect what we want infrastructure to do. We do not build infrastructure for infrastructure’s sake; we build it to allow our economy and our country to flourish.
Would one of the things that we need to do differently be to think about low carbon, for example?
Absolutely. Infrastructure is a means of tackling a number of issues, and we need to ask how it is doing that in relation to health, social inequality, carbon and sustainability—and we can add to that list.
No one else has thoughts on the Government’s planned £1.5 billion a year increase, so I will move on.
We will look at finance with the next panel, but it is an issue that comes up with the Scottish Futures Trust. There seems to be alchemy involved in the funding of public infrastructure in particular. Can Peter Reekie give us a flavour of where the Scottish Futures Trust is going with the question of financing infrastructure?
The ambition to increase infrastructure investment by £1.5 billion a year by 2025-26 will not be deliverable from within capital budgets as they are currently set, so there will need to be an element of financing to deliver that increase. I think that there should be public financing where that is possible, and the approach may include private financing if we still need increased activity to get to the infrastructure investment levels that we need.
Last year, we were asked to look at possible profit-sharing approaches to the financing of future infrastructure investment. We are currently doing that. The other panellists and members of the committee might know that the Welsh Government is using a mutual investment model arrangement, which is similar to the non-profit-distributing model that we used in Scotland in the past. However, the mutual investment model has a profit-sharing approach rather than the profit-capping approach that we had with NPD. It is a very similar overall arrangement that involves the public sector taking a stake of around 20 per cent in the projects and investing up to around 20 per cent in them. We are looking at such options, should they need to be used to deliver the national infrastructure mission.
What kind of projects is such a model anticipated for?
That is currently in the too-early-to-say bucket. If we can use public forms of financing, we would go to them first. It depends on the nature of the investment projects that come forward in a future infrastructure investment plan and what would be suitable for such investment.
A lot of infrastructure—for private housing, broadband and some utilities, for example—is now privately financed.
Yes.
Is there a suggestion that the increased stake for the public sector should apply to private housing, digital and energy infrastructure?
I am sorry; I was talking about projects that are ultimately paid for or funded by Government budgets. The private sector will have to finance its own infrastructure in the way that it needs to in order to deliver—
Is there any merit in thinking about giving the public sector more of a role? It is just as important to have electricity grids, digital grids and private housing—
We have not considered public financing interventions in private infrastructure markets.
Okay. Thanks very much.
I agree with that. There is also an international dimension to the discussion about attracting private finance to public infrastructure. There are many reasons for and against that. In general, it is even more important that there is increased transparency in some of the public-private partnership-type arrangements, because they include a different type of risk, which quite often falls more on the Government even if private finance is involved, in line with what Peter Reekie said.
Another view that does not contradict the idea of attracting private finance to public investment is that we should look at how to obtain better value from the money that is already invested or available and how to close efficiency gaps. The International Monetary Fund has estimated that, in all types of countries, there are efficiency gaps in public investments that range from 10 to 30 per cent. It quantifies the gap as 13 per cent for advanced economies, although each country will, of course, have different, specific losses from efficiency gaps in public investment.
There is growing consensus that one of the ways of mitigating, addressing or closing the efficiency gap is to improve infrastructure governance and to try to avoid some of the pitfalls with public infrastructure that are all too well known with regard to things running over time and over budget or not delivering within the expected costs. That is why we promote the idea of more transparency and accountability in infrastructure investments in general.
You are sitting in one of those projects.
I am well aware of that.
Do you think that private sector contractors should be included on the infrastructure investment board?
Thank you for asking for clarification on that issue. We generally recommend more structured and systematic stakeholder engagement in infrastructure governance, including the possibility of discussing policy options.
One of our core features is multistakeholder working. Perhaps I should explain that a bit more. Our approach brings Government, industry and civil society together to pursue the goal of improving transparency and accountability in public infrastructure. In our member countries, what are called multistakeholder working groups are formed to oversee the implementation of programmes. When we were developing the Scotland case study, we started to look at how our core features could be adapted to a high-income country or advanced economy, but we found that our usual model did not appear to be the most constructive way forward.
As a result, we were very keen to look at existing institutional set-ups that could adopt features such as multistakeholder working. Interestingly, we found that in Scotland there was quite an advanced level of strategic planning as well as an institutional set-up to oversee its implementation, and we believe that such institutions can increase their legitimacy and credibility if they are constituted in a manner that is representative of different sectors of society. We therefore suggest not that contractors as such should be on the infrastructure investment board, but that it should be possible for representative bodies and associations to be included.
You said that such an approach would increase legitimacy, but would it increase effectiveness? There is a difference between people saying, “This is a great idea,” and the idea actually working. What if people buy into something at a high level, so to speak, but it does not actually accomplish the goal that you set out at the beginning of your answer? Is that not the question?
That is very true, and I know that there is a history of attempts to improve the efficiency of the body in Scotland. In our experience, multistakeholder working helps build trust and enables different sectors to understand one another’s points of view earlier. There is a minister in one country who has said that, because of the multistakeholder working group, things can be discussed that would otherwise end up on the front pages of the next day’s newspapers.
That is not a good thing!
The question is whether efficiency gains can be found at the beginning of the process.
My question is not about something ending up on the front page of the newspaper the next day; it is about whether the approach actually works. Obviously there must be transparency and public accountability, too—it is not a matter of brushing things away or discussing them privately without anything being worked out. Do you agree?
Yes.
I know that other committee members have questions to ask and other panellists want to comment. I believe that Dean Lockhart has a follow-up question.
It is a brief follow-up question on sources of investment. As the panel will be aware, legislation is being introduced to establish the Scottish national investment bank, one of the main missions of which will be infrastructure development. Could the panel members explain briefly the role of the investment bank in infrastructure development? What discussions have you had with the Scottish Government about how it will affect the work of your organisations?
Mr Reekie, I guess we should start with you because the Scottish Futures Trust will obviously have a close working relationship with the new bank.
I think that Peter Reekie wanted to reply to my point so perhaps he can give a dual answer.
I will try my best.
I was involved in some of the early work on the SNIB but I have not been involved in that for some time now. The SNIB will be a source of public funding, so it will be able to provide finance to projects that are ultimately in the private sector but in relation to which there is a policy interest in taking them forward. For example, we might think of renewable energy projects that will ultimately be part of the energy system, or increasing the energy efficiency of buildings, which ultimately will be paid for by the occupiers.
The structure under which the SNIB will provide a source of public finance means that it will not be able to fund things such as schools, hospitals and roads because of the rules about balance sheet treatment—it would just be seen as public capital funding and would not deliver any additionality. The SNIB has a role to play in the infrastructure sector, possibly in new areas or low-carbon areas—it rather depends on the mission that it is set during the period before it is set up. We will certainly be keeping close to the SNIB and working closely with it.
Should I come back on the IIB point, convener?
If you want to, but briefly please.
I should probably say that I am a member of the infrastructure investment board, which functions as an internal governance system for projects and programmes. I am really pleased that the Government set up the infrastructure commission for Scotland to look at longer-term plans for infrastructure, and that sitting on that is a set of stakeholders from across industry and academia and from other interested bodies. It is particularly important that all those stakeholders are involved in looking to the future and helping us to set good priorities for Scotland.
On what the bank might fund, there are a couple of major challenges in housing. First, although land might be available, it is often difficult to fund the infrastructure that is necessary to develop sites. If the bank could help with enabling the development of large sites by putting infrastructure in up-front, that would be extremely helpful and a more effective way to fund development.
The second challenge goes back to Peter Reekie’s point. There is a great need to increase the energy efficiency of existing housing to address fuel poverty and meet climate change targets. There is a need to switch to low-carbon energy, particularly low-carbon heating. If the bank could help to fund that for all tenures of housing, it would extremely helpful.
During the inquiry, the committee has heard various views on whether the construction sector has the capacity to deliver the country’s infrastructure needs. What are your views on whether the appropriate skills and capacity exist in the industry?
It is critical to be mindful, in working with the industry, of the required capacity and capability for the future, in order to make sure that skills are introduced. Our experience is that the industry will grow in order to deliver what we need it to deliver, but we also have to work closely with the industry to facilitate that by promoting intake of graduates and apprentices, and attracting different types of people into the industry. We have to work with the industry to understand the different mix of work that is coming in the future.
We heard earlier about the impact of digital and the need to focus on low carbon. One of the challenges that we face is that we will be moving increasingly towards investment in maintaining the existing asset stock. There will be a lot more mechanical and electrical work, as well as civils work.
Colin Beattie has asked a key question. I summarise by saying that we think that the capacity and capability exist, but we recognise that they have to grow, and that we need to work closely with all our suppliers on a long-term basis, if we can, to facilitate that.
I will come to David Stewart in a second. Is there capacity to deliver what is in the pipeline?
Looking ahead to the next 10 years or so, I suggest that we will have to grow capability and capacity for certain types of work over two, three or four years. From talking to many people who work in the industry, we get no sense that it cannot be done. That is linked to forward planning of the pipeline. The capacity and capability will be there if we move gradually into the new types of work that are coming down the pipeline. The core skill sets are certainly there.
In the SFHA’s understanding, there is a challenge with capacity. There is, for example, an ageing workforce, certainly in housing construction. The sector can be quite reliant on European Union migrants, so there is a potential challenge coming in that respect.
We have entered a partnership with the Construction Scotland innovation centre to promote the potential of off-site construction and use of digital technology. That is partly to increase capacity and partly to increase the quality of the buildings that are produced. It is also based on our understanding that we need to attract new—and different—entrants to the industry. At the moment, the profile is very much of an ageing and largely male workforce, so a real effort to modernise and make construction a more attractive career for a wider range of people is needed.
Am I correct to take from what you are saying that although capacity does not exist at the moment to deliver what is in the pipeline, it is hoped that it will be?
It is more the case that capacity might be just about there. However, we have received anecdotal feedback from our members who are working to increase delivery of affordable housing, that the step change from the 30,000 units target in the previous session of Parliament to 50,000 in this session of Parliament has led to difficulty in attracting enough workers to some trades, including bricklaying, and that there is a premium in certain trades. In the medium to long term, action needs be taken to remedy that.
Is that any different from what the situation was previously? Historically, there have always been periodic shortages in certain trades, but they correct themselves. Are we not just in such a situation at the moment?
The difference at the moment might be due to the fact that the workforce is ageing. It is not just that there is a shortage; there is the question of what happens when so many people retire.
I remember people talking years ago about the ageing workforce, but it always seems to adjust itself as time goes on. In the natural course of time, people retire and a fairly high percentage of people at any time will be over 50, let us say.
I do not know about the period that you are referring to, but if the workforce’s profile is very top heavy, there is a need to ensure that new entrants and apprentices are coming in and that the industry is seen as attractive to people.
I have a simple question, in that case. Are enough apprentices coming in, at the moment?
There is a challenge in that respect.
We hear the word “challenge” a lot. What does that mean?
I think that we would like a yes or no answer. Are there enough apprentices coming in?
No, arguably, there are not. There certainly needs to be something that is more attractive to women, for example.
I have a few brief points to make. We should remember that the industry largely reacts to client needs: that is what we are good at doing. When client requirements need us to ramp up, we do it. We have done that for a long time, and I think that we will continue to do it, because we are market driven.
We need to look at the issue of capacity through a couple of lenses. From the national and international perspective, we know that Ireland is very hot at the moment in infrastructure terms. A great deal is going on there and there is great demand for skills. There are also major projects here, such as high speed 2, that soak up capacity. We cannot see Scotland in isolation when we think about capacity, because projects elsewhere impact on the available skills and people. Tier 1 projects in Scotland will always get the high level of skills that they require, just because of their profile and what they are. However, when we have pressure on skills and resources, the danger is that the tier 2 projects will suffer as a result. That is the global and national lens.
There is also a local lens. When we are constructing or designing, we can max out the supply-chain base pretty quickly in particular parts of Scotland. It is therefore really important for consultants and contractors that we have a wide supply-chain base across Scotland.
We need to understand that the infrastructure of tomorrow will not need exactly the same skills base as the infrastructure of yesterday and today. For example, we have developed a whole new digital solutions division. That has been a significant investment, but we see it as a major area of growth.
For Jacobs, Scotland is one of our global design centres, so we have major skills and resources here. Actually, in balancing demand locally in Scotland, we have teams operating on an international front. For example, my rail-signalling group was working on Australian stuff the other month. There are people sitting in Scotland working on international projects.
I want to bring the issue to life and link it back to planning. Colleagues have talked about bringing in apprentices and graduates. That is a live issue for us all; we are working hard to bring in lots of new people. In terms of planning, we know that over the next five to 10 years we will probably need to double the level of investment in maintaining existing assets, and we know that in order to do that, we will probably need to double the amount of work that we do on mechanical and electrical installations. We are working with our supply chain to build that capacity.
The key is planning. We cannot switch on that capacity overnight, but if we plan we can build capacity, especially if we have good long-term relationships with the supply chain. The key is understanding what is coming and ramping up capacity. Clearly, if we were to double investment in a certain type of work tomorrow we would not have sufficient capacity, but if we know that it is coming down the line two or three years in advance, we can work with the supply chain and ramp up capacity.
We recognise that it is not just about capacity; it is also about capability. It is a live issue and we have to tie it back to how we plan for what is coming down the line.
You have raised a good point—on which we have not put much emphasis—about maintaining the infrastructure that is already built. I presume that that will take resources away from new infrastructure. How well has that been factored in?
We have certainly put a lot of time into and paid a lot of attention to that. More and more investment in the future will go towards maintaining existing assets: ergo, the nature of projects will be different and we will have to grow skills in that space, as well as in the new-build space. That will be true for all types of infrastructure. As Graeme Dodds said, as we maintain the infrastructure, we will have to grow additional skills, including digital, as well as traditional civils skills. We are alive to that and are putting a lot of time and effort into it, at the moment.
Investment in infrastructure equals investment in new infrastructure plus investment in maintaining the infrastructure that we already have. It is all part of the same overall picture.
At the risk of oversimplifying, I say that if we are going to increase our investment levels by £1.5 billion a year in six or seven years’ time, we will need investment by the industry in its people and productivity, because we do not have much spare capacity hanging on pegs in the industry now. We will probably need more people and more output per person—productivity—in the digital arena and manufacturing, whether it is off-site or on-site manufacturing.
The public sector has the responsibility to help the industry to invest in its people and productivity in order to ensure that the industry has visibility of the pipeline and the procurement approaches that will allow it to invest. Setting that as a long-term ambition is the right thing to do. Over the next five or six years, there is work for the industry to do and for the public sector to do to allow the industry to do that.
Before I proceed to my question on procurement, I want to return to Scottish Water and to probe something that Mark Dickson said. Scottish Water is planning increased capital spend to protect the existing infrastructure. Of what order of magnitude will that be compared with current expenditure? I am interested to know who will pay for it and whether there will be an increase in people’s water bills as a consequence.
Ultimately, the investment that is undertaken by Scottish Water is funded through customer charges and supplemented by borrowing, which is why I did not answer the earlier question about the SNIB.
With regard to what is coming down the line, there is probably a need to increase investment in maintenance. We are going through a planning cycle just now: investment is currently about 50:50 between maintaining existing infrastructure and building new infrastructure. However, we are probably moving more towards 70:30. Please do not take that as gospel, because it is just going through the planning cycle at the moment. It will probably be 70 per cent of investment for maintaining existing asset stock and 30 per cent for new asset stock.
What that will mean for total levels of investment is still being worked on by a multi-stakeholder group. I cannot really comment on how it will be paid for.
Most of our water pipes and infrastructure were built post-war, and many of our non-infrastructure components—water and waste-water treatment works—were built in the early 80s. By the time when water and waste-water treatment works are 25 or 30 years old, many of the components are starting to come to the end of their lives. The post-war pipelines are starting to come to the end of their lives, so we will have to refurbish and maintain a lot of our asset stock.
If it helps, I am making no criticism of the maintenance of our existing infrastructure; I am interested in how we pay for it. There used to be a principle that repayment of investment in water infrastructure was done over generations because it impacts on more than just the current generation. I am not sure whether that principle still exists or whether the current bill payers will pay the cost of the substantial increase in spending that is associated with all the infrastructure.
I am probably not best equipped to answer that question right now. However, ultimately, in our sector it is the customers who pay, whether through charges in the short term or through repayment of borrowing in the long term.
You spoke about external capacity of contractors, and, naturally, you are working with your supply chain. What about internal capacity? Does Scottish Water use a lot of agency workers to supplement its staff?
We use agency workers, but most of our staff are Scottish Water employees. We use agency workers to deal with peaks and troughs in our workload, and when we need a certain skill set for a period of time that might not be long enough to justify employing other people—
What percentage of the overall Scottish Water staff are agency workers?
I could not tell you that.
It has been suggested to me that it might be about 20 per cent. Do you recognise that figure?
I would need to check. In my part of the business—the capital investment part—it flexes between 15 per cent and 20 per cent. Most of that is because of the need to bring in particular skills for particular types of work. I do not have the information to hand for the company as a whole, but I can certainly supply it to the committee.
That would be helpful. I will now move on to the question that I was supposed to ask.
The committee has received evidence that suggests that procurement hurdles act as a disincentive to firms that are bidding for public sector contracts. Do current procurement arrangements act as a barrier for firms? If so, what improvements would make it easier for firms—in particular, small and local firms—to tender to access the supply chain opportunities? Peter Reekie might want to answer first.
The first thing to say is that it would be entirely wrong for me to disagree, given the evidence that the committee has received during its inquiry.
However, it is also true to say that public procurement is difficult to do well. Compared with procurement of construction works in the private sector, we in the public sector are required to work in accordance with a significant volume of public regulation and guidance to ensure fair play and that everything is transparent. That is not wrong—it is right—but it adds to the complexity of what we do.
We also have to deliver on a lot of agendas, aside from building the new asset. We must work on community engagement and training opportunities, and we must work with small and medium-sized enterprises. Again, that is not wrong—it is entirely right—but it gives procurers a lot to do other than focusing on the asset that they are going to buy.
As Jackie Baillie alluded slightly to, we also have competing priorities, which I think you have heard evidence on already. Some elements of the industry that supply to us say that, if we bring demand together and create framework opportunities and long-term opportunities for them, they will be able to invest in productivity and in people in a way that will enable them to deliver better for us.
There is another subset of people with whom we work who say that it would be better if we reviewed everything individually and at local level so that smaller firms could access the top level in supply chains in delivery of projects, rather than have access only lower down the supply chains. We have to ensure that the right kinds of projects appeal to the right sorts of contractors, so that there is a good fit between those operations. We cannot go all one way, and we cannot go all the other way.
The skills base in public procurement can always do with more investment. Wherever the SFT, as a central body, can help people, we do that. However, most of the procurement activity for social infrastructure is done in health boards and local authorities, and it is a challenging thing for people to do well.
Everyone is doing the best that they can, but there is always more that we can do with regard to the two things that are needed: provision of longer-term opportunities in some areas, to allow people to invest; and keeping some things small and local, to allow SME contractors to get in at tier 1 stage delivery and—I hope—grow to become the next generation of larger contractors.
Far from saying that we have got everything right in that regard, my organisation is trying to do better. We have just restructured, such that one of my directors is looking explicitly at the interaction between the public sector and industry in order to try to improve things over time.
I largely agree with what Peter Reekie just said. I cannot disagree with the suggestion that public procurement rules can be complex and challenging and therefore can put SMEs off bidding.
In our sector, we have found that where the public procurement rules apply, they can be a challenge for housing associations. The average housing association in Scotland has fewer than 1,000 units and does not have the same capacity—in terms of procurement teams or expertise—as a national health service trust or Police Scotland.
On the other hand, the procurement rules are in place for a good reason. It is public money that is being spent, and it is right that community benefits and value for money are sought and that fair work practices are encouraged.
I cannot provide a magic solution. I can say a little about what my sector has done to help to engage SMEs, and other practices that I am aware of in that regard. We have provided training to our members to increase capacity, which is about helping people to not just comply with procurement rules but engage with SMEs and help them to understand what housing associations are looking for, and deliver better community benefits from spend.
We have also worked with the supplier development programme, whose mission is to engage with suppliers, particularly small and medium-sized enterprises, to enable them to do what they have to do to comply with rules and succeed in bids.
Finally, it is often possible for contracts to be broken up into smaller lots, so that it is not just very large contractors and multinationals that can bid, and so that there is scope for local companies to bid and to bring in their local expertise and provide local employment.
If the witnesses want to make further comments in writing after today’s meeting, including on points that we have covered, they should feel free to do so. We have limited time, so I will bring in Graeme Dodds and then we will move on to questions from Jamie Halcro Johnston.
I will make a few brief points. On procurement at the start of a project and deciding what projects should be, quite often when we look at something that comes out, we think, “Well, if you had asked the question slightly differently, you would probably have ended up with a slightly different answer—or a better-framed infrastructure solution.” The scenarios in which we have had industry engagement, such as industry days, in the lead-in to procurement, have been valuable in enabling conversations and providing feedback to agencies that has enabled them to frame the question that they want answered.
I know that the committee has taken evidence on how procurement processes can drive—or not drive—innovation. One issue is that industry largely reflects the procurement process that it stands alongside. If we want innovation, the procurement process needs to be driven by that rather than by cost as the biggest element. The committee will take evidence from contractors on the next panel, so I will not comment further on that area.
The public contracts Scotland system is working to improve things. Particularly for SMEs, throughout the year it is valuable to be able to upload, or to have one hit of, information that changes only on an annual basis, such as accounts and the hygiene stuff that goes with bidding. To some extent, that issue is fine for companies such as mine, because we have dedicated teams that operate on that side of things. However, making the process more effective for SMEs would be useful.
In my region, the Highlands and Islands, there are a number of companies of different sizes, and a lot of smaller local companies have been involved in larger projects that have been going on in the area. Some witnesses to the committee have said that frameworks can be a positive way of managing procurement. How do such frameworks impact on the ability of local companies to access larger contracts?
As well as frameworks, we have a series of rural contractors. We have some larger alliances, some tier 1 contractors and 50-odd rural contractors, a number of which are in the Highlands and Islands. We endeavour to support them through complex procurement exercises. Three times a year, we run rural roadshows, which involves going round and meeting rural contractors and doing what we can to connect them with larger organisations that are using frameworks, through which there might be opportunities for them. We also connect rural contractors to our organisation and assist them with direct procurement opportunities.
We need the support of local organisations for a lot of the stuff that we deliver in rural areas, and many of our frameworks and larger contractors need the support of local organisations. The key point is to recognise that and to ensure that all the connections between the relevant organisations are in place.
We give support not just with procurement, but with health and safety and training, and we try to take that support out to local organisations as much as we can.
On the housing side, the issue is about frameworks being developed appropriately, bearing in mind the range of geographies and different projects in Scotland. For example, a framework that originated in England had a housing framework with only one Scottish contractor, which was not ideal.
Perhaps we should talk about some of the players in the housing landscape. We work quite closely with Scotland Excel, and the majority of its business goes to SMEs. The Scottish procurement alliance has set up new-build housing frameworks for different geographic areas, in acknowledgement of the need for different contractors to do jobs of different scales, from very rural projects to larger development in Glasgow or Edinburgh, for example.
Finally, hub West Scotland, which is a mix of the public and private sector, has recently developed a two-scale housing offer covering both larger developments and the kind of smaller developments that allow SMEs to be part of the framework. It is about setting up and using these things appropriately, not just to respond to different clients’ different needs but to allow SMEs to take part.
How does Scotland compare with the rest of the UK with regard to the level of information available on public sector infrastructure and the construction sector’s ability to engage in infrastructure projects? Are there other lessons that we should be learning from international experience?
Interestingly, research that we have carried out at the UK level shows that the level of transparency in Scotland is not only higher but significantly higher than it is in the UK. I said earlier that the figures for transparency when measured against the CoST infrastructure data standard are 95 per cent for larger projects and 70 per cent for medium-sized projects; in the UK, the equivalent figures are only 60 per cent for larger projects and 35 per cent for medium-sized projects. I do not have time to explain the infrastructure data standard in detail, but I am happy to submit that information subsequently.
It would also be possible to strengthen that position even more by, as we said in our initial conversation, avoiding having the data scattered over different websites and reports. It would be quite easy to create a single online platform that connects the locations of the different data points, and that would make Scotland a real international leader in infrastructure transparency.
Mr Reekie, do you have anything to add about how Scotland compares to the UK or, indeed, what is happening further afield with regard to the level of information on infrastructure projects that is available and the construction sector’s ability to engage with infrastructure projects?
I think that Søren Kirk Jensen will have more of an international focus than we do, but I will say that we are always trying to do more on engagement. That said, we have a pretty good network with contractors, and we in the SFT are now involved in a structured and regular set of discussions with the Government and the contracting community on what needs to change in the future. We engage on specific projects and programmes before they kick off to ensure that the industry has a good sense of what is coming, and, with individual projects, we are increasingly involving contractors early and bringing them in at development stage. I would say that there is a pretty good level of understanding between the private sector delivery organisations and the public sector, but it can always be better, and more work can always be done on the matter.
On your question about international comparisons, we are certainly keen to learn about best practice from around the world. When the New Zealand infrastructure group came over, they learned something from us and we learned something from them, and I also spoke at their infrastructure conference—by videoconference, I should point out. We have done all sorts of different things at an international level. For example, we are a member of some of the European Investment Bank groupings in order to share experience across Europe, and the Organisation for Economic Co-operation and Development has some good infrastructure networks, too. I should point out that we also interact with our colleagues in the other nations of the UK.
We are always keen to do more, but we have a fairly good working relationship with the industry in Scotland, which is helped by our scale, and we learn from what is going on internationally and take an outward-looking approach.
Thank you. I will leave it there, convener, because I am conscious of the time.
I thank our panel for coming in today. As I have said, if you wish to add anything to what you have said, please feel free to write to the committee.
I suspend the meeting for a changeover of witnesses.
I welcome our second panel of witnesses: Stephen Slessor, operations director, infrastructure Scotland, Morrison Construction; Shona Frame, partner, CMS Cameron McKenna Nabarro Olswang LLP; and Gavin Paton, partner, Burness Paull LLP. Len Bunton was meant to be here but, unfortunately, he is not able to attend today.
I will start with a question on finance. What are your views on whether financial institutions are properly engaged with the construction industry and companies?
Since the recent demise of Carillion, the business environment has been quite challenging for construction companies. Traditionally, banks have supported the businesses and although mainstream lenders are still engaged with the sector, there is a trend away from that—we can see that in the way that Interserve and Kier have been treated by the markets.
Average debt has risen significantly because, over the years, cheap funding has been available, and some companies have used that to capitalise to fund growth. However, in some instances that is changing rather dramatically, and that is one of the reasons why the market is currently quite challenging.
The other issue is that construction is quite cash intensive. Liquidity is really important. In 2016, net debt levels across the industry were 10.5 times the combined UK income of the top 10 contractors—that is compared to 6.5 times that income in 2009. That shows that there has been a real move towards debt.
On a smaller level, SMEs are struggling to obtain accessible and reasonable finance.
I do not know whether Shona Frame and Gavin Paton are involved in the acquisition of finance or work more on the setting up of finance that has already been agreed with clients. Do either of you have any comments on how financial institutions currently relate to the construction industry?
I am principally involved in implementing arrangements, rather than negotiating them. However, the feedback that we get is that a combination of low margins, high-risk projects and recent insolvencies, in particular, means that the construction sector is viewed with caution by lenders. Where there are high risks and low margins, difficulties can arise quite suddenly, as we have seen in some recent high-profile cases. That model and recent high-profile cases have had an impact.
Do you have anything to add, Shona?
No. My expertise is on the other end of construction projects.
Recently, we carried out an inquiry into the business gateway support provided by local authorities to businesses and my question follows on from that. In general terms, looking across business support—business gateway, Scottish Enterprise and so on—does the construction sector get the same level of support from public sector bodies, including financial support, as other sectors, or is it treated somewhat differently?
It has been the case that, because of the thin margins that we operate and the procurement models that work is based on, we effectively fund public and private sector contracts for the first 30 days. We get paid 60 days after we first start on site, but there is an expectation that cash will immediately flow down our supply chain from day 31. On top of that, getting access to finance can be difficult, depending on some of the terms and conditions that certain local authorities or procurement authorities put in place. In some instances, we take the decision not to pursue projects because of that.
Most of the Scottish Enterprise and business gateway support is targeted at the Scottish SME sector, so for us as a tier 1 contractor, a great deal of that is not visible.
If you were contemplating tendering to build a hospital, let us say, how would you fund the first 30 days?
That would be funded from our net cash reserves. We use a mixture of cash reserves, trade credit, bank borrowing and private equity finance to do that. One of the attractions of using a major contractor is that they have a strong balance sheet, and strong balance sheets are really important.
Does any of the panel members have experience of alternative sources of finance in the construction industry? Obviously, we have had recent experience of PPP and private finance initiative projects, and the Scottish Futures Trust has made attempts to generate new models of funding. Do you have any comments on different ways of funding construction?
My practice is focused on mainstream construction and development in the public and private sectors, and on project finance. In the 20-odd years that I have been in the profession, the availability of project finance models and the pipeline associated with them has certainly been quite spiky, and that has an impact on the market. We have a strong core of expertise in project finance in Scotland, but it waxes and wanes depending on what models are available. At the moment, we have the hub DBFM—design, build, finance, maintain—model, which is a project finance model within the hub framework that is delivering a lot of fantastic projects. Obviously, NPD projects have not been proceeding recently because of accounting treatment issues, but the market would certainly welcome further development of NPD and of new project finance models to deliver big infrastructure projects.
Shona Frame deals with the disputes that arise when things fall apart, so to speak. Which finance models tend to work rather than not work in that regard?
The disputes that I deal with are focused around time, money and defects—those are the constant themes that we see across all the methods of procurement. With the different standard forms and, increasingly in recent years, PFI/PPP models, the exact same issues are coming through. At the moment, with PFI contracts, we are seeing a large increase in the number of disputes concerning performance deduction payment mechanisms.
You would not single out any particular procurement or finance model as better than another in that sense.
We are starting to see a trend towards more partnering and alliancing forms of contract, but I have dealt with many disputes under those forms of contract. The way to deal with dispute management and avoidance is to live those contracts rather than just enter into them. If disputes are to be avoided, it is not enough for the parties just to use the terminology and the sorts of clauses that we see in NEC contracts about acting with good faith and mutual trust and co-operation; that has to actually mean something in the way that the contract is operated. It is not necessarily about the contract model; it is about parties’ behaviours and how the contract is operated.
Does the panel have any views on whether the building Scotland fund has helped to improve the availability of funding for the sector? Mr Slessor might have views on that.
I had a look at the figures and found that, up to the end of the current financial year, about £51 million has been allocated from the £150 million that was set aside, around half of which is for one project, the Winchburgh development. The fund is helpful for the sector. It has helped that project come to market much more quickly than it might have done in the past. However, there is a challenge with transparency around how to access the fund, and there are a number of constraints that prevent many developers from accessing it.
The fund is a good idea. It helps to bring more projects to market and is a useful step towards understanding how the Scottish national investment bank will be able to support construction infrastructure in Scotland in the next 10 to 15 years.
Given that the building Scotland fund was launched as a precursor to the national investment bank, how do you expect the bank to improve the sector’s access to finance?
The biggest challenge will be in replacing the European Investment Bank if it decides not to invest heavily in Scotland post-Brexit. Over the past 10 or 15 years, it has invested in the region of £3 billion in Scotland, which has delivered some of the largest infrastructure projects around. There is a £2 billion pot for the Scottish national investment bank, which leaves a gap against what we would have hoped for.
The other issue will be the constraints that are placed around the funding to satisfy accounting regulations as to whether it should be on or off the Government’s books. We are in the early stages of trying to understand what that will mean. Our hope is that it will continue, in some way, shape or form, to fill the gap that will be left by the European Investment Bank.
We have heard that the national investment bank will take quite a mission-orientated approach. Is it your hope and expectation that there will be a specific mission around construction?
That is certainly my hope, though not necessarily my expectation. The national investment bank has to cover lots of things, but it could add real value to the renewables sector and the low-carbon economy. There is a lot of opportunity in Scotland to explore those areas, and I would like the investment bank to push in that direction.
Quite a lot of people who responded to the committee’s consultation have commented on retentions. What do the witnesses think about retentions? I ask you to paint us a picture of how common they are and of what percentages we are talking about. A long time ago, when I was an auditor, retentions were pretty standard and people just accepted that they happened. Has the situation changed?
Retention is typical in almost every project. The usual percentage is between 3 and 5 per cent, although I have recently heard of projects in which it has been as high as 10 per cent, which seems particularly onerous. As you are probably aware, the usual mechanism is that half of the retention is released on practical completion and the other half is released at the end of the defect liability period.
If retention of 10 per cent is a bit unusual, what do you think happened there? I presume that the contractor signed an agreement about it.
I do not know whether that retention was agreed to. Contractors would assess any retention clause in assessing the risk profile of the contract and whether they were prepared to take it on, given their working capital and cash flow requirements. Such a retention would take out any profit from the job and withhold it until a later stage, which could make it very difficult for the contract to be viable.
I always thought that there was a certain logic to a retention, because, if work is not done properly or if odds and ends need to be tied up at the end, it gives the main organisation, be it private or public, a hold over the contractor. Is that not accepted as much as it used to be?
That logic still applies; the question mark is over the fact that it is a relatively small pot. If the work is properly managed and inspected as it proceeds, there should not be an enormous number of defects left at practical completion, and contracts provide for people to come back for snagging works.
A relatively small pot is left, but it has become a very big hot potato with regard to headlines about retention amounts. That is brought to bear when there is an insolvency and the retention fund is lost. However, I am not convinced that the Construction (Retention Deposit Schemes) Bill is the way forward, because it addresses the problem from one perspective and does not look at the issue in the round.
Is that a Westminster bill?
Yes—it is a private member’s bill that is being considered at Westminster.
Would it apply to the whole UK or just to England?
I do not know.
Would either of the other witnesses like to comment?
The example that Shona Frame gave was interesting. On all the projects that I am involved in, there will be a retention, which is normally 3 per cent. Recently, requests have been made for higher retentions. That seems to be being driven partly by—we discussed this earlier—anxiety among lenders to the construction sector and bond providers. Some contractors at a lower level are having difficulty in obtaining performance bonds, which are typically for 10 per cent of the contract. Performance bonds provide an element of performance security. If the contractor is unable to obtain a performance bond, the client’s next step might be to ask for a higher retention.
For those of us who are not terribly technical, is a performance bond an alternative to retention? Is it a sort of insurance policy? Is that how it works?
It is provided by a bank or a specialist bond provider. Essentially, it is a pot of cash that can be claimed if there is any default under the contract. On the projects that we are involved in, there would normally be a 3 per cent retention and a 10 per cent performance bond. If the contractor is unable to obtain a performance bond, the client might seek to increase the retention to compensate for the lack of a performance bond.
Has it become more difficult to get a performance bond in recent years?
Anecdotally, I would say that it has become more difficult for contractors at SME level to get a performance bond, which simply compounds the issue. Stephen Slessor might be able to comment on that. If retentions of 3 per cent are a challenge from the point of view of cash flow, a retention of 10 per cent is obviously more problematic.
If retentions were to be done away with, the client would be left unprotected, but there are alternatives. A more measured response would be to find an alternative or to challenge bad practice. Retention serves a purpose. If it is properly used, it is legitimate; however, if it is used abusively, a more focused response might be to target the abuse.
I might come back to that point after we have heard from Mr Slessor.
I support some of the points that have been made. I will put my cards on the table: I am definitely pro the abolition of retention, which I think is a product of a yesteryear industry. As we move to a more digital age in which we can embrace technology such as blockchain technology and artificial intelligence, that will help to remove clients’ concerns about quality and defects.
In reality, we often have to provide a performance bond and a parent company guarantee, as well as having some retention taken from us, in order to undertake some contracts—that is the case with public sector contracts as well as with private sector contracts. Three or four different methods of obtaining financial security are available to clients if they wish to use them, and they do not necessarily impact on people’s cash flow. Cash is really important for all areas of the business, not just tier 1s.
The vast majority of defects that the pot of money is supposed to be held for are latent—we are talking about things that might happen five, 10, 15 or 20 years down the line. On some large projects, significant sums of money can be held. In better times—although not so much in recent times—some nice interest could be made on that pot. In addition, some unscrupulous employers will use that money as an advantage in agreeing final account sums.
Generally speaking, I am definitely pro-abolition.
Is everybody else in favour of the abolition of retentions? Is that the general feeling?
Retention gives rise to disputes about when the money should be released and the securing of its release—particularly the release of the second tranche of retention, which comes at the end of the defect liability period. For main contractors, we see disputes about whether the conditions to allow that release are in place, such as the rectification of any snagging works. However, for subcontractors or tier 2 contractors, the retention release is often linked to certifications further up the line to the main contractor.
Individually, retentions are relatively small amounts of project money, but, if there are a lot of projects on the subcontractor’s books, they can add up to a large amount of cash. Accessing a dispute mechanism that allows that cash to be released is also not economic, because the cost of pursuing those small debts outweighs the sums involved. It is a real issue for contractors’ bottom line to get cash in the bank once it has been withheld during a project.
If a retention is not released without good reason, what are the options for the person who is seeking to release that retention? Is it court or an arbitration system?
Adjudication is an option. That is the fast-track 28-day process. If the amount is small enough, there is the court procedure for smaller debts—it is not called small claims any more. However, that applies only for amounts under £5,000.
It is tricky, because there is a cost to adjudication. The parties fund the process themselves—there is no recovery of cost—and they have to pay for the adjudicator. It is difficult to recover money when someone has a list of retentions on their books, particularly when those retentions are linked to certification further up the line. They have no control over it. The defects in a very early subcontract might have been dealt with long ago, but, if the main contractor’s retention has not been released, it is very difficult for the subcontractors to get their retention released.
Somebody suggested to the committee that, even though there is an adjudication process and even after a positive decision, the payment is sometimes still not made and has to be chased in court. Does that happen?
That can happen. My experience is that most adjudication decisions are implemented. A small number go to court for enforcement procedures, but those tend to involve larger amounts and cases in which there is a real issue with the process or the jurisdiction of the adjudicator. The courts have set out their stall: they will enforce adjudication decisions unless there is very good reason not to.
Mr Paton, you mentioned abuse of the retention system. Can you expand on that?
Coming back to my original comment, pressure on cash flow, low margins and high risk can lead to poor behaviour from some contractors in order to keep their own business afloat; retention can be a means of making it to the end of the week. I suspect that there is poor practice among a minority rather than a majority of contractors and that, to some extent, it is driven by financial necessity.
The Construction (Retention Deposit Schemes) Bill creates an interesting issue—although the detail of it is not particularly well developed, because it anticipates that there will be detailed statutory instruments to cover its implementation in the various territories. Retentions, as a concept, can exist in the form of cash retentions or retention deposit schemes, but there is a very big difference for clients, in that with a retention deposit scheme, they will have to draw down the cash to put it into the deposit scheme. Therefore, if a developer is taking bank funding, for example, they will have to draw down the bank funding sooner and ring fence it by placing it in the deposit scheme, which will add to the overall cost of the project. I can understand why contractors would say that that should be the client’s issue and that contractors should not be funding the project.
So in one sense, it makes it safer, but it could push up the overall cost of the project.
Yes. If a developer is taking funding, they will draw it down sooner and the interest costs will run from an earlier date, but I can see why, from a contractor perspective, that is perhaps a fairer outcome than the contractor funding the 3 per cent for the duration of the project.
Okay, thanks.
I have one follow-up point on that, which is the abolitionist position, as it were: getting rid of retentions altogether. Mr Slessor, could that not go against smaller firms? Presumably, the client has to have some security for seeing the project completed and smaller firms might be less well placed to get the required bond, or the cost of their doing so would be prohibitive.
In order to get past that issue, we need to take a more long-term, wider view of the sector. It comes down to how we procure things. If we are looking to engage with SMEs and the supply chain across Scotland and we want to be fair to them—which, in my mind, includes abolishing retentions, which was part of your question—we need to have a framework; we need a way of working with SMEs that allows them to grow, to build resources and capability and to bid for work and we need to take a more mature approach to procurement to facilitate that. In order to ensure that clients still get protection from SMEs in such instances, bonds are available—they do not necessarily need to be performance bonds; retention bonds are available and can be procured.
If we still have retentions, in some instances, having a fiduciary trust, which the Construction (Retention Deposit Schemes) Bill talks about, might help. One of the biggest issues is insolvency, especially for those who are subcontracted to a tier 1. Carillion was an example of a tier 1, and a lot of subcontractors would have been in a much better place if the money had been held in a trust that they would have been able to access. For me, that is the only real benefit of such an arrangement.
If we want a mature industry that will develop and deliver the infrastructure needs of Scotland in the next 25 years, we need to start having a more mature discussion about how we treat our supply chain, and the expectation that those in the chain will not come back to rectify a defect is part of the discussion. A local SME that is here for the long term will, of course, come back to repair the defect.
How prevalent are late payments in the sector? How much of a problem are they?
I deal with construction disputes and a lot of the cases that I deal with are to do with payment—I do not know about late payment; the ones that I see are more around disputed levels of payment. Payment procedures in the industry are very heavily regulated through the Housing Grants, Construction and Regeneration Act 1996, and that flows through to the standard forms of contract. However, what I see is more around disputed values, rather than timing.
Do any of the other panel members have a view?
Disputes are generally around values, but delayed payment can be used up the contractual chain as a means of improving cash flow. If there is a 30-day payment period at one level and a longer payment period at another, that has a cash-flow benefit.
| https://www.parliament.scot/chamber-and-committees/official-report/search-what-was-said-in-parliament/EEFW-26-03-2019?iob=108775&meeting=12024 |
The Oxford Oratory
A sanctuary in the midst of the city
The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman.
The Oratory Prayer Book is now shipping internationally!
We’ve made it even easier to buy the Oratory Prayer Book from anywhere in the world.
And we’ve made it easier to order multiple copies too — in the UK and worldwide.
Order your copy here:https://tinyurl.com/opb-buy
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Worship
What does it actually mean to worship God? In the New Testament, the word we most often translate as ‘worship’ doesn’t mean to reverence another in some abstract sense. It always involves some kind of bodily action. When we think about the magi visiting the Holy Family, we sometimes convey this motion by describing them — after they fall to their knees — as ‘doing homage’. But it’s actually that same word here we might translate elsewhere as ‘worship’. It’s just that we recognise the need to describe the bodily sign of their submission and adoration of the new born King with something that sounds a bit more physical.
The word we usually translate as ‘worship’ ( proskuneo) comes literally from a root meaning ‘to make yourself like a dog before the other person’. It originally meant prostrating yourself on the floor to show your humble submission before another. By the time of the New Testament, people wouldn’t necessarily have had the root of this word in mind whenever they used it,* but the word still carries with it the idea of doing something with your body to express your worship.
The feast of Corpus Christi is all about this kind of bodily worship. It’s tied to the fact that we are not pure spirits, but that we are human beings, body and soul. To worship God is not just a spiritual act. The right worship of God does not consist in simply having the right kinds of thoughts towards him. But the worship of God involves the humble submission of our entire human being, body and soul, before the God who is greater than all of us.
And ever since the Incarnation, we do this not just before an abstract spirit. Because, from the moment of the Incarnation, God really does have a human body, that we can worship, that we fall down on our knees before, like the magi and the Canaanite woman, and so many others in the Gospel who kneel down and worship Christ. When we worship God, we kneel before God who is present in the flesh, under the appearances of bread and wine, in our churches all over the world.
Corpus Christi is a joyful celebration of Christ’s presence among us, and it gives us an opportunity to think about how we respond to that gift. All this talk of kneeling and worship might not sound so joyful, but one of the great paradoxes of Christianity is that we find our greatest freedom in the humble service of God. Our greatest joy really should be found in finding ways to express this loving worship. So at least once a year, it is no bad thing to think about how we express with our own bodies that worship of God’s body, and what ways we can find to worship him even more perfectly.
This Sunday, we will carry Christ’s Body through the streets of our city. We have a chance to demonstrate to the world our love, our joyful service, our worship of him, through our presence. The procession leaves our church at 2:30pm. Make sure you are there.
But we should also think about the more ordinary things, like making sure we show that worship whenever we are in his presence. We should show through our behaviour in church that we believe him to be there: by genuflecting before him in the tabernacle of the church, and by keeping the church quiet and prayerful.
We show our worship above all by kneeling down before him — like all those people in the Gospel — for the moment of Holy Communion. And we allow the priest to place the Host on our tongues, so that we don’t handle unnecessarily what is holy and precious, and no particles of Our Lord’s Body are ever dropped or lost through carelessness.
We continue that worship in our prayers of thanksgiving after Communion and once the Mass has ended. We certainly never leave church during Communion. And we might think of ways of extending the time we spend with Christ present in the Blessed Sacrament: by attending Mass during the week sometimes, or visiting him during the times each week when his Body is exposed solemnly on the altar for Adoration, or even just by visiting an empty church, where he is waiting for us to show him our worship.
Our Lord is hidden there, waiting for us to come and visit him, and make our request to him. See how good he is! He is there in the Sacrament of his love, sighing and interceding incessantly with his Father for sinners. To what outrages does he not expose himself, that he may remain in the midst of us! He is there to console us; and therefore we ought often to visit him. How pleasing to him is the short quarter of an hour that we steal from our occupations, from something of no use, to come and pray to him, to visit him, to console him for all the outrages he receives! When he sees pure souls coming eagerly to him, he smiles upon them. They come with that simplicity which pleases him so much, to ask his pardon for all sinners, for the outrages of so many ungrateful men. What happiness do we not feel in the presence of God, when we find ourselves alone at his feet before the holy tabernacles! ‘Come, my soul, redouble thy fervour; thou art alone adoring thy God. His eyes rest upon thee alone.’
— St John Mary Vianney
* One exception is that I do think Christ had this root meaning in mind when he spoke to the Canaanite woman in Matthew 15:21–28. He wasn’t randomly insulting her by comparing her to a dog, but drawing attention to the fact that she was making herself like a dog before him — i.e. worshipping him — because she recognised him to be God. In other words, he was acknowledging her worship as proof of her faith and humility.
On Saturday, Fr Rupert led Men’s Oratory on a walking pilgrimage to Islip, birthplace of St Edward the Confessor. #oxfordoratory
Congratulations to Elizabeth who was received into the Church yesterday evening on the Feast of the Visitation. #oxfordoratory
Congratulations to Livi, baptised on the vigil of Pentecost.
“Therefore, Lord, we pray: graciously accept this oblation of our service, that of your whole family, which we make to you also for those to whom you have been pleased to give the new birth of water and the Holy Spirit, granting them forgiveness of all their sins; order our days in your peace, and command that we be delivered from eternal damnation and counted among the flock of those you have chosen. Through Christ our Lord. Amen.”
#oxfordoratory
Courtesy
I recall how, as a child at school, we were sometimes made to learn poetry. At the time I hated it, and baulked at the idea of having to commit to memory The Ancient Mariner, and in fact, never did. But one poem which did touch me, was Belloc’s Courtesy. It began:
Of Courtesy, it is much lessThan Courage of Heart or Holiness,Yet in my Walks it seems to meThat the Grace of God is in Courtesy.
The poet goes on to tell us how, on one occasion he visited the ‘monks’ at Storrington in Sussex, and that ‘They took me straight into their Hall’where he ‘saw Three Pictures on a wall, And Courtesy was in them all.’
He then tells us the subject of those paintings:
The first the Annunciation;The second the Visitation;The third the Consolation,Of God that was Our Lady’s Son.
The first was of St. Gabriel;On Wings a-flame from Heaven he fell;And as he went upon one kneeHe shone with Heavenly Courtesy.
Our Lady out of Nazareth rode —It was Her month of heavy load;Yet was her face both great and kind,For Courtesy was in Her Mind.
The third it was our Little Lord,Whom all the Kings in arms adored;He was so small you could not seeHis large intent of Courtesy.
Today is the feast of the Visitation, when we celebrate how our Lady made the long and uncomfortable journey to see her older kinswoman, Elizabeth, and her husband Zachariah, who lived in the hill country of Judah. Courtesy seems to me to be a perfect description of what this moment is all about. Imagine the cordial welcome extended to Mary by the older woman, solicitous for her health and how both women were eager to share with one another the joy of the forthcoming births of their sons. Our Lady had herself gone to visit her older cousin, not simply because she wanted to ‘be there’ for her, but because she wanted to share her own good news, which was not hers alone but for her people and, ultimately for the entire world.
This is something Elizabeth seemed to know already! Her enthusiastic greeting is wonderful when she cries out ‘Oh that I should be visited by the Mother of my Lord’. Her unborn son joins in the greeting, kicking and letting his mother know that he too is part of this exciting thing that is happening. Elizabeth’s gracious words: ‘Blessed art thou among women and blessed is the fruit of thy womb’ have been enshrined in our prayer to the Virgin, incorporated with the Angelic Salutation: ‘Hail Mary, full of grace!’
And if today’s feast is about courtesy (so much more than stiff politeness or polished manners, but a warm and real concern for the wellbeing and interest of the other) then it is also about joy. Mary’s presence, together with that of her Divine Son, transformed the home of Elizabeth and Zachariah. ‘Elizabeth was filled with the Holy Spirit’ because of it. St Jose Maria puts it thus: ‘Mary brought joy to her cousin’s home, because she “brought” Christ’. Dame Julian liked to call Jesus ‘our courteous Lord,’ no doubt on account of his gracious dealings with us, flowing from his ‘large intent of Courtesy’!
Julian writes in her Showings:
And this is a supreme friendship of our courteous Lord, that he protects us so tenderly whilst we are in our sins; and furthermore he touches us most secretly, and shows us our sins by the sweet light of mercy and grace. But when we see ourselves so foul, then we believe that God may be angry with us because of our sins. Then we are moved by the Holy Spirit through contrition to prayer, and we desire with all our might an amendment of ourselves to appease God’s anger, until the time that we find rest of soul and ease of conscience. And then we hope that God has forgiven us our sin; and this is true. And then our courteous Lord shows himself to the soul, happily and with the gladdest countenance, welcoming it as a friend, as if it had been in pain and in prison, saying: My dear darling, I am glad that you have come to me in all your woe. I have always been with you, and now you see me loving, and we are made one in bliss.
So sins are forgiven by grace and mercy, and our soul is honourably received in joy, as it will be when it comes into heaven, as often as it comes by the operation of grace of the Holy Spirit and the power of Christ’s Passion.
Even though we have just changed all the light bulbs, our church looks its best when we don’t need to use them.
#oxfordoratory
The flag goes up on feast days!
#oxfordoratory
Blessings with St Philip’s relic after Vespers on Thursday.
#oxfordoratory
Look down from heaven, Holy Father, from the loftiness of that mountain to the lowliness of this valley; from that harbour of quietness and tranquillity to this calamitous sea. And now that the darkness of this world hinders no more those benignant eyes of thine from looking clearly into all things, look down and visit, O most diligent keeper, this vineyard which thy right hand planted with so much labour, anxiety and peril. To thee then we fly; from thee we seek for aid; to thee we give our whole selves unreservedly. Thee we adopt for our patron and defender; undertake the cause of our salvation, protect thy clients. To thee we appeal as our leader; rule thine army fighting against the assaults of the devil. To thee, kindest of pilots, we give up the rudder of our lives; steer this little ship of thine, and, placed as thou art on high, keep us off all the rocks of evil desires, that with thee for our pilot and our guide, we may safely come to the port of eternal bliss.
#oxfordoratory
Our celebrations for St Philip began with First Vespers last night and continue with Masses today. Here St Philip’s relic and altar are incensed during Vespers.
#oxfordoratory
Our new longer term temporary digital organ was hoisted up to the gallery this week in time for First Vespers of Our Holy Father St Philip. Catch up on our YouTube channel if you missed it, and join us for the Solemn Mass at 6pm this Friday.
#oxfordoratory
Vessel of the Holy Spirit
This year the novena in preparation for the feast of Our Holy Father St Philip corresponds almost exactly with the novena of novenas, the first novena, the nine days of prayer between the Ascension and Pentecost when we wait once more with the Apostles for the outpouring of the Holy Spirit. And this is most appropriate, as St Philip was, more than anything else, a man of the Spirit — as we say in his litany, he is the “vessel of the Holy Spirit”. The story of his life, which we read during the novena, really begins with his singular experience of the Spirit on the Vigil of Pentecost 1544 in the catacomb of St Sebastian when the Spirit descended like a ball of fire, entering his mouth and then into his heart. After that experience — Philip’s own Pentecost — his life would never be the same again.
Behind his holiness of life, and his preaching, and his miracles, and his founding of our Institute, there is something fundamental we can learn from St Philip — conveniently for this time in the Church’s liturgical calendar, something about the Holy Spirit. St Philip’s life shows us what happens when we do not simply possess the Holy Spirit, but allow ourselves to be possessed by him. We all have the Holy Spirit dwelling in us — all of us who have been baptised and confirmed. He is in us as much as he was in St Philip Neri, as much as he was in the Apostles at Pentecost. But we are very good at closing ourselves to the Spirit — we, through our sins and our selfishness, our attachments and our self-will, block him out; we ignore his prompting and are deaf to his call, we partition him away into a little forgotten compartment in our souls. Or we make of him a very petty little thing indeed, our God — a God who always agrees with what we say, who wants us to do precisely what we want to do, and makes me right and everyone else wrong.
But this is not the Holy Spirit whom we worship; this is not the awesome power of Almighty God, who hovered over the waters at creation, who raised Jesus from the dead, who came down on the Apostles and Our Lady in the Upper Room, who wonderfully penetrated the heart of St Philip, and who gives power and authority to the Church. The Holy Spirit blows where he wills; his ways are not always our ways; and if we give ourselves to him and allow him to possess us completely — as St Philip did — then we will find that he will do more for us than we ask or even imagine; do more through us and with us. St Philip wanted to be a layman — the Spirit called him to the priesthood; he wanted to be a martyr, the Spirit made him a martyr not of blood, but of charity; Philip wanted to preach the Gospel to the pagans in the Indies, the Holy Spirit had other plans. He wanted to be a humble, hidden servant of the Church, living at San Girolamo and doing what good he could, but the Spirit gave him the gift of preaching and teaching and working miracles and reading men’s hearts and winning souls, and brought him to the Vallicella, and through him founded the Congregation of the Oratory, spread, as it now is, across the world. St Philip loved to be unknown — the Holy Spirit moulded and fashioned and transformed him into one of the most popular saints, the Apostle of Rome. St Philip wanted to reform the hearts and souls of those men and women he met — the Spirit used him to reform the very heart of the Church herself.
It is not enough to have the Holy Spirit — it is not enough even to think we are serving God or doing great things in his honour. We must allow ourselves to be led by the Spirit, formed and transformed by the Spirit. We must be prepared to give up our own desires and plans — even the good ones — and be taken over by the Holy Spirit to be used for his own purposes. If we do this, if we open up to the Spirit who dwells in our hearts, then the life of St Philip Neri, and indeed of all the saints, shows us that the Spirit will do great things for, in, and through us. St Philip, Vessel of the Holy Spirit and Sweetest of Fathers. Pray for us.
A Prayer of Our Holy Father St Philip:
My Lord Jesus, I want to love you but you cannot trust me. If you do not help me, I will never do any good. I do not know you; I look for you but I do not find you. Come to me, O Lord. If I knew you, I would also know myself. If I have never loved you before, I want to love you truly now. I want to do your will alone; putting no trust in myself, I hope in you, O Lord.
The Paschal Candle has been lit for Masses since the Easter Vigil to represent Christ’s presence among us, as with his disciples for forty days. After the Gospel of the Solemn Mass yesterday, it is extinguished to symbolise his ascension into heaven.
#oxfordoratory
Look up to heaven
On Monday this week some of the Fathers and Brothers spent the day erecting and moving scaffolding — with all due health and safety measures observed — in order to change and improve the lighting on the sanctuary of our church. It is already a great boon for us to see more clearly the beautiful decoration which adorns that focal point of the whole building, as well as being a great help for the priest reading from the missal. Tomorrow as we celebrate the feast of the Ascension, our eyes are directed upwards once more as Our Risen Lord ascends to heaven and for a moment like the Apostles we gaze upwards as he is taken from our sight.
How very much more clearly do we see when we make that effort to lift up our eyes towards the Lord. We not only contemplate his glory but from that vantage point are able to see all things in their fullness, seeing them from the perspective of heaven. Prayer, the lifting of the mind and heart to God, enables us to understand and to see clearly, all those other things of life in which we are otherwise immersed. That daily shifting our focus from the things of this world to the vantage point of heaven is that great encouragement for our daily striving for God, so that where Christ goes we too may follow him.
It is often an effort for us to pull ourselves out of the daily round in order to lift up our heads and our hearts to the things of heaven, but if we are to have the desire for heaven to drive us on, it is essential that we always keep our goal before us. Not only in prayer, but all those things which form the way we see things must have heaven as their vantage point and aim. Monsignor Knox wrote:
In all ages, in all countries, the world acts as a solvent to Catholic piety; breathes an air in which Catholic piety languishes. Man’s intellect always wants to approach things from the human side, from the side from which they can be known by man; shirks and burkes discussion of things from the side of reality, from the side which relates them to God. Man’s art and literary genius is constantly concerned with man at his most human level, his passions, his craven fears, the rebellion of his will against the order in which he lives. All that breathes a poison, for which writers who care about the truth as it is in God have to provide an antidote; they must fight, they must react, but still more they must see things, they must record things, from that higher standpoint which is God’s. You must, sometimes, give the lungs of your soul an airing on these heights, even if the atmosphere of it is more rare, is breathed with more effort, than the other. Or else, the miasma of the modern world will get you down, will weaken your resistance; you will be a prey to the germs of infidelity, to the infection of bad example. And you will forget your Friend.
As the Church invites us then on the Ascension to gaze up towards heaven, to contemplate Our Lord, Risen and Ascended, it is perhaps a good time for us to think on the place we give to the things of heaven in our life each day — not only in terms of the time we give to heaven, but also in terms of what we strive for, on what really all our efforts are in fact based.
And from our gazing upon heaven, we can then go on like the Apostles, down from that mountain and into the world — to teach the Good News and make disciples of all nations, keeping ever in mind that he whom we meet on those heights of prayer is with us always, even to the end of time.
Q: How many Oratorians does it take to change a lightbulb?A: “Change”?
Actually the real answer turns out to be three, plus one very helpful volunteer and a lot of scaffolding. The sanctuary lighting is all working at full brightness again!
#oxfordoratory
Monday 15 May 2023
Congratulations to David who was baptised on Saturday!
#oxfordoratory
Saturday 13 May 2023
One of this month’s relics on display is St Philip’s own copy of Jacapone da Todi’s “Laude”, which St Philip has written his name in. The story of how it was rediscovered in our church — only days before the first Fathers of the Oratory arrived here from Birmingham — is extraordinary. You might find it hard to believe, unless you heard it straight from the priest who found them, who is now the Bishop of Leeds. Read his account from his St Philip’s day sermon on our website:
www.oxfordoratory.org.uk/blog/post/1335-solemnity-of-our-holy-father-saint-philip
The novena to St Philip begins on Tuesday after the evening Mass. You will be able to place your own prayer intentions for the novena in St Philip’s chapel over the weekend.
There will be Solemn Choral Vespers on Thursday 25 May at 6:30pm.
We will welcome Fr Robert Ombres OP from Blackfriars to preach at the Solemn Mass for the feast day itself on Friday 26 May at 6pm.
#oxfordoratory
Friday 12 May 2023
May Music
Sunday 7 MaySolemn Mass 11:005th Sunday of EasterMissa Simile est regnum caelorum LoboJubilate Deo universa terra PalestrinaCaro mea vere est cibus Guerrero
Sunday 14 MaySolemn Mass 11:006th Sunday of EasterMissa Regina caeli PalestrinaBenedicite gentes PalestrinaPortio mea White
Thursday 18 MaySolemn Mass 18:00The Ascension of the LordMissa Ascendens Christus VictoriaAscendit Deus PhilipsO Rex gloriae Marenzio
Sunday 21 MaySolemn Mass 11:007th Sunday of EasterMissa Jam Christus astra ascenderat PalestrinaViri Galilaei PalestrinaEgo sum panis vivus Palestrina
Thursday 25 MaySolemn Vespers 18:30Our Holy Father St Philip NeriDeus in adjutorium PadillaMagnificat primi toni VictoriaPangamus Nerio SewellO salutaris hostia LalouxTantum ergo WidorAlleluia GabrieliRespice de caelo Sewell
Friday 26 MaySolemn Mass 18:00Our Holy Father St Philip NeriMissa Papae Marcelli PalestrinaIn spiritu humilitatis CroceJubilate Deo a8 G Gabrieli
Sunday 28 MaySolemn Mass 11:00PentecostMissa De la Batalla GuerreroConfirma hoc deus LassusLoquebantur variis linguis Palestrina
The Oratory
25 Woodstock Road
© 2023 Oxford Oratory. All rights reserved. The Oxford Oratory of St Philip Neri is a Registered Charity number 1018455
| https://www.oxfordoratory.org.uk/publications/blog/post/9979-courtesy/blog/post/9918-9918/giving.php |
Horizons Unlimited - The HUBB - DR650SE - 2-up comfort
Horizons Unlimited - The HUBB ( https://www.horizonsunlimited.com/hubb/ )
- - DR650SE - 2-up comfort ( https://www.horizonsunlimited.com/hubb/suzuki-tech/dr650se-2-up-comfort-73207 )
Mal_C 25 Nov 2013 12:00 I have a DR 650 and it has many good features. The engine does not have a lot of power or torque for two up riding in my opinion. I only ride solo. The seat can be an issue in terms of comfort. If you look at the stock seat you will notice it narrows and thins out at the pillion area. I think this can limit effectiveness for the pillion. The seat can be modified without a lot of money. I find the seat ok but to get around the lack of comfort I ride with bike nicks (lightly padded insert)and a set of foam padded shorts made for off-road riders, under my riding gear. Works for me. The bike is really a good bike - light weight; simple; no fuel injection and can maintain 100kph with the load; easy on fuel. etc. It does need (and I have) a safari tank; extra carry racks; tool carriers and tube carrier on the front mud guard. For two up I think I would look at the V Strom. The twin cylinder motor provides more power and torque and will rev out better. Bike is a bit heavier than a DR however. Looked at these but for weight I chose the DR. A GS is a great touring bike (I have one) but too heavy when the going gets a bit technical. M
mollydog 5 Dec 2013 05:44 Quote: Originally Posted by Mal_C (Post 444814) For two up I think I would look at the V Strom. The twin cylinder motor provides more power and torque and will rev out better. Bike is a bit heavier than a DR however. Looked at these but for weight I chose the DR. A GS is a great touring bike (I have one) but too heavy when the going gets a bit technical. M Some good posts on the DR650's two up ability! bier I've owned both the Vstrom and DR ... and must admit, unless A LOT of off road riding is intended, then a DL650 (or something similar) may be the better travel bike riding two up. As Grif mentioned, if pilot and pillion are small folk and pack lite and a GOOD aftermarket seat is installed, it could work .... But RTW is a very long ride. Petite pillions fit fine on my DR with the wide Corbin seat. I am not a big guy either, so that helps. Large humans will not do so well. And then you've got to deal with luggage and packing for two. doh Two up I can still easily hold a true 70 mph. Power falls off in the mountains over about 2500 meters and aggressive passing is limited. At slower speeds on tight paved roads, its fine and fine riding technical dirt roads as well, even two up loaded. At that is where a DR650 will pay it's way ... on technical, slippery, rutted or rocky dirt roads, it will out pace a Vstrom and many other larger bikes. Torque is very good for 650 single with simple minor Carb/air box/Exhaust mods, all DIY. So if lots of dirt riding is the plan ... then the DR could work out. By the way ... a DR650 is roughly 100 lbs. (45 kgs.) lighter weight than a DL650. Maybe this would help? https://lh6.googleusercontent.com/-p...0/IMG_1390.jpg
jaykay 12 Dec 2013 00:06 Thats a great trailer you've got there. Hadn't thought of doing that. Where did you get it from?
mollydog 12 Dec 2013 01:47 Quote: Originally Posted by jaykay (Post 446657) Thats a great trailer you've got there. Hadn't thought of doing that. Where did you get it from? That is Big Al's bike. He did a fly and ride from Seattle to down South somewhere. The Seller through in the trailer. Not sure who makes it ... but there are several outfits doing lightweight trailers for dual sport/dirt bikes. Find Big Al's ride report here and PM him. Perhaps he can provide info the trailer? ... or maybe he'll sell it to you? He pulled it all the way cross country with NO ISSUES. (he and his buddy rode DR650's to Tierra del Fuego ... but no trailer)
jaykay 12 Dec 2013 12:39 I appreciate the thought but I'm in Australia
jaykay 12 Dec 2013 12:40 That was going to be my next question, how does it handle RTW?
petrolhead4 17 Feb 2014 14:24 Juast brought a DR650RS Hi, I am in the UK and just brought a DR650RS 2001 model, I was a bit unsure about the 650, I was going for a newer DR400, but a friend told about a DR650 he knew was good and going at a good price, I loved the bike when I saw it, they are rare in the UK, this one was owned by a bike nut who has stripped it and powder coated everything! frame, swinging arm etc., I was really happy with the bike, then I went to a Trail riders federation meeting, first time, they are the guys to know, but was told people buy big bikes as a compensation for a small "" well I got I bit put out by it and questioned my purchase! but I love it, and don’t give a f##k after reading the post on here, I think my gut feeling was right and the most important thing is to love the bike you ride, yer a CRF or KTM would have been more sensible for TRF stuff, but I want to get familiar with big bikes off road and hope to do a big trip, Thanks! Kind Regards Andy
johnnail 17 Feb 2014 14:32 Quote: Originally Posted by *Touring Ted* (Post 444115) How I dream this bike was available in the UK. When they do come up for sale, they're either ragged or really overpriced. and we want the XT660 and Transalp over here
mollydog 17 Feb 2014 17:35 Quote: Originally Posted by petrolhead4 (Post 454873) Hi, I am in the UK and just brought a DR650RS 2001 model, I was a bit unsure about the 650, I was going for a newer DR400, but a friend told about a DR650 he knew was good and going at a good price, I loved the bike when I saw it, they are rare in the UK, this one was owned by a bike nut who has stripped it and powder coated everything! frame, swinging arm etc., I was really happy with the bike, then I went to a Trail riders federation meeting, first time, they are the guys to know, but was told people buy big bikes as a compensation for a small "" well I got I bit put out by it and questioned my purchase! but I love it, and don’t give a f##k after reading the post on here, I think my gut feeling was right and the most important thing is to love the bike you ride, yer a CRF or KTM would have been more sensible for TRF stuff, but I want to get familiar with big bikes off road and hope to do a big trip, Thanks! Kind Regards Andy If you have a DR650RS ... then you've I believe you got a different model DR than the one shown in this thread. (DR650SE) Take a look at the other DR650SE pics shown in this thread ... is your bike like those? The DR650 RS model is a totally different bike. No interchangeable parts. It's also news to me that Suzuki still even made the RS in 2001. That model was discontinued here in the USA in 1995 or '96. Perhaps production was continued in UK and EU? Dunno? For more info, check out the Zen Seeker page: Suzuki DR650 History Page
petrolhead4 18 Feb 2014 13:17 Hi http://www.segurojoven.com/img/ficha...R-650-RS-3.jpg Mines the same as this only with full engine bars fitted, the logbook says DR650SE, the bike is an DR650RS? 2001, but these were all imported to the UK, prob. from New Zealand?
petrolhead4 18 Feb 2014 13:26 Had a look at Zens page I think mines the 1991? because it was imported the log book is probably quoting the the year it was imported to the UK?
mollydog 18 Feb 2014 18:52 I have no idea what was imported or what bike was called what in the UK. What I do know is that bike IS NOT a DR650SE. The bike above is a totally different bike. Different motor, swingarm, frame, forks ... and more. Take a CLOSE look at the SE model (from 1996 onward) and you can see the differences. Not much support for the pre '96 S models here in USA, maybe better in UK? Good luck with it! bier https://lh3.googleusercontent.com/-v...P1020387-L.jpg Left side, 2006 DR650SE. No changes since 1996. https://lh6.googleusercontent.com/-4...0/P1020513.JPG This is the right side of my bike after a 4000 mile trip through Baja .. so it's a bit dirty after a month on the road. Is this your motor?
petrolhead4 21 Feb 2014 09:39 Nope Thanks for the reply, I have got confused due to the log book! imported bikes seem to be registered a little different? it's registered as a DR650SE, I think the SE means special edition? It's a 1991 DR650RS, identical to the pic, apart from a few edition bits, parts don’t seem to be an issue on eBay! yet! lol, it's got a 21lt tank as standard, and I’m really happy with it! done 30'000 miles. The tyres are very similar to yours, how do you find the off-road riding with them? at the trail riders meeting I was recommended to fit a good set of off-road tyres, the ones I have are brand new, I'm not changing anything until I have tried it out first. I was pleased to see people using the DR650 as an adventure bike! that’s what really made my day!!!! it’s exactly what I thought it should do well! I paid £1350!! for the bike, it’s had a bolts up rebuild, good to go! if you’re interested I can post a few more pics, when the sun shows itself! My intention is to learn the basics for off-road riding, on the road repairs, kit etc., I don’t have the cash for a BMW, or new bike, especially as I am likely to drop it a few times in a ditch, (hope not!)
pecha72 21 Feb 2014 10:11 I´m no expert on DR650-models, but I do know there are at least two, and probably three very different models.. (and yes, even their engines ARE different). Suzuki´s model naming policy is sometimes just weird. Well, at least they don´t have a ´650´ or ´700´ that is actually an 800...... :rofl:
mollydog 21 Feb 2014 17:49 Quote: Originally Posted by petrolhead4 (Post 455375) Thanks for the reply, I have got confused due to the log book! imported bikes seem to be registered a little different? it's registered as a DR650SE, I think the SE means special edition? It's a 1991 DR650RS, identical to the pic, apart from a few edition bits, parts don’t seem to be an issue on eBay! yet! lol, it's got a 21lt tank as standard, and I’m really happy with it! done 30'000 miles. The tyres are very similar to yours, how do you find the off-road riding with them? at the trail riders meeting I was recommended to fit a good set of off-road tyres, the ones I have are brand new, I'm not changing anything until I have tried it out first. I was pleased to see people using the DR650 as an adventure bike! that’s what really made my day!!!! it’s exactly what I thought it should do well! I paid £1350!! for the bike, it’s had a bolts up rebuild, good to go! if you’re interested I can post a few more pics, when the sun shows itself! My intention is to learn the basics for off-road riding, on the road repairs, kit etc., I don’t have the cash for a BMW, or new bike, especially as I am likely to drop it a few times in a ditch, (hope not!) It's all good! You got a good deal on your bike. I'd go onto ADV Rider, Thumpers forum. Find the pre 1996 DR650 thread. Lots of good info for you! Pre '96 Suzuki DR650S - ADVrider Also, go to DRRiders.com forum. There they have a pre 1996 forum ... just for your bike. Ask questions, read and find solutions! :thumbup1: Pre-96 DR650 Forum Tires sizes are the same as post '96 DR650SE: 90/90-21" front, 120 or 130-17 rear. Tires like Conti TKC 80 are expensive but work well off road. They wear out quickly however. Also, Michelin T-66 is a popular off road tire that comes in your bikes size. There are a few others ... look around. (Maxxis, Shinko, more) Regular knobbies are good too ... but the rear size is a bit rare. You could switch up to a 18" rear wheel which would mean hundreds of knobby tire choices. Good luck! bier
| https://www.horizonsunlimited.com/hubb/suzuki-tech/dr650se-2-up-comfort-73207-2-print |
United Medical Associates PC - GuideStar Profile
GuideStar connects donors and grantmakers to non-profit organizations.
United Medical Associates PC
Vestal, NY | http://WWW.NYUHS.ORG
Mission
SEE SCHEDULE OTHE MISSION OF THE UHS MEDICAL GROUP IS TO IMPROVE THE HEALTH STATUS OF THE COMMUNITY BY PROVIDING EASILY ACCESSIBLE PROVIDER SERVICES, SUPPORT FOR TEACHING, MEETING THE REQUIREMENTS NECESSARY FOR RESEARCH AND MEDICAL ADMINISTRATION AND BY PARTICIPATING IN AN INTEGRATED CONTINUUM OF CARE THAT IMPROVES THE PATIENT'S EXPERIENCE AND THE QUALITY OF THE HEALTH SERVICES OUTCOME.
Ruling year info
1998
Principal Officer
4408 Vestal Parkway East
Vestal, NY 13850 United States
EIN
16-1395906
NTEE code info
Group Health Practice (Health Maintenance Organizations) (E31)
IRS filing requirement
This organization is required to file an IRS Form 990 or 990-EZ.
Sign in or create an account to view Form(s) 990 for 2019, 2018 and 2017.Register now
Programs and results
What we aim to solve
Our programs
SOURCE: IRS Form 990
Program 1
UNITED MEDICAL ASSOCIATES, PC (UMA) PERFORMS MEDICAL SERVICES, EDUCATION AND RESEARCH ACTIVITIES IN A VARIETY OF SETTINGS, ADDING TO THE BENEFIT OF THE COMMUNITY AND ENHANCING THE HEALTH STATUS OF ITS PATIENTS. UMA, PC PROVIDES A WIDE RANGE OF PROFESSIONAL SERVICES IN THE PRIMARY AND SPECIALTY CARE AREA. UMA PROVIDERS SUPPORT TWENTY-TWO FAMILY PRACTICES, FIVE INTERNAL MEDICINE CLINICS, FIVE PEDIATRICS CLINICS, TWO SCHOOL BASED HEALTH CLINICS, AND FOUR WALK-IN CENTERS LOCATED THROUGHOUT A MULTI-COUNTY SERVICE AREA. THE SPECIALTY CARE CENTERS INCLUDE ADDICTION MEDICINE, AMBULATORY SURGERY, AUDIOLOGY, GENERAL SURGERY, BARIATRIC SURGERY, BREAST SURGERY, UROLOGY, VASCULAR SURGERY, OB/GYN, CARDIOLOGY, CARDIAC REHABILITATION, CARDIOTHORACIC SURGERY, CHIROPRACTIC, **SEE SCHEDULE O FOR CONTINUATION** CONCUSSION CENTER, DENTAL SERVICES, DIABETES MANAGEMENT/ENDOCRINOLGY, HAND SURGERY AND THERAPY, NEPHROLOGY AND DIALYSIS, PHYSICAL MEDICINE AND REHABILITATION, PLASTIC SURGERY, WOUND CARE, OTOLARYNGOLOGY, RHEUMATOLOGY, PODIATRY, PATHOLOGY, EMERGENCY ROOM AND TRAUMA SERVICES, DERMATOLOGY, ORTHOPEDICS, SLEEP/NEURODIAGNOSTIC CENTER, NEUROCRITICAL CARE, GERIATRIC MEDICINE, HOSPITALISTS, INFECTIOUS DISEASE, , WOMENS' (GYN) SERVICES, RADIATION ONCOLOGY, GASTROENTEROLOGY, MEDICAL ONCOLOGY, NEUROSURGERY, GENERAL NEUROLOGY, NEURO-INTERVENTIONAL SURGERY AND PAIN MANAGEMENT. TOTAL PATIENTS SERVICED BY UMA PHYSICIANS AT YEAR END 2021 TOTALED 856,074.THESE SERVICES ASSIST UMA IN FULFILLING ITS EXEMPT PURPOSE UNDER THE IRS CODE 501(C)(3). UMA IS INVOLVED IN COMMUNITY SERVICE BY BEING PART OF THE FOLLOWING ACTIVITIES: (1) UMA IS INVOLVED IN THE SOUTHERN TIER HEALTHY LIVING PARTNERSHIP WHICH IS A UNIQUE COLLABORATION OF GOVERNMENT AND COMMUNITY BASED SYSTEMS THAT PROMOTE HEALTHY LIVING THROUGH OUTREACH EDUCATION AND ACCESS TO SERVICES FOR THE PURPOSE OF REDUCING THE RISK OF CHRONIC DISEASE. THE NEW YORK STATE DEPARTMENT OF HEALTH AND CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC) PROVIDES FUNDING FOR LOCAL COMMUNITY HEALTH CARE PRACTITIONERS TO PROVIDE CLINICAL BREAST EXAMS, MAMMOGRAMS, PAP TESTS, COLORECTAL SCREENING, AND LIMITED FOLLOW-UP. THESE SCREENING PROCEDURES ARE FOR THE INCOME ELIGIBLE WOMEN WHO ARE UNINSURED OR UNDER INSURED. (2) UMA PROVIDES FOR THE HEALTH MAINTENANCE OF THE ELDERLY POPULATION BY PARTICIPATING IN LECTURES TO THE UHS HOSPITALS MEMBERS FREE OF CHARGE. (3) UMA PROVIDERS STAFF THE UHS WILSON MEDICAL CENTER BRAIN/SPINE TRAUMA CENTER. THIS IS A LEVEL II TRAUMA CENTER WITHIN CENTRAL NEW YORK'S REGIONAL SYSTEM. THE TRAUMA CENTER ACCEPTS SEVERELY INJURED TRAUMA PATIENTS FROM ALL SURROUNDING COUNTIES. THE TRAUMA CENTER IS LOCATED WITHIIN THE EMERGENCY DEPARTMENT AT WILSON MEDICAL CENTER, WITH SPACIOUS, SPECIALIZED TRAUMA ROOMS THAT CAN PROVIDE CARE SIMULTANEOUSLY TO AS MANY AS FOUR VICTIMS OF SUDDEN, SERIOUS INJURY.(4) UMA PROVIDERS STAFF THE ARTICLE 28A CLINICS OPERATED BY UNITED HEALTH SERVICES HOSPITALS, CHENANGO MEMORIAL HOSPITAL, AND DELAWARE VALLEY HOSPITAL. THESE FACILITIES PROVIDE HEALTH CARE SERVICES TO A LARGE MEDICAID POPULATION.(5) UMA PROVIDERS STAFF THE UHS PERINATAL CENTER. THE CENTER OFFERS A COMPREHENSIVE RANGE OF SERVICES FROM GYNECOLOGY TO MATERNITY & CHILDBIRTH TO BREAST HEALTH. THE STAFF OF SPECIALIZED PHYSICIANS, NURSE PRACTITIONERS, AND CERTIFIED NURSE MIDWIVES CREATE A CARING AND COMPASSIONATE ENVIRONMENT SERVING WOMEN AT EACH STATE OF LIFE: FROM TEENAGE AND CHILDBEARING YEARS TO MID-LIFE AND SENIOR YEARS ALL HAVING THEIR OWN UNIQUE HEALTH ISSUES. UHS HOSPITALS' PRIMARY CARE CENTERS, ALSO STAFFED BY UMA PROVIDERS, AND THE PERINATAL CENTER PARTICIPATE IN THE PRENATAL CARE ASSISTANCE PROGRAM (PCAP) OFFERING FINANCIAL ASSISTANCE TO HELP EXPECTANT MOTHERS WITH THE COST OF PRENATAL CARE. (6) UHS HOSPITALS, UHS CHENANGO MEMORIAL HOSPITAL, UHS DELAWARE VALLEY HOSPITAL AND UMA HAVE IMPLEMENTED A PATIENT-CENTERED MEDICAL HOME PROGRAM. THE OVERALL GOAL IS TO INCREASE THE QUALITY AND IMPROVE HEALTH OUTCOMES FOR ALL PATIENTS BUT ESPECIALLY FOR THOSE WITH SOCIAL DETERMINANTS OF HEALTH THAT LEAD TO DISPARITIES IN CARE, INCLUDING PERSONS ENROLLED IN NY MEDICAID. THE PATIENT-CENTERED MEDICAL HOME IS A PROACTIVE MODEL OF CARE THAT SEEKS TO STRENGTHEN THE PHYSICIAN-PATIENT RELATIONSHIP BY REPLACING REACTIVE, EPISODIC CARE BASED ON ILLNESS AND PATIENT COMPLAINTS WITH COORDINATED CARE AND A LONG-TERM HEALING RELATIONSHIP. UMA PHYSICIANS CURRENTLY STAFF TWENTY-SIX LEVEL 3 MEDICAL HOME SITES THAT HAVE RECEIVED NCQA PATIENT CENTERED MEDICAL HOME RECOGNITION.(7) UMA PROVIDERS SERVE ON VARIOUS BOARDS OF HEALTH AND AS DIRECTORS FOR EMERGENCY SERVICE AGENCIES INCLUDING AMBULANCE SQUADS AS WELL AS VARIOUS CAMP PROGRAMS. (8) UMA PROVIDERS FROM THE INTERNAL MEDICINE AND FAMILY PRACTICE RESIDENCY PROGRAMS, UHS SPORTS MEDICINE FELLOWSHIP PROGRAM, UHS EMERGENCY AND TRAUMA SERVICES AS WELL AS OTHER AREAS OF UHS HOSPITALS VOLUNTEER THROUGHOUT THE YEAR TO STAFF MEDICAL TENTS AT NUMEROUS COMMUNITY EVENTS INCLUDING THE SPIEDIE FEST (WHICH DRAWS MORE THAN 100,000 PEOPLE), THE DICK'S SPORTING GOODS OPEN (A WEEKLONG EVENT WHICH INCLUDES THE PRACTICE ROUNDS, PRO-AM AND A COMMUNITY CONCERT), MACK SHOOT OUT LACROSSE TOURNAMENT, BINGHAMTON BRIDGE RUN, BINGHAMTON RUMBLE PONIES GAMES, AND BINGHAMTON DEVILS HOCKEY GAMES. (9) UMA PROVIDERS ARE INVOLVED WITH PROFESSIONAL EDUCATION WHICH TAKES THE FORM OF ORGANIZING SEVERAL TEACHING DAYS. THIS INVOLVES UMA, NATIONALLY RECOGNIZED EXPERT SPAKERS, AND OTHER LOCAL AND REGIONAL STAFF, PHYSICIAN EXTENDERS AND PHYSICIANS. TEACHING DAY PROGRAMS INCLUDE GASTROENTEROLOGY, CARDIOLOGY, OSTEOPATHIC MEDICINE, HEALTH AND WELLNESS, CHRONIC KIDNEY DISEASE, BUPRENORPHINE PRESCRIBING, AND THE ANNUAL BINGHAMTON UNIVERSITY BIOMEDICAL CONFERENCE. DUE TO THE PANDEMIC, THESE EVENTS WERE CANCELED IN 2020 AND 2021. THESE ARE ANTICIPATED TO RESUME WHEN THE PANDEMIC RESTRICTIONS ARE REMOVED. (10) UMA WAS CHOSEN BY THE CDC AND NY STATE DOH AS THE NATIONAL TEST SITE FOR THE STEADI PROGRAM. THIS IS A PROGRAM DONE JOINTLY BY UMA, THE BROOME COUNTY HEALTH DEPT, AND NEW YORK STATE DEPT OF HEALTH AND OVERSEEN BY THE CDC TO ASSESS THE IMPACT OF FALL RISK ASSESSMENT AND A COMMUNITY BASED INTERVENTION PROGRAM ON PREVENTION OF FALLS AND INJURIES IN OUR PATIENTS GREATER THAN 65 YEARS OLD. DURING THE PANDEMIC, THE CDC PAUSED STUDY OF THIS PROGRAM. HOWEVER, UMA CONTINUES TO SCREEN OUR PATIENTS FOR THEIR RISK OF FALLS AS A PART OF OUR MEDICARE WELLNESS EXAMS. (11) UMA PROVIDERS ARE ACTIVELY ENGAGED IN IMPROVING THE HEALTH OF OUR PATIENTS. TO FACILITATE THIS, WE HAVE A DIRECTOR OF POPULATION HEALTH POSITION AND HAVE ADDED WELLNESS COORDINATORS OR SOCIAL WORKERS AT EACH OF OUR SITES. CARE MANAGEMENT PATHWAYS HAVE BEEN DEVELOPED TO ASSIST IN DIABETES AND HYPERTENSION MANAGEMENT AND TO INCREASE THE NUMBER OF PATIENTS GETTING BREAST AND COLON CANCER SCREENING. (12) UMA PROVIDERS PROVIDE MAT (MEDICALLY ASSISTED TREATMENT [BUPRENORPHINE (SUBOXONE) AND METHADONE]) PROGRAMS FOR THE ONGOING SUCCESSFUL TREATMENT OF OPIOID USE DISORDER (OUD). (13) UMA PROVIDERS PROVIDE DIAGNOSTIC AND TREATMENT SERVICES FOR HIV AND HCV PATIENTS. (14) UMA PROVIDER STAFFED A28 VIRTUAL URGENT CARE CENTER IS THE FIRST HOSPITAL-BASED CONSUMER-TO-PROVIDER PROGRAM TO ACHIEVE NATIONAL ACCREDITATION. (15) UMA PROVIDERS DELIVER CARE VIA VIRTUAL HEALTH (TELEHEALTH) ON 62,876 PATIENT ENCOUNTERS IN 2021. VIRTUAL HEALTH ENCOUNTERS INCREASE ACCESS TO CARE FOR PATIENTS WITH BARRIERS TO CARE SUCH AS TRANSPORTATION, WORK SCHEDULE CONFLICTS, AND/OR FEAR OF CONTAGION FROM BEING SEEN IN-PERSON AT THE PRACTICE.
Expenses
$145,092,850
Revenue
$134,110,307
Financials
The people, governance practices, and partners that make the organization tick.
| https://www.guidestar.org/profile/16-1395906 |
Latest content added for The Portal to Texas History Title: Texas Parks & Wildlife
Latest content added for The Portal to Texas History Title: Texas Parks & Wildlife
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<updated> 2023-06-04T11:16:27-05:00 </updated>
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<name> UNT Libraries </name>
This is a custom feed for browsing The Portal to Texas History Title: Texas Parks & Wildlife
<entry>
<title>
Texas Parks & Wildlife, Volume 52, Number 2, February 1994
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568759/" rel=" alternate"/>
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<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568759/"><img alt="Texas Parks & Wildlife, Volume 52, Number 2, February 1994" title="Texas Parks & Wildlife, Volume 52, Number 2, February 1994" src="https://texashistory.unt.edu/ark:/67531/metapth1568759/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
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</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 52, Number 1, January 1994
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568758/" rel=" alternate"/>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568758/
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<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568758/"><img alt="Texas Parks & Wildlife, Volume 52, Number 1, January 1994" title="Texas Parks & Wildlife, Volume 52, Number 1, January 1994" src="https://texashistory.unt.edu/ark:/67531/metapth1568758/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568758/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 12, December 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568757/" rel=" alternate"/>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568757/
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<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568757/"><img alt="Texas Parks & Wildlife, Volume 55, Number 12, December 1997" title="Texas Parks & Wildlife, Volume 55, Number 12, December 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568757/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568757/small/"/>
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<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 11, November 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568756/" rel=" alternate"/>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568756/
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<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568756/"><img alt="Texas Parks & Wildlife, Volume 55, Number 11, November 1997" title="Texas Parks & Wildlife, Volume 55, Number 11, November 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568756/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
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<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 10, October 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568755/" rel=" alternate"/>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568755/
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<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568755/"><img alt="Texas Parks & Wildlife, Volume 55, Number 10, October 1997" title="Texas Parks & Wildlife, Volume 55, Number 10, October 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568755/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568755/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 9, September 1997
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568754/" rel=" alternate"/>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568754/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568754/"><img alt="Texas Parks & Wildlife, Volume 55, Number 9, September 1997" title="Texas Parks & Wildlife, Volume 55, Number 9, September 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568754/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568754/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 8, August 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568753/" rel=" alternate"/>
<published> 2023-06-04T11:15:25-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568753/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568753/"><img alt="Texas Parks & Wildlife, Volume 55, Number 8, August 1997" title="Texas Parks & Wildlife, Volume 55, Number 8, August 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568753/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568753/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 7, July 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568752/" rel=" alternate"/>
<published> 2023-06-04T11:15:23-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568752/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568752/"><img alt="Texas Parks & Wildlife, Volume 55, Number 7, July 1997" title="Texas Parks & Wildlife, Volume 55, Number 7, July 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568752/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568752/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 6, June 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568751/" rel=" alternate"/>
<published> 2023-06-04T11:15:14-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568751/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568751/"><img alt="Texas Parks & Wildlife, Volume 55, Number 6, June 1997" title="Texas Parks & Wildlife, Volume 55, Number 6, June 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568751/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568751/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 5, May 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568750/" rel=" alternate"/>
<published> 2023-06-04T11:14:56-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568750/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568750/"><img alt="Texas Parks & Wildlife, Volume 55, Number 5, May 1997" title="Texas Parks & Wildlife, Volume 55, Number 5, May 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568750/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568750/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 4, April 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568749/" rel=" alternate"/>
<published> 2023-06-04T11:14:50-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568749/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568749/"><img alt="Texas Parks & Wildlife, Volume 55, Number 4, April 1997" title="Texas Parks & Wildlife, Volume 55, Number 4, April 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568749/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568749/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 3, March 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568748/" rel=" alternate"/>
<published> 2023-06-04T11:14:44-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568748/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568748/"><img alt="Texas Parks & Wildlife, Volume 55, Number 3, March 1997" title="Texas Parks & Wildlife, Volume 55, Number 3, March 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568748/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568748/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 2, February 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568747/" rel=" alternate"/>
<published> 2023-06-04T11:14:43-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568747/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568747/"><img alt="Texas Parks & Wildlife, Volume 55, Number 2, February 1997" title="Texas Parks & Wildlife, Volume 55, Number 2, February 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568747/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568747/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 55, Number 1, January 1997
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568746/" rel=" alternate"/>
<published> 2023-06-04T11:14:42-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568746/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568746/"><img alt="Texas Parks & Wildlife, Volume 55, Number 1, January 1997" title="Texas Parks & Wildlife, Volume 55, Number 1, January 1997" src="https://texashistory.unt.edu/ark:/67531/metapth1568746/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568746/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 12, December 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568745/" rel=" alternate"/>
<published> 2023-06-04T11:14:40-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568745/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568745/"><img alt="Texas Parks & Wildlife, Volume 35, Number 12, December 1977" title="Texas Parks & Wildlife, Volume 35, Number 12, December 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568745/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568745/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 11, November 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568744/" rel=" alternate"/>
<published> 2023-06-04T11:14:38-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568744/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568744/"><img alt="Texas Parks & Wildlife, Volume 35, Number 11, November 1977" title="Texas Parks & Wildlife, Volume 35, Number 11, November 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568744/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568744/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 10, October 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568743/" rel=" alternate"/>
<published> 2023-06-04T11:14:28-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568743/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568743/"><img alt="Texas Parks & Wildlife, Volume 35, Number 10, October 1977" title="Texas Parks & Wildlife, Volume 35, Number 10, October 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568743/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568743/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 9, September 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568742/" rel=" alternate"/>
<published> 2023-06-04T11:14:11-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568742/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568742/"><img alt="Texas Parks & Wildlife, Volume 35, Number 9, September 1977" title="Texas Parks & Wildlife, Volume 35, Number 9, September 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568742/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568742/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 8, August 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568741/" rel=" alternate"/>
<published> 2023-06-04T11:14:04-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568741/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568741/"><img alt="Texas Parks & Wildlife, Volume 35, Number 8, August 1977" title="Texas Parks & Wildlife, Volume 35, Number 8, August 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568741/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568741/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 7, July 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568740/" rel=" alternate"/>
<published> 2023-06-04T11:13:59-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568740/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568740/"><img alt="Texas Parks & Wildlife, Volume 35, Number 7, July 1977" title="Texas Parks & Wildlife, Volume 35, Number 7, July 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568740/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568740/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 6, June 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568739/" rel=" alternate"/>
<published> 2023-06-04T11:13:56-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568739/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568739/"><img alt="Texas Parks & Wildlife, Volume 35, Number 6, June 1977" title="Texas Parks & Wildlife, Volume 35, Number 6, June 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568739/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568739/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 5, May 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568738/" rel=" alternate"/>
<published> 2023-06-04T11:13:53-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568738/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568738/"><img alt="Texas Parks & Wildlife, Volume 35, Number 5, May 1977" title="Texas Parks & Wildlife, Volume 35, Number 5, May 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568738/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568738/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 4, April 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568737/" rel=" alternate"/>
<published> 2023-06-04T11:13:52-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568737/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568737/"><img alt="Texas Parks & Wildlife, Volume 35, Number 4, April 1977" title="Texas Parks & Wildlife, Volume 35, Number 4, April 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568737/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568737/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 3, March 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568736/" rel=" alternate"/>
<published> 2023-06-04T11:13:50-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568736/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568736/"><img alt="Texas Parks & Wildlife, Volume 35, Number 3, March 1977" title="Texas Parks & Wildlife, Volume 35, Number 3, March 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568736/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568736/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 2, February 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568735/" rel=" alternate"/>
<published> 2023-06-04T11:13:47-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568735/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568735/"><img alt="Texas Parks & Wildlife, Volume 35, Number 2, February 1977" title="Texas Parks & Wildlife, Volume 35, Number 2, February 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568735/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568735/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 35, Number 1, January 1977
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568734/" rel=" alternate"/>
<published> 2023-06-04T11:13:22-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568734/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568734/"><img alt="Texas Parks & Wildlife, Volume 35, Number 1, January 1977" title="Texas Parks & Wildlife, Volume 35, Number 1, January 1977" src="https://texashistory.unt.edu/ark:/67531/metapth1568734/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568734/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 36, Number 12, December 1978
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568733/" rel=" alternate"/>
<published> 2023-06-04T11:13:20-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568733/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568733/"><img alt="Texas Parks & Wildlife, Volume 36, Number 12, December 1978" title="Texas Parks & Wildlife, Volume 36, Number 12, December 1978" src="https://texashistory.unt.edu/ark:/67531/metapth1568733/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<summary type=" html"> ... </summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568733/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 36, Number 11, November 1978
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568732/" rel=" alternate"/>
<published> 2023-06-04T11:13:14-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568732/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568732/"><img alt="Texas Parks & Wildlife, Volume 36, Number 11, November 1978" title="Texas Parks & Wildlife, Volume 36, Number 11, November 1978" src="https://texashistory.unt.edu/ark:/67531/metapth1568732/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<summary type=" html"> ... </summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568732/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 36, Number 10, October 1978
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568731/" rel=" alternate"/>
<published> 2023-06-04T11:13:10-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568731/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568731/"><img alt="Texas Parks & Wildlife, Volume 36, Number 10, October 1978" title="Texas Parks & Wildlife, Volume 36, Number 10, October 1978" src="https://texashistory.unt.edu/ark:/67531/metapth1568731/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568731/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 36, Number 9, September 1978
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568730/" rel=" alternate"/>
<published> 2023-06-04T11:13:08-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568730/
</id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568730/"><img alt="Texas Parks & Wildlife, Volume 36, Number 9, September 1978" title="Texas Parks & Wildlife, Volume 36, Number 9, September 1978" src="https://texashistory.unt.edu/ark:/67531/metapth1568730/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568730/small/"/>
</entry>
<entry>
<title>
Texas Parks & Wildlife, Volume 36, Number 8, August 1978
</title>
<link href=" https://texashistory.unt.edu/ark:/67531/metapth1568729/" rel=" alternate"/>
<published> 2023-06-04T11:13:06-05:00 </published>
<id>
https://texashistory.unt.edu/ark:/67531/metapth1568729/
</id>
<id> ... </id>
<summary type=" html">
<p><a href="https://texashistory.unt.edu/ark:/67531/metapth1568729/"><img alt="Texas Parks & Wildlife, Volume 36, Number 8, August 1978" title="Texas Parks & Wildlife, Volume 36, Number 8, August 1978" src="https://texashistory.unt.edu/ark:/67531/metapth1568729/small/"/></a></p><p>Magazine discussing natural resources, parks, hunting and fishing, and other information related to the outdoors in Texas.</p>
</summary>
<summary type=" html"> ... </summary>
<media:thumbnail url=" https://texashistory.unt.edu/ark:/67531/metapth1568729/small/"/>
</entry>
| https://texashistory.unt.edu/explore/titles/t02653/feed/?sort=added_d&start=240&t=fulltext |
Akhop Branch Post Office, Bilthara Road 15, Ballia, Uttar Pradesh
Get Akhop post office address, pincode, phone number, Akhop speed post tracking, saving scheme and location map.
Akhop Post Office, Bilthara Road
Akhop Post Officeis located at Akhop, Bilthara Road, Balliaof Uttar Pradesh state. It is a branch office (B.O.). A Post Office (PO) / Dak Ghar is a facility in charge of sorting, processing, and delivering mail to recipients. POs are usually regulated and funded by the Government of India (GOI). Pin code of Akhop POis 221715. This Postoffice falls under Ballia postal division of the Uttar Pradesh postal circle. The related head P.O. for this branch office is Rasra head post office and the related sub-post office (S.O.) for this branch office is Bilthra Road Rs post office.
Akhop dak ghar offers all the postal services like delivery of mails & parcels, money transfer, banking, insurance and retail services. It also provides other services including passport applications, P.O. Box distribution, and other delivery services in Akhop. The official website fo this PO is http://www.indiapost.gov.in.
Types of Post Offices
are basically classified into 3 types, namely – Head Post Office, Sub-Post Office including E.D. Sub-Office and Branch Postoffice. Akhop P.O. is a Branch Post Office. So far as the public is concerned, there is basically no difference in the character of the service rendered by Sub-Post Offices and Head-Post Offices except in regard to a few Post Office Savings Bank (SB) transactions. Certain Sub Post Offices do not undertake all types of postal business. Facilities are generally provided at Branch Post Offices for the main items of postal work like delivery and dispatch of mails, booking of registered articles and parcels accepting SB deposits and effecting SB withdrawals, and issue and payment of money orders, though in a restricted manner.
Post Office Type Head Post Office Sub-Post Offices including E.D. Sub-Offices Branch Post Office
Akhop Post Office & Its Pin Code
Branch Office Information
Akhop Post Office Services
Mail Services
Parcels
Retail Services
Premium Services
Speed Post
India Post Speed Post Tracking
Tracking System
India Post Tracking Number Formats
Express Parcel Post
Media Post
Greetings Post
Logistics Post
ePost Office
Financial Services
Savings Bank (SB) Account
Recurring Deposit (RD) Account
Monthly Income Scheme (MIS)
Monthly Public Provident Fund (PPF)
Time Deposit (TD)
Senior Citizen Saving Scheme (SCSS)
National Savings Certificate (NSC)
Kisan Vikas Patra (KVP)
Sukanya Samriddhi Accounts (SSA)
Post Office Timings
India Post Tracking
Akhop Post Office Recruitment
Location Map
Contact Details
About India Post
Akhop Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Akhop Post Office has the Postal Index Number or Pin Code 221715. A Pincode is a 6 digit post code of postal numbering system used by India Post. The first digit indicates one of the regions. The first 2 digits together indicate the sub region or one of the postal circles. The first 3 digits together indicate a sorting / revenue district. The last 3 digits refer to the delivery post office type.
P.O. Name Akhop PO Pincode 221 715
The first digit of 221715 Pin Code '2' represents the region, to which this Post Office of Akhop belongs to. The first two digits of the Pincode '22' represent the sub region, i.e, Uttar Pradesh. The first 3 digits '221' represent the post-office revenue district, i.e, Ballia. The last 3 digits, i.e, '715' represent the Akhop Delivery Branch Office.
Branch Office Information
The Akhop Post Office is a branch office. The Delivery Status for this PO is that it has delivery facility. Postal division name for this Dak Ghar is Ballia, which falls under Gorakhpur region. The circle name for this PO is Uttar Pradesh and it falls under Bilthara Road Taluka and Ballia District. The state in which this Dakghar is situated or located is Uttar Pradesh. The related head postoffice is Rasra post office and the related sub post office is Bilthra Road Rs post-office. The phone number of Akhop post office is unavailable at present.
PO Type Branch Office Delivery Status Delivery Postal Division Ballia Postal Region Gorakhpur Postal Circle Uttar Pradesh Town / City / Tehsil / Taluka / Mandal Bilthara Road District Ballia State Uttar Pradesh Related Sub PO Bilthra Road Rs Sub Office Related Head PO Rasra Head Post Office
Akhop Post Office Services
Traditionally the primary function of Akhop post office was collection, processing, transmission and delivery of mails but as of today, a Post Office offers many other vital services in addition to its traditional services. The additional services provided by a Dak Ghar include – Mail Services, Financial Services, Retail Services and Premium Services.
Mail Services
Mail Services are the basic services provided by Akhop P.O. Mails and mail services include all or any postal articles whose contents are in the form of message which may include Letters, Postcards, Inland letter cards, packets or parcels, Ordinary mails etc.
Parcels
Mail Service also includes transmission and delivery of Parcels. A parcel can be anything ranging from a single written letter or anything addressed to an addressee. No parcel shall be by any chance be in a shape, way of packing or any other feature, such that it cannot be carried or transmitted by post or cause serious inconvenience or risk. Every parcel (including service parcels) that needs to be transmitted by post must be handed over at the window of the post office. Any parcel found in a letter box will be treated and charged as a registered parcel. Delivery services are provided by some selected delivery and branch post offices. This dakghar have the facility of delivery, thus the people of Akhop and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Akhop Post Office offer most of the retail services. They offer the facility to accept or collect constomer bills like telephone or mobile bills, electricity bills for Government and private organizations through Retail Post. Some of the aditional agency services that Post offices offers through retail services are as follows - Telephone revenue collection, e-Ticketing for Road Transport Corporations and Airlines, Sale of UPSC forms, university applications, Sale of Passport application forms, Sale of Gold Coins, Forex Services, Sale of SIM and recharge coupons, Sale of India Telephone cards, e-Ticketing of Railway tickets etc. The postal customers of Akhop can pay their bills and avail other retail services from this Dak Ghar.
Premium Services
Most of the premium services can be availed by the Akhop peoples and nearby living people. The premium services provided by Akhop Post Office are - Speed Post, Business Post, Express Parcel Post, Media Post, Greeting Post, and Logistics Post.
Speed Post
Speed Post is a time bound service in express delivery of letters and parcels. The max weight up to which an article or parcel be sent is 35 kgs between any two specified stations in India. Speed Post delivers 'Value for money' to everyone and everywhere, delivering Speed Post upto 50 grams @ INR 35 across the country and local Speed Post upto 50 grams @ INR 15, excluding applicable Service Tax. Kindly check official website for updated Speed Post service charges.
India Post Speed Post Tracking
Speed Post offers a facility of on-line tracking and tracing that guarantees reliability, speed and customer friendly service. Using a 13 digit barcode that makes a Speed Post consignment unique and identifiable. A web-based technology (www.indiapost.gov.in/speednettracking.aspx) helps the Akhop customers track Speed Post consignments from booking to delivery.
Tracking System
Except Speed Post, India Post also allows people to track their order information for certain products like Parcels, Insured letters, Speed Post, Registered Post, Electronic Money Orders (EMO) and Electronic value payable parcel (EVPPs) etc. The tracking number is available on the receipt given at Akhop Post Office. Using the tracking number postal customers can find out the date and time of dispatch of an article at various locations. The time of booking and the time of delivery of article.
India Post Tracking Number Formats
Different types of postal service have different kinds of tracking number formats. The tracking number for Express Parcel is a 13 digit alphanumeric format. The format for Express Parcel is XX000000000XX. The tracking number for a Registered Mail is a 13 digit alphanumeric number and its format is RX123456789IN. But a Electronic Money Order (EMO) has a 18 digit tracking number and its format is 000000000000000000. For domestic Speed Post (EMS) there is a 13 digit alphanumeric tracking number with the format EE123456789IN.
Bharatiya Dak Ghar Seva Tracking Number Format Number of Digits Electronic Money Order (eMO) 000000000000000000 18 Express Parcel XX000000000XX 13 International EMS Artilces to be delivered in India EE123456789XX 13 Registered Mail RX123456789IN 13 Speed Post (EMS) Domestic EE123456789IN 13
Express Parcel Post
In Express Parcel Post, the Akhop postal customer gets time bound delivery of parcels. These parcels will be transmitted through air or any other fastest mean available at that time. Minimum chargeable weight for which Express Parcel consignments will be booked is 0.5 Kg. Maximum weight of Express Parcel consignments which shall be booked across the Post Office counter by a retail customer shall be 20 Kg and maximum weight that can be booked by corporate customer is 35 kgs.
Media Post
India Post offers a unique way or concept to help the Indian corporate organisations and the Government organizations reach potential customers through media post. Through media post people can advertise on postcards, letters, aerogramme, postal stationary etc. Customers get to see the logo or message of the respective corporate or government organizations. The Aerogramme even gives the organizations the opportunity to make their product have a global impact.
Greetings Post
Greeting Post is yet another innovative or unique step by India Post. It consists of a card with an envelope with pre-printed and pre attached postage stamp on the envelope. The stamp on the envelope is a replica of the design that appears upon the card but in miniature form. Thus there is no need affix postage stamps on the envelope implicitly saving your time of going to post offices and standing in the queue. All the rules and that are applicable for the postage dues will also be applicable to the Greeting Post.
Logistics Post
Logistics Post manages the entire transmission and distribution side of the parcels. It deals with collection of goods, storage of goods, carriage and distribution of the various parcels or goods, from order preparation to order fulfilment. And that too at the minimum possible price. Logistics Post services provides the Akhop postal customer with cost-effective and efficient distribution across the entire country.
ePost Office
The advent of internet made communication very rapid through emails. But, the internet has not yet reached most of the rural parts of India. To change this division between rural & urban life, and to get the benefit of internet technology to Akhop people's lives, Indian Postal Department has introduced e-post. e-post is a service in which personalized handwritten messages of customers are scanned and sent as email through internet. And at the destination address office, these messages are again printed, enveloped and delivered through postmen at the postal addresses. E-post centres are established in the Post Offices, covering a large geographical area including major cities and districts. These e-post centres are well equipped with internet connection, scanners, printers and other necessary hardware equipment. However, this e-post service doesn’t particularly need a e-post centre, but can this facility can be availed at any normal Post Office or you can visit www.epostoffice.gov.in to access postal services on your desktop, laptop or even on mobile. If a message is booked at Akhop post office, the post is scanned and sent to an e-post centre by e-mail and a mail received at e-post centre is printed and sent to nearby Post Office for dispatch.
A Akhop customer can also avail these services of an e-post, at his/ her home. All he/ she has do is to register as a user at www.epostoffice.gov.in website. After registration, a user can use e-post by scanning and sending messages, printing and receive messages. The message to be scanned must not be written in a paper not more A4. There is no limit for sending number of sheets of messages in e-post.
E-Post Office offers certain services like – Philately, Postal Life Insurance, Electronic Indian Postal Order, Information Services, Track & Trace and Complaints & Guidelines services.
Philately
Philately service deals with collection, sale and study of postage stamps. Philately includes lot of services Philately Information, Stamp issue Program, Stamps List and Buy Stamps service.
Postal Life Insurance (PLI)
A service offered by the Government to pay a given amount of money on the death of an individual to his prescribed nominee. The amount may also be paid to the person himself, in case he survives that maturity period. The two services offered under Postal Life Insurance are – Pay Premium service and PLI information.
Electronic Indian Postal Order
eIPO or Electronic Indian Postal Order is a facility to purchase an Indian Postal Order electronically by paying a fee on-line through e-Post Office. This service is launched by the Department of Posts, Ministry of Communications & IT, Government of India.
eIPO can now be used by Indian Citizens living in India for paying online fee, whoever seeks information under the RTI Act, 2005. eIPO offers 2 types of services – eIPO information and payment of online fees.
Information Services
This helps Akhop customers to get information regarding certain products like – Pin Code search, Speed post, Banking, Insurance, Business Post, Logistics Post, IMTS and many more other services.
Track & Trace
The track & trace service is very helpful as it aids in getting information of our valuables. Track & Trace service offers 5 different services – Pin Code search, EMO tracking, Speed Post tracking, WNX tracking and International mail service.
Complaints & Guidelines
Using e-post office service Akhop postal costumer can access services based on – complaint registration, complaint status and guidelines on complaints.
ePost Office Website www.epostoffice.gov.in
Financial Services
The customers of Akhop can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Akhop area. The Financial service offered by PO includes Savings and Postal Life Insurance (PLI). There are various options available to save and invest with post-offices. The commonly used ones include - Savings account, Recurring Deposit, Monthly Income Scheme, Monthly Public Provident Fund, Time Deposit, Senior Citizen Saving Scheme, National Savings Certificate, Kisan Vikas Patra and Sukanya Samriddhi Yojana. Post Office also offers Insurance product through Postal Life Insurance (PLI) and Rural Postal Life Insurance (RPLI) schemes that offer low premium and high bonus.
Post Office Financial Services Kisan Vikas Patra (KVP) Monthly Income Scheme (MIS) Monthly Public Provident Fund (PPF) National Savings Certificate (NSC) Recurring Deposit (RD) Account Savings Bank (SB) Account Senior Citizen Saving Scheme (SCSS) Sukanya Samriddhi Accounts (SSA) Time Deposit (TD)
Savings Bank (SB) Account
A Savings bank account serves the need of regular deposits for its customers as well as withdrawals. Cheque facility is also avail by Akhop postal consumers.
Recurring Deposit (RD) Account
A post office offers a monthly investment option with handsome return at the time period with an option to extend the investment period. Insurance facility is also available with certain conditions.
Monthly Income Scheme (MIS)
MIS offers a fixed investment technique for five or more years with monthly interest payment to the account holder. There is also a facility of automatic crediting of interest to SB account of the Akhop postal customer.
Monthly Public Provident Fund (PPF)
This service offers intermittent deposits subject to a particular limit for a time period of 15 years with income tax exemptions, on the investment. It also offers loan and withdrawal facilities for the postal customers.
Time Deposit (TD)
Fixed deposit option for periods ranging from one, two, three to five years with facility to draw yearly interest offered at compounded rates. Automatic credit facility of interest to SB account.
Senior Citizen Saving Scheme (SCSS)
Offers fixed investment option for senior citizens for a period of five years, which can be extended, at a higher rate of interest that are paid in quarterly instalments.
National Savings Certificate (NSC)
NSC is offered with a fixed investment for 5 or 10 years on certificates of various denominations. Pledging facility available for availing loan from Banks.
Kisan Vikas Patra (KVP)
Kisan Vikas Patra is a saving certificate scheme in which the amount Invested doubles in 110 months (i.e. 9 years & 2 months). It is available in denominations of Rs 1,000, 5000, 10,000 and Rs 50,000. Minimum deposit is Rs 1000/- and there is no maximum limit. The KVP certificate can be purchased by any adult for himself or on the behalf of a minor. This certificate can also be transferred from one account holder to another and from one post office to another. This certificate can be en-cashed only after 2 and 1/2 years from the date of issue.
Sukanya Samriddhi Accounts (SSA)
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Nutrients | Free Full-Text | Nitrate and Nitrite Metabolism in Aging Rats: A Comparative Study
Nitric oxide (NO) (co)regulates many physiological processes in the body. Its short-lived free radicals force synthesis in situ and on-demand, without storage possibility. Local oxygen availability determines the origin of NO—either by synthesis by nitric oxide synthases (NOS) or by the reduction of nitrate to nitrite to NO by nitrate/nitrite reductases. The existence of nitrate reservoirs, mainly in skeletal muscle, assures the local and systemic availability of NO. Aging is accompanied by changes in metabolic pathways, leading to a decrease in NO availability. We explored age-related changes in various rat organs and tissues. We found differences in nitrate and nitrite contents in tissues of old and young rats at baseline levels, with nitrate levels being generally higher and nitrite levels being generally lower in old rats. However, there were no differences in the levels of nitrate-transporting proteins and nitrate reductase between old and young rats, with the exception of in the eye. Increased dietary nitrate led to significantly higher nitrate enrichment in the majority of old rat organs compared to young rats, suggesting that the nitrate reduction pathway is not affected by aging. We hypothesize that age-related NO accessibility changes originate either from the NOS pathway or from changes in NO downstream signaling (sGC/PDE5). Both possibilities need further investigation.
Nitrate and Nitrite Metabolism in Aging Rats: A Comparative Study
by Barbora Piknova * , Ji Won Park , Samantha M. Thomas , Khalid J. Tunau-Spencer and Alan N. Schechter
Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD 20892, USA
Author to whom correspondence should be addressed.
Nutrients 2023 , 15 (11), 2490; https://doi.org/10.3390/nu15112490
Received: 17 April 2023 / Revised: 19 May 2023 / Accepted: 24 May 2023 / Published: 26 May 2023
(This article belongs to the Special Issue The Life of Nitric Oxide: From Nitrate and Nitric Oxide Synthase to Nitric Oxide and Beyond )
Abstract
Nitric oxide (NO) (co)regulates many physiological processes in the body. Its short-lived free radicals force synthesis in situ and on-demand, without storage possibility. Local oxygen availability determines the origin of NO—either by synthesis by nitric oxide synthases (NOS) or by the reduction of nitrate to nitrite to NO by nitrate/nitrite reductases. The existence of nitrate reservoirs, mainly in skeletal muscle, assures the local and systemic availability of NO. Aging is accompanied by changes in metabolic pathways, leading to a decrease in NO availability. We explored age-related changes in various rat organs and tissues. We found differences in nitrate and nitrite contents in tissues of old and young rats at baseline levels, with nitrate levels being generally higher and nitrite levels being generally lower in old rats. However, there were no differences in the levels of nitrate-transporting proteins and nitrate reductase between old and young rats, with the exception of in the eye. Increased dietary nitrate led to significantly higher nitrate enrichment in the majority of old rat organs compared to young rats, suggesting that the nitrate reduction pathway is not affected by aging. We hypothesize that age-related NO accessibility changes originate either from the NOS pathway or from changes in NO downstream signaling (sGC/PDE5). Both possibilities need further investigation.
Keywords:
nitric oxide
;
nitrate
;
nitrite
;
aging
1. Introduction
Nitric oxide is one of the most versatile signaling molecules in nature. Its short-lived nature and reactivity with other free radicals predetermine the needs of its synthesis in situ, without the possibility of storage. The origin of NO in the mammalian body depends on oxygen availability in tissues. NO can either be directly synthetized by a family of nitric oxide synthases (NOS) [ 1 ] or created during the two-step reduction of nitrate to nitrite by molybdenum-containing proteins (xanthine oxidoreductase (XOR), aldehyde oxidase (AO), sulfite oxidase (SO) and mitochondrial amidoxime-reducing component (mARC)) [ 2 ] and then the reduction of nitrite to NO by molybdenum- or heme-containing proteins [ 3 ]. The second pathway is predominant in a low-oxygen environment, such as that found in the tissues of most internal organs [ 4 ]. Recently, we showed that some organs, such as skeletal muscle, contain higher levels of nitrate, and can be regarded as a global body nitrate reservoir [ 5 , 6 ]. Other organs, such as the liver, show higher XOR activity/levels and can be regarded as sites of nitrate reduction to nitrite [ 7 ]. After nitrate reduction by XOR, nitrite is then transported by the bloodstream and reduced to NO on the site of demand by deoxy heme-proteins [ 8 , 9 , 10 , 11 ] or further reduced to NO by XOR or AO tissue [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. On the cellular level, nitrate/nitrite transporters, such as sialin and CLC-proteins, shuffle these ions into and from cells [ 19 , 20 , 21 , 22 ]. To complete the picture, nitrate originates from several sources, such as diet, the oxidation of nitrite and unused NO by oxyhemoglobin and oxymyoglobin, and the direct synthesis of nitrate by NOS, mainly NOS1, during its so-called futile cycle [ 23 , 24 , 25 ].
Here, we investigate how this delicate balance of the storage, transport and reduction of nitrate/nitrite ions is affected/disturbed by processes naturally occurring during aging. We concentrate mainly on changes in the skeletal muscle, cardiovascular system, brain, and eye as these organs and systems (in humans at least) are likely to be the most affected by age-related conditions, such as sarcopenia, cardiovascular and neurodegenerative/cognitive diseases and/or glaucoma or macular degeneration.
We studied these age-related changes at the baseline state and after dietary intervention where animals consumed a high nitrate diet for 5 days. The main purpose of this approach was to disturb the existing baseline equilibrium to determine whether nitrate/nitrite physiology and metabolism are affected by age. Secondly, dietary nitrate supplementation is used quite frequently in the exercise field in order to improve endurance [ 26 , 27 ]. It has been known to decrease elevated blood pressure [ 28 ] and there is some evidence that it could be beneficial in improving several disease states, such as PAD [ 29 ] and Becker muscular dystrophy [ 30 ]. All these facts are highly relevant to the aging human population.
2. Materials and Methods
Two sets of healthy Wistar rats (Envigo, Indianapolis, IN, USA) aged 3 (“young”, n = 16, 8 males/8 females, weight 240 g) and 18 (“old”, n = 8, 4 males/4 females, weight 350–450 g) months, respectively, were randomly divided into 2 groups: a control group eating a regular rat diet (NIH-07, Envigo, Indianapolis, IN, USA) and a nitrate-supplemented group with 1 g/l of NaNO 3 (Sigma, St. Louis, MO, USA) added to their drinking water. We chose the dose and duration of nitrate supplementation based on our previous studies where such treatment led to significantly elevated nitrate/nitrite levels in rat organs [ 6 , 31 , 32 , 33 ]. The size of the rat groups was determined based on previous reports [ 34 , 35 ]. After 5 days of dietary intervention, rats were euthanized, samples from organs and blood were collected, and nitrate and nitrite levels in plasma and tissues were measured using chemiluminescence, as described in detail in our previously published work [ 5 , 36 ]. The results are shown as mean ± SD. Statistical analysis was performed using ANOVA, p < 0.05.
Details regarding all materials, data and protocols associated with the publication are available upon written request. All animal procedures were approved by the NIDDK Animal Care and Use Committee (protocol number K049-MMB-20) and carried out according to recommendations in the Guide for the Care and Use of Laboratory Animals of NIH. This animal study is reported in accordance with ARRIVE guidelines.
3. Results
Note: We organized each of the two panels in Figure 1 , Figure 2 and Figure 3 into three groups. The first group—liver, plasma and gluteus—represent events at muscle and whole-body levels; the second group—eye, lacrimal glands and brain—mirror events at the neuronal level; and the third group—salivary glands, heart, aorta and vena cava, together with plasma—reflect the cardiovascular system.
Figure 1. Nitrate ( A ) and nitrite ( B ) levels in young rats at baseline (light gray bar) and after nitrate supplementation for 5 days (dark gray bar). Values are presented as average ± SD, n = 4 for all organs, * denotes p < 0.05.
Figure 2. Nitrate ( A ) and nitrite ( B ) levels in old rats at baseline (light green bar) and after nitrate supplementation for 5 days (dark green bar). Values are presented as average ± SD, n = 4 for all organs, * denotes p < 0.05.
Figure 3. Ratios of nitrate ( A ) and nitrite ( B ) contents in organs and tissues of old vs. young rats at baseline (light orange bars) and after 5 days of nitrate supplementation (dark orange bars). Ratios were calculated as concentrations of nitrate (nitrite) in old rat organs/nitrate (nitrite) in young rat organs at both dietary conditions. Ratio < 1 reflects higher content of nitrate (nitrite) in young rat tissues; ratio > 1 reflects higher content of nitrate (nitrite) in old rat tissues.
3.1. Nitrate and Nitrite in Young Rats at Baseline vs. after Nitrate Treatment
Nitrate and nitrite levels at baseline and after 5 days of nitrate treatment for young rats are plotted in Figure 1 . As expected, dietary nitrate supplementation led to, in most cases, a significant increase in nitrate and nitrite levels in the studied organs and tissues.
At baseline in young rats (
Figure 1
A, light gray bars), we observed a nitrate gradient from gluteus to plasma to liver, with nitrate content per gram tissue highest in the gluteus (34.2 ± 16.5 nmol/g), intermediate in plasma (15.1 ± 3.9 nmol/g) and lowest in the liver (11.3 ± 3.5 nmol/g). The values for nitrate in several other muscles (tibias anterior (TA), extensor digitorum longus (EDL), soleus, gastrocnemius) are summarized in
Supplementary Table S1
. Baseline nitrate concentrations in the eyes, lacrimal glands and brains of young rats were 8.5 ± 0.4; 15.5 ± 4.5 and 16.4 ± 5.9 nmol/g, respectively. Nitrate concentrations in the salivary glands, heart, aorta and vena cava were 8.4 ± 3.5, 22.9 ± 3.6, 10.5 ± 2.3 and 20.9 ± 7.2 nmol/g, respectively.
After dietary nitrate treatment, nitrate contents in young rats increased several folds in all organs and tissues when compared to baseline values (
Figure 1
A, dark gray bars). Plasma, as a nitrate carrier, increased to 58.8 ± 30.8 nmol/g, gluteus increased to 48.8 ± 10.4 nmol/g and liver increased to 15.7 ± 6.3 nmol/g. The values of nitrate concentration in several other muscles after supplementation (tibias anterior (TA), extensor digitorum longus (EDL), soleus, gastrocnemius) are summarized in
Supplementary Table S1
. Nitrate concentrations were 18.9 ± 7.4 nmol/g in the brain, 15.5 ± 2.0 nmol/g in the eye and 26.2 ± 9.1 nmol/g in the lacrimal glands. The nitrate concentrations across cardiovascular organs were elevated compared to baseline values to similar values across all organs, with 27.5 ± 5.9 nmol/g in the vena cava, 26.0 ± 10.1 nmol/g in the heart, 24.6 ± 10.2 in the aorta and 20.1 ± 9.4 nmol/g in the salivary glands.
The relative enrichment of all organs by nitrate caused by dietary nitrate supplementation is summarized in Supplementary Table S2A . As expected, the greatest nitrate increase was observed in plasma (3.9-fold), followed by the salivary glands (2.4-fold), aorta (2.3-fold), eye (1.8-fold), lacrimal glands (1.7-fold), muscle (1.4-fold), liver (1.4-fold), vena cava (1.3-fold), brain (1.2-fold) and heart (1.1-fold).
In general, nitrite at baseline in the tissues of young rats (
Figure 1
B, light gray bars) was much more uniformly distributed than nitrate. Nitrite concentrations in the liver and gluteus were similar (0.36 ± 0.11 and 0.40 ± 0.14 nmol/g, respectively), which was in the same range as values for other muscle groups (TA, EDL, soleus, gastrocnemius; see
Supplementary Table S1B
). Plasma contained 0.24 ± 0.08 nmol/g of nitrite, which was the lowest concentration from all studied organs and tissues. Nitrite concentration in the brain was 0.82 ± 0.38 nmol/g, which was the third highest of all the organs studied, with the lacrimal glands and eye containing 0.62 ± 0.11 and 0.25 ± 0.01 nmol/g, respectively. From the organs of the cardiovascular system, the vena cava was the tissue with the highest concentration of nitrite (1.65 ± 0.42 nmol/g), followed by the aorta (1.02 ± 0.43 nmol/g). The heart and salivary glands contained 0.32 ± 0.09 and 0.32 ± 0.13 nmol/g of nitrite, respectively.
After dietary nitrate treatment, nitrite contents in young rats increased several folds in all organs and tissues when compared to baseline values (
Figure 1
B, dark gray bars). Nitrite content increased to 0.59 ± 0.15 nmol/g in plasma, 0.76 ± 0.20 nmol/g in the gluteus and 0.44 ± 0.14 nmol/g in the liver. The values for nitrate in several other muscles (tibias anterior (TA), extensor digitorum longus (EDL), soleus, gastrocnemius) are summarized in
Supplementary Table S1
. The concentration of nitrite increased to 0.92 ± 0.14 nmol/g in the brain, 0.78 ± 0.29 nmol/g in the lacrimal glands and 0.49 ± 0.11 nmol/g in the eye. The circulatory system organs reached levels of 2.31 ± 0.86 nmol/g in the aorta, 1.79 ± 0.22 nmol/g in the vena cava, 0.43 ± 0.19 nmol/g in the salivary glands and 0.41 ± 0.10 in the heart. The relative enrichment of all organs by nitrite caused by dietary nitrate supplementation is summarized in
Supplementary Table S2B
. The greatest increase was observed in plasma (2.5-fold), followed by the aorta (2.3-fold), eye (2-fold), gluteus (1.9-fold), salivary glands (1.3-fold), heart (1.3-fold), lacrimal glands (1.3-fold), liver (1.2-fold), brain (1.1-fold) and vena cava (1.1-fold).
3.2. Nitrate and Nitrite in Old Rats at Baseline vs. after Nitrate Treatment
Nitrate and nitrite levels measured at baseline and after 5 days of nitrate treatment for old rats are plotted in Figure 2 . As expected, and similar to young rats, dietary nitrate supplementation led to, in most cases, a significant increase in nitrate and nitrite detected in the studied organs and tissues of old rats.
At baseline ( Figure 2 A, light green bars), liver, plasma and gluteus nitrate levels reached 12.5 ± 7.2, 7.6 ± 1.6 and 50.0 ± 16.6 nmol/g tissue, respectively. The nitrate concentrations for other muscle groups studied (TA, EDL, soleus, gastrocnemius) are shown in Supplementary Table S1A . Nitrate concentrations in the eyes, lacrimal glands and brains of old rats were 1.04 ± 0.1, 11.1 ± 5.3 and 26.9 ± 4.5 nmol/g, respectively. Nitrate concentrations in the salivary glands, heart, aorta and vena cava reached 10.3 ± 6.6, 14.7 ± 6.0, 8.9 ± 1.5 and 13.2 ± 7.2 nmol/g, respectively. After 5 days of nitrate supplementation, there was a major increase in nitrate concentrations in all measured organs ( Figure 2 A, dark green bars). Nitrate concentrations increased to 65.8 ± 33.9 nmol/g in plasma, as a major dietary nitrate transporter; 57.1 ± 24.4 nmol/g in the gluteus; and 27.4 ± 10.5 nmol/g in the liver. The nitrate concentrations in other muscle groups (TA, EDL, soleus, gastrocnemius) are shown in Supplementary Table S1A . Nitrate levels increased to 62.6 ± 15.5 nmol/g in the lacrimal glands, 29.3 ± 4.5 nmol/g in the brain to and 3.3 ± 1.6 nmol/g in the eye. The circulatory system organs reached values of 45.0 ± 20.8 nmol/g in salivary glands, 34.9 ± 10.7 in the aorta, 23.3 ± 9.4 in the heart and 21.2 ± 8.8 nmol/g in the vena cava. The relative enrichment of all organs by nitrate caused by dietary nitrate supplementation is summarized in Supplementary Table S2A and plotted in Supplementary Figure S3A . Five days of dietary nitrate treatment led to a major increase in nitrate contents in all organs and tissues of old rats, with the greatest increase observed in plasma (8.7-fold), followed by the lacrimal glands (5.6-fold), salivary glands (4.4-fold), aorta (3.9-fold), eye (3.3-fold), vena cava (1.6-fold), heart (1.6-fold), gluteus (1.1-fold) and brain (1.1-fold).
Baseline nitrite contents in the organs of old rats (
Figure 2
B, light green bars) were in a similar range to those of young rats. Nitrite concentrations in the liver, plasma and gluteus were uniform, with 0.24 ± 0.07, 0.27 ± 0.03 and 0.25 ± 0.07 nmol/g, respectively. The nitrite values for other muscle groups (TA, EDL, soleus, gastrocnemius) are in
Supplementary Table S1B
. Similar to young rats, the brains of old rats contained the second-highest nitrite concentration (0.96 ± 0.22 nmol/g). Nitrite in the lacrimal glands reached 0.31 ± 0.18 nmol/g, and nitrite concentrations in the eye were the lowest of all studied organs, at only 0.18 ± 0.06 nmol/g. From the organs of the cardiovascular system, the vena cava was the tissue with the second highest concentration of nitrite (0.77 ± 0.24 nmol/g), followed by the aorta (0.53 ± 0.11 nmol/g), heart (0.37 ± 0.05 nmol/g), plasma (0.27 ± 0.03 nmol/g) and salivary glands (0.20 ± 0.05 nmol/g).
After nitrate supplementation, nitrite values increased in all organs (
Figure 2
B, dark green bars). The nitrate concentration was 0.46 ± 0.08 nmol/g in plasma, 0.40 ± 0.11nmol/g in the liver and 0.30 ± 0.04 nmol/g in the gluteus (see
Supplementary Table S1B
for values in TA, EDL, soleus and gastrocnemius). The largest increase in nitrite concentration in old rats was noted in the brain (1.13 ± 0.54 nmol/g), while that in the lacrimal glands and eye reached 0.37 ± 0.34 and 0.24 ± 0.02 nmol/g, respectively. On the circulatory side, there was a large increase in nitrate concentration in the aorta (1.48 ± 0.58 nmol/g), followed by the vena cava (0.99 ± 0.82 nmol/g), heart (0.69 ± 0.20 nmol/g) and salivary glands (0.26 ± 0.08 nmol/g).
After dietary nitrate treatment, nitrite contents in old rats increased in all organs and tissues compared to baseline values (
Supplementary Table S2B and Supplementary Figure S3B
). The greatest increase was observed in the aorta (2.8-fold), followed by the heart (1.9-fold), plasma (1.7-fold), liver (1.7-fold), eye (1.3-fold), salivary glands (1.3-fold), vena cava (1.3-fold), gluteus (1.2-fold), lacrimal glands (1.2-fold) and brain (1.2-fold). In skeletal muscles, nitrite increased only modestly, by 1.2-fold in the gluteus, with similar modest increases in all other measured skeletal muscles (TA, EDL, soleus, gastrocnemius).
3.3. Nitrite Levels in Young vs. Old Rats at Baseline and after Nitrate Treatment
We calculated the ratios of nitrate and nitrite concentrations related to age at baseline and after 5 days of dietary nitrate supplementation ( Figure 3 ) to compare the effects of nitrate and nitrite in these groups. Supplementary Figures S1 and S2 present the absolute values of nitrate and nitrite at baseline and after nitrate supplementation that were already described in previous sections for young and old rats. The calculated ratios are summarized in Supplementary Table S2A,B .
The distribution of nitrate in the bodies of old rats differed from that in young rats at baseline levels ( Figure 3 A, light orange bars). Old rats had higher nitrate concentrations in the brain (1.6-fold), gluteus (1.5-fold) and liver (1.1-fold) compared to young rats. In all other organs, nitrate concentrations were lower in old rats than in young rats in the aorta (0.9-fold), lacrimal glands (0.7-fold), heart (0.6-fold), vena cava (0.6-fold) and plasma (0.5-fold), with the most significant difference observed in the eye (only 0.1-fold).
After nitrate supplementation (
Figure 3
A, dark orange bars), differences were attenuated, but some persisted. Nitrate concentrations in salivary and lacrimal glands in old rats became higher than those in young rats (2.4- and 2.2-fold, respectively) and in the liver, the difference reached 1.8-fold. The brains and aortas of old rats had 1.6- and 1.4-fold higher nitrate contents, respectively, than those of young rats. The gluteus had a 1.2-fold enrichment and plasma had a 1.1-fold enrichment. The heart, vena cava and, in particular, the eye, had lower nitrate contents than their young counterparts, with 0.9-, 0.8- and 0.21-fold, respectively.
At baseline levels, there were substantial differences in nitrite distributions among the organs of young rats compared to old rats ( Figure 3 B, light orange bars). Old rats had higher contents of nitrite in the plasma (1.1-fold), brain (1.2-fold) and heart (1.2-fold). Nitrite concentrations were lower in the organs of old rats than in those of young rats for all other organs, including the eye (0.7-fold), liver (0.7-fold), gluteus (0.6-fold), salivary glands (0.6-fold), aorta (0.5-fold), lacrimal glands (0.5-fold) and vena cava (0.5-fold).
After nitrate supplementation, the differences persisted, but were attenuated ( Figure 3 B, dark orange bars). Old rats still had higher nitrate contents in the heart (1.7-fold) and brain (1.2-fold), but a comparable amount of nitrate in the liver (0.9-fold). Nitrite concentrations were lower in old rats in all other organs and tissues, including the plasma (0.8-fold), aorta (0.6-fold), vena cava (0.6-fold), salivary glands (0.6-fold), eye (0.5-fold), lacrimal glands (0.5-fold) and gluteus (0.4-fold).
3.4. Protein Level Changes in Young and Old Rats at Baseline and after Nitrate Treatment
We evaluated the levels of proteins involved in nitrate transport (sialin) and the reduction of nitrate to nitrite and nitrite to NO (xanthine oxidoreductase, XOR) in the liver, gluteus and eye using Western blotting ( Figure 4 ). Except for the eye, there was no difference in sialin or XOR expression between old and young rats. After nitrate supplementation, there was no significant change in the levels of sialin or XOR compared to baseline levels.
Figure 4. Western blot for sialin and xanthine oxidoreductase (XOR) in the liver, eye and gluteus of young and old rats ( A ); relative expression levels of sialin and XOR in liver, eye and gluteus of young rats (light gray bars) and old rats (dark gray bars) ( B ), n = 4 for old and young rats, * denotes p < 0.05.
4. Discussion
Over the past decade, there has been a noticeable shift of focus away from NOS enzymes as an almost exclusive source of NO towards the nitrate/nitrite reductive pathway as an equally important NO generator. Being less reactive than NO, both ions serve as an almost-immediate source of NO and nitrate in particular can be stored in the body and used when the need arises. Based on our previous work with rodents, we showed that nitrate concentrations in skeletal muscle (in particular, in the gluteus) exceed that observed in the bloodstream and other tissues several-fold [ 5 ]. We formulated a hypothesis postulating that the skeletal muscle tissue as a mammalian body nitrate reservoir is freely accessible to the bloodstream to be transported and used in sites of NO deficiency and, similar to the liver [ 7 ], the skeletal muscle itself can generate nitrite/NO by the reduction of nitrate to nitrite and NO, using XOR as a nitrate reductase [ 37 ]. We also showed that this reservoir reacts to dietary nitrate changes by either increasing its storage (high nitrate diet) or releasing more nitrate into the bloodstream for use (dietary nitrate deficiency) [ 31 , 33 ]. We confirmed a similar dynamic in humans [ 27 , 38 , 39 ]. Here, we discuss the effect of age on the levels/availability of nitric oxide metabolites in healthy, aged rats.
4.1. Baseline Conditions
4.1.1. Baseline Nitrate
Consistent with our previous reports, nitrate distribution among the organs and tissues of young rats was nonuniform, with nitrate concentration gradients present from the gluteus through plasma and liver, with gluteus nitrate concentrations 3-fold higher than those in the liver and plasma nitrate 1.4-fold higher than that in the liver. This is consistent with the idea of skeletal muscle serving as a nitrate reservoir, a hypothesis we previously formulated and investigated [
5
,
31
,
33
,
37
]. However, this picture significantly differs for the group of old rats at baseline. Here, the gluteus still seems to act as a nitrate reservoir, with a 4-fold excess of nitrate over the liver, with other collected muscles (TA, EDL, soleus, gastrocnemius) supporting this finding (6.5-, 5.4-, 5.4- and 3.2-fold, respectively). However, nitrate levels in plasma are significantly lower than those in the liver or gluteus (0.6- and 0.2-fold, respectively). Interestingly, when compared to young rats, nitrate levels in the gluteus and brains of old rats were greater by 1.5- and 1.6-fold, respectively, but the blood of old rats contained only half the nitrate levels (0.5-fold) of young rats. Other significant changes included those observed in the eye and vena cava (0.1-fold and 0.6-fold changes in old rats vs. young ones).
A first look at the picture reveals that, in old rats, the function of skeletal muscle as a place for nitrate storage, and likely that of the liver as a nitrate reduction “factory,” seems to be intact, as the nitrate concentration gradient from muscle to liver persists, implying the existence of active nitrate transport between tissues and blood. However, it seems that the ability of blood to act as a transporting medium in old rats is significantly diminished for reasons that are not yet well understood. There are no differences in the expression of the nitrate transporter (sialin) or nitrate reductase (XOR) proteins in the skeletal muscle (or liver), as revealed by the Western blot results; thus, the levels of transporting and reducing proteins are likely unaffected by age in these tissues. Currently, we do not have information about their activity levels, which could be playing a significant role. We can only speculate on what could prevent the diffusion of stored nitrate from muscle into the bloodstream, for example, age-related changes in the vessel walls themselves [ 40 ]. Another possibility is a lower supply of endogenously generated NO and nitrate by endothelium and other organs due to age-related changes in NOS expression/activity in general and, in particular, in vessel walls [ 41 ]. Diminishing NOS activity in blood vessels would result in lower NO (and nitrate) levels in the blood since NOS is one of the major endogenous nitrate sources via its futile cycle [ 24 ]. One factor in favor of such changes might be that all other parts of the circulatory system of old rats (heart, aorta, vena cava) showed slightly diminished nitrate concentrations. One should also keep in mind the possibility of increased oxidative stress due to NOS uncoupling and increased XO activity in the vascular system [ 42 , 43 , 44 ], which may add to changes in NO production on both sides of the pathway (NOS- and nitrate-related). As this study is the first attempt to establish the array of changes in nitrate metabolism related to aging, unfortunately, we can only offer the aforementioned “educated guesses,” as more detailed work related to the NOS part of the NO equation must be conducted in order to answer such questions.
Possibly one of the most surprising findings here is that the brains of old rats are significantly enriched by nitrate and their eyes are dramatically depleted of nitrate compared to their young counterparts. The brain and eye both seem to be very good candidates for the use of the nitrate reduction pathway to support function [
45
,
46
,
47
]. The eye is also the only place with significantly altered expression of sialin and XOR: expression of both was 2.6- and 2-fold greater, respectively, in old rats compared to young rats, which is not that surprising when thinking about the importance of NO for eye function [
48
]. More research must be conducted to understand the actions and functional significance of NO and the consequences of a lack of NO in the eye.
4.1.2. Baseline Nitrite
Nitrite was, in general, almost uniformly distributed among the plasma, eyes, livers, salivary glands and hearts of young rats. This picture is consistent with the notion of the “local” use of nitrate by organs—nitrate is reduced by residing nitrate reductase (XOR and possibly other MoCo-proteins) into nitrite (and then to NO) when and where the need for NO arises. We also noticed that nitrite is elevated in the brains and hearts of old rats compared to young ones. The brain is the most energy-demanding organ in mammals [
49
], with extensive blood flow that is very tightly regulated to ensure a constant supply of oxygen and nutrients [
50
]. The NO/endothelin system plays a crucial role in balancing the vasodilation/vasoconstriction of blood vessels and ensuring constant cerebral blood flow. As we showed in our previous work, nitrite is present in cerebral circulation and is one of the sources of NO that can compensate for impaired NOS function [
46
]. Therefore, one can easily expect and explain a 3.4-fold increase in nitrite concentrations in this tissue when compared to plasma. A similar explanation could be true for nitrite increases in the aorta and vena cava (4.3- and 6.9-fold increases over plasma, respectively). As two major blood vessels, the aorta and vena cava diameters and the associated blood pressure within them must also be under tight control to assure the proper functioning of all organs. However, this hypothesis requires experimental evidence.
Nitrite in old rats follows the same distribution pattern as that described for young rats. Nitrite levels in old rat organs tended, in general, to be lower than those in young rats, except for slightly elevated nitrite levels in the plasma, brain and heart (1.1-, 1.2- and 1.2-fold increases, respectively). This would suggest that XOR reduces nitrate to nitrite with similar (or better) efficiency in old and young animals, as nitrate levels in old rats are, in general, higher than those in young rats. However, because the XOR active site (MoCo cofactor) is used for nitrate- and nitrite-reductase activity, it is possible that the higher nitrate contents in old rats might partially inhibit XOR nitrite reduction in NO, as reported in rat vessels by [ 51 ]. NO deficiency related to older age could also result from increased oxidative stress leading to a dysfunctional NOS system [ 52 ]. Downstream signaling, namely, soluble guanyl cyclase (sGC), or other members of the cascade (such as PDE5) could also malfunction in older age [ 53 , 54 , 55 , 56 , 57 , 58 ]. We consider that this might be the most likely explanation for our findings, but this hypothesis requires further experimental evidence to be confirmed.
4.2. Changes following Dietary Nitrate Supplementation
4.2.1. Nitrate after Dietary Supplementation
When fed a high nitrate diet, nitrate levels increased in all organs of young rats, as expected based on previously reported results. The most significant nitrate increase was observed in plasma (a 3.9-fold increase over baseline values), with other significant increases observed in the salivary glands, aorta, eye and lacrimal glands (2.4-, 2.3-, 1.8 and 1.7-fold, respectively). Nitrate levels also increased in the gluteus (1.4-fold), as well as in all other examined muscles (TA, EDL, soleus, gastrocnemius; 2.1-, 2-, 1.6- and 1.6-fold, respectively). Similarly, in old rats, increased access to dietary nitrate led to a significant increase in the nitrate concentrations of all organs except the brain (which showed only a slight increase over baseline values), with the most notable changes in the plasma (8.7-fold), lacrimal glands (5.7-fold), salivary glands (4.4-fold) and aorta (3.9-fold). Nitrate levels in the gluteus increased slightly (1.1-fold), with similar increases observed in other muscles (TA, soleus, gastrocnemius; 1.6-, 1.1- and 1.1-fold, respectively). This suggests that nitrate transport into and from plasma to cells (sialin, CLC-family of proteins [
59
]) is well functioning even in old age. Interestingly, in contrast to humans, neither young nor old rat salivary glands showed marked increases in nitrate or nitrite. This could be related to a low contribution of the rat oral microbiome to the nitrate–nitrite–NO reductive pathway [
60
]. When compared across age groups, nitrate levels in old rats after supplementation were higher than those in young rats, with the notable exception of the eye. This was related to the generally higher nitrate baseline values observed in old rats. Based on the above results, we believe that the organs of old rats are just as able as those of young rats to transport, store and use nitrate. We also believe that differences in NO availability related to aging are likely due either to NOS-related NO generation or to NO downstream signaling.
4.2.2. Nitrite after Dietary Supplementation
Increased access to nitrate led to increased nitrite concentrations in all organs of young and old rats. Similar to the results measured at baseline, the resulting concentrations of nitrite after a high nitrate diet were lower in old rats than in young rats, with the exception of the brain and heart, where nitrite in old rat organs exceeded 1.2-fold and 1.7-fold, respectively, that in young rats. In general, there could be at least two underlying explanations: that less nitrate is reduced to nitrite by XOR or more nitrite is oxidized back to nitrate if conditions are more pro-oxidative. In either case, this would lead to (apparent) nitrite deficiency. Another possibility is that the nitrate reductase activity of XOR is decreased in old age. All the above hypotheses must be explored experimentally.
4.2.3. Summary and Hypothesis
Our findings and hypotheses are summarized in
Figure 5
. Based on our data, nitrate seems to accumulate in most of the organs of old rats, either from dietary nitrate or by increased NOS futile cycle activity. Despite higher nitrate concentrations in old rats, nitrite concentrations in the majority of their organs were relatively lower when compared with young rats. We believe that a major source of nitrite for rat organs is the nitrate reductase activity of XOR and other MoCo proteins since the oral microbiome is not a significant contributor to nitrite levels in rats [
55
]. There are several possible causes that could contribute to the observed nitrite deficiency or depletion in old rats. Lower XOR nitrite reductase activity would lead to nitrite deficiency [
46
], while increased nitrite reduction to NO by heme proteins and/or increased nitrite oxidation back to nitrate (in sites with higher oxidative stress in old rats) would cause nitrite depletion. At this point, we can only speculate about the reason; more experiments are needed to elucidate the underlying processes.
Figure 5. Schematic representation of differences in the NO metabolic pathway of old and young rats at baseline levels. Levels of nitrate and nitrite in young rats are plotted as “standards,” they are used only as a reference for the relative changes observed/proposed in old rats, with no other associated meaning.
NOS enzymes are also equally important contributors to NO balance and evaluations of the relative contributions of NOS vs. dietary nitrate to NO balance in old vs. young rats are needed. The results could generate new hypotheses about general changes in the NO pathway (including both sources—NOS and nitrate) due to the aging process.
Equally importantly, one could also hypothesize that additional changes in downstream signaling require consideration, especially at the level of soluble guanyl cyclase (sGC), which is susceptible to inactivation due to its heme oxidation and/or PDE5, which destroys cGMP [ 56 ].
5. Conclusions
Aging is a natural process that brings its own irreversible challenges and manifests itself by changes occurring in all metabolic pathways. One of the changes seems to be decreased access to NO. Previously, we studied the reductive pathways of NO production that use nitrate as a source of NO. We found that, in young, healthy rats, nitrate is sequestered from the bloodstream and stored mainly in skeletal muscle tissue. When there is a dietary shortage of nitrate (or an increased local NO need by some metabolic pathway), the muscle can release the stored nitrate into the bloodstream, transport it to the site of need and use it to fuel its reduction to nitrite and NO. The muscle itself uses the stored nitrate to supply/supplement NO for its functioning, especially during exercise. In the present study, we investigated how this delicate balance of the storage, transport and reduction of nitrate/nitrite ions is affected/disturbed by processes naturally occurring during aging. We concentrated mainly on changes in the skeletal muscle, cardiovascular system, brain and eye as these organs and systems (in humans at least) are likely most affected by age-related conditions, such as sarcopenia, cardiovascular and neurodegenerative/cognitive diseases and/or glaucoma and macular degeneration.
We found that aging does not profoundly affect all of the processes related to the uptake and storage of nitrate as nitrate in the organs of old rats increased in similar patterns to those observed in young rats. The main difference at baseline conditions was the nitrate and nitrite concentrations in the eye, which were significantly lower in old rats than in their young counterparts. Unexpectedly, the decrease of both ions in the eyes of old rats was accompanied by significantly higher expression of the nitrate transporter, sialin, and nitrate reductase, XOR. Interestingly, worsening eyesight and some ocular diseases (glaucoma, macular degeneration) in humans are one of the first changes related to aging. We are currently working on elucidating the role of the nitrate/nitrite pathway in the eye. Additionally, currently, there is little doubt that, with aging, the mammalian body experiences a deficit of NO that might eventually lead to an array of metabolic diseases and syndromes. However, the conclusion from our present work is that as we age, the main changes in NO production are not related directly to the NO reductive pathway but might be caused either by irreversible changes in NOS-related NO production (so-called “endothelium dysfunction”) or by changes in downstream NO signaling—especially by the oxidation of sGC (or increase in the fraction of apo-sGC) or the increased activity of PDE5 [
61
], as schematically expressed in
Figure 5
. The first of these hypotheses (aging does not alter the nitrate reductive pathway) leaves open the possibility of using dietary nitrate supplementation to compensate for changes in NOS-related NO production. If, after NO levels increase, there is still an apparent NO deficiency, we believe that this could be a sign of dysregulated downstream signaling, which is a condition requiring a different approach, depending on the exact site of malfunctioning. One could then start considering the use of PDE5 inhibitors or sGC activators. However, currently, there is not enough experimental evidence in favor of either of these hypotheses.
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Figure 1. Nitrate ( A ) and nitrite ( B ) levels in young rats at baseline (light gray bar) and after nitrate supplementation for 5 days (dark gray bar). Values are presented as average ± SD, n = 4 for all organs, * denotes p < 0.05.
Figure 2. Nitrate ( A ) and nitrite ( B ) levels in old rats at baseline (light green bar) and after nitrate supplementation for 5 days (dark green bar). Values are presented as average ± SD, n = 4 for all organs, * denotes p < 0.05.
Figure 3. Ratios of nitrate ( A ) and nitrite ( B ) contents in organs and tissues of old vs. young rats at baseline (light orange bars) and after 5 days of nitrate supplementation (dark orange bars). Ratios were calculated as concentrations of nitrate (nitrite) in old rat organs/nitrate (nitrite) in young rat organs at both dietary conditions. Ratio < 1 reflects higher content of nitrate (nitrite) in young rat tissues; ratio > 1 reflects higher content of nitrate (nitrite) in old rat tissues.
Figure 4. Western blot for sialin and xanthine oxidoreductase (XOR) in the liver, eye and gluteus of young and old rats ( A ); relative expression levels of sialin and XOR in liver, eye and gluteus of young rats (light gray bars) and old rats (dark gray bars) ( B ), n = 4 for old and young rats, * denotes p < 0.05.
Figure 5. Schematic representation of differences in the NO metabolic pathway of old and young rats at baseline levels. Levels of nitrate and nitrite in young rats are plotted as “standards,” they are used only as a reference for the relative changes observed/proposed in old rats, with no other associated meaning.
| https://www.mdpi.com/2072-6643/15/11/2490/htm |
Retirada rápida versus lenta de los fármacos antiepilépticos - Ayuga Loro, F - 2020 | Cochrane Library
Anticonvulsants [*administration & dosage, therapeutic use]; Drug Administration Schedule; Epilepsy [*drug therapy]; Quality of Life; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Risk Assessment; Time Factors
Retirada rápida versus lenta de los fármacos antiepilépticos
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Serra 2005 {published data only}
Serra JG, Montenegro MA, Guerreiro MM.
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Randomised study of antiepileptic drug withdrawal in patients in remission
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Peters AC, Brouwer OF, Geerts AT, Arts WF, Stroink H, Van Donselaar CA.
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Gasparini S, Ferlazzo E, Giussani G, Italiano D, Cianci V, Sueri C, et al.
Rapid versus slow withdrawal of antiepileptic monotherapy in 2‐year seizure‐free adult patients with epilepsy (RASLOW) study: a pragmatic multicentre, prospective, randomized, controlled study
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Bouma PA, Peters AC, Arts RJ, Stijnen T, Van Rossum J.
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Journal of Neurology, Neurosurgery, and Psychiatry
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50
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Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P.
Patterns of treatment response in newly diagnosed epilepsy
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Callaghan N, Garrett A, Goggin T.
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New England Journal of Medicine
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Duncan JS, Shorvon SD.
Rates of antiepileptic drug reduction in active epilepsy – current practice
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Epilepsy Research
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1
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Emerson R, D'Souza BJ, Vining EP, Holden KR, Mellits ED, Freeman JM.
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Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al.
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Ranganathan 2004
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Characteristics of studies
Characteristics of included studies [ordered by study ID]
excluded studies
ongoing studies
Serra 2005
MethodsRandomized, unblinded, prospective studyInclusion criteria: diagnosis of epilepsy and seizure control by an AED for ≥ 2 years.2 study arms: 1‐month AED withdrawal group (rapid tapering) or 6‐month AED withdrawal group (slow tapering).Type of randomization not specified.Mean duration of follow‐up: 54 months (range: 6 months to 4 years and 3 months).ParticipantsNumber of participants: 5733 boys and 24 girlsRapid‐tapering group: 30 participants (17 boys and 13 girls)Slow‐tapering group: 27 participants (16 boys and 11 girls)EEG was normal in 41 participants and abnormal in 15 participants. In 1 participant, EEG information was not available.All participants received 1 AED: 35 (61.4%) received carbamazepine, 12 (21%) phenytoin, 6 (10.5%) valproic acid, and 4 (7%) phenobarbital.No difference between the 2 groups according to age, gender, family history of epilepsy, type of epileptic syndrome, EEG abnormality, and AED (P > 0.05).InterventionsDrug tapering: rapid vs slowRapid tapering in 1 month (n = 30); dosage reduced by 25% every 10 days.Slow tapering in 6 months (n = 27); dosage reduced by 25% every 2 months.EEG was routinely performed prior to randomization.OutcomesProportion of participants remaining seizure free after AED withdrawalSeizure recurrenceTime for seizure recurrenceNotesTotal enrolled: not specifiedLoss to follow‐up: not specifiedNo flowchartClinical characteristics of participants were similar across study groups. Risk of bias Bias Authors' judgement Support for judgementRandom sequence generation (selection bias)Unclear riskInsufficient information to permit judgment.Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgment.Blinding (performance bias and detection bias)All outcomesHigh riskNo blinding.Blinding of participants and personnel (performance bias)All outcomesHigh riskNo blinding.Blinding of outcome assessment (detection bias)All outcomesHigh riskNo blinding.Incomplete outcome data (attrition bias)All outcomesUnclear riskInsufficient information to permit judgment.Selective reporting (reporting bias)Low riskNo evidence of selective reporting.Funding sourceLow riskReported (sponsored by a public Foundation).Conflicts of interestUnclear riskNot specified.
Tennison 1994
MethodsRandomized, unblinded, prospective study.2 study arms: 6‐week AED withdrawal group (rapid tapering) or 9‐month AED withdrawal group (slow‐tapering group).Randomization by 2 coin tosses. The 1st toss for rate of tapering. The 2nd toss for deciding when the withdrawal of AEDs would begin, after 2 or 4 years.Mean duration of follow‐up: 39 months (range: 11–105 months).ParticipantsTotal number enrolled: 149Mean age: 11 yearsLoss to follow‐up: 16Number actually participated: 13379 boys and 54 girlsRapid‐tapering group: 70 participants (41 boys and 29 girls)Slow‐tapering group: 63 participants (38 boys and 25 girls)Total number of seizures > 10 events in 51%. 54% were free of seizure for 2 years and 46% for 4 years.63% had focal seizures.Mean age of onset of seizure: 4 years in rapid‐tapering group, 5 years in slow‐tapering group.Approximately 40% had normal EEG at the start of tapering period.24 participants in rapid‐tapering group and 25 participants in slow‐tapering group received ≥ 2 AEDs.InterventionsDrug tapering: rapid vs slowRapid tapering in 6 weeks (n = 70); tapering divided into 3 equal periods of 2 weeks each; dose reduction 25% during each periodSlow tapering in 9 months (n = 63); tapering divided into 3 equal periods of 3 months each; dose reduction 25% during each periodWhen participant had > 1 AED, each drug was tapered sequentially, barbiturates were the last to be tapered.EEG was performed in all participants before tapering began.OutcomesProportion of participants remaining seizure free after AED withdrawalSeizure recurrenceNotes16 lost to follow‐up11 in rapid‐tapering group, 5 in slow‐tapering group63/81 in rapid‐tapering group, 48/68 in slow‐tapering group completed the protocol correctlyClinical characteristics of participants were similar across study groups. Risk of bias Bias Authors' judgement Support for judgementRandom sequence generation (selection bias)Low riskAdequate.Quote: "The eligible children were randomly assigned by two coin tosses."Allocation concealment (selection bias)Low riskInvestigators and participants were unable to predict to which group each of the participants was allocated.Blinding (performance bias and detection bias)All outcomesHigh riskNo blinding.Blinding of participants and personnel (performance bias)All outcomesHigh riskNo blinding.Blinding of outcome assessment (detection bias)All outcomesHigh riskNo blinding.Incomplete outcome data (attrition bias)All outcomesLow riskNo missing outcome data.Selective reporting (reporting bias)Low riskNo evidence of selective reporting.Funding sourceUnclear riskFunding not reported.Conflicts of interestUnclear riskNot specified.
AED: antiepileptic drug; EEG: electroencephalography; n: number of participants.
Characteristics of excluded studies [ordered by study ID]
ongoing studies
StudyReason for exclusionAidaros 2010Compared rapid vs slow withdrawal of AEDs but was a non‐randomized trial. Included 106 children with epilepsy in remission: 61 children underwent AEDs withdrawal over 6 months and 45 children underwent AED withdrawal over 3 months.Braathen 1996RCT in children, in whom AEDs were withdrawn after 1–3 years of seizure freedom. The drugs were tapered over 3‐month period. Study did not compare rapid vs slow withdrawal.Gebremariam 1999RCT on the withdrawal of AEDs in children after 18 or 24 months of seizure freedom. AEDs tapered sequentially if > 1 AED. Each drug tapered by 1/4 dose every 2 weeks until completely stopped. Hence, taper period was variable for each child. Study did not compare rapid vs slow withdrawal.Gherpelli 1992Cohort study not specifically assessing drug titration. Predictive model related to other variables.He 2016Cohort study addressing rapid vs slow withdrawal of AEDs.MRC 1991Large RCT investigating the effects of gradual AED withdrawal compared to continuation of AED in people who had been seizure free for 2 years. Study did not compare rapid vs slow withdrawal.Peters 1998RCT investigated withdrawal of AEDs in children who were seizure free for 6 or 12 months. Withdrawal was over 4 weeks. Study did not address the rapid vs slow withdrawal.Todt 1984RCT of AED withdrawal after 1, 2, 3, and 4 years. Study did not compare rapid vs slow withdrawal.Verrotti 2000RCT of AED withdrawal in children after 1 or 2 years of seizure freedom. Study did not compare rapid vs slow withdrawal.
AED: antiepileptic drug; RCT: randomized controlled trial.
Characteristics of ongoing studies [ordered by study ID]
Gasparini 2016
Trial name or titleRapid versus slow withdrawal of antiepileptic monotherapy in 2‐year seizure‐free adult patients with epilepsy (RASLOW) study.MethodsMulticenter, prospective, randomized controlled studyParticipantsAdults with focal or generalized epilepsy, who are seizure free on monotherapy for ≥ 2 yearsInterventionsSlow (160 days) vs rapid (60 days) withdrawal scheduleOutcomesPrimary outcome: time to seizure relapseSecondary outcomes: compliance to the assigned schedule; and occurrence of status epilepticus, seizure‐related injuries, and mortalityStarting dateNot reportedContact informationProfessor Umberto Aguglia,u.aguglia@tin.itNotes
Data and analyses
Comparison 1. Rapid versus slow antiepileptic drug (AED) withdrawal
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size1 Seizure freedom after 1 year of AED withdrawal Show forest plot1149Risk Ratio (M‐H, Fixed, 95% CI)0.76 [0.58, 1.01] Open in figure viewer Analysis 1.1Comparison 1 Rapid versus slow antiepileptic drug (AED) withdrawal, Outcome 1 Seizure freedom after 1 year of AED withdrawal.2 Seizure freedom after 2 years of AED withdrawal Show forest plot1149Risk Ratio (M‐H, Fixed, 95% CI)0.87 [0.58, 1.29] Open in figure viewer Analysis 1.2Comparison 1 Rapid versus slow antiepileptic drug (AED) withdrawal, Outcome 2 Seizure freedom after 2 years of AED withdrawal.3 Seizure freedom after 5 years of AED withdrawal Show forest plot1149Risk Ratio (M‐H, Fixed, 95% CI)1.40 [0.54, 3.65] Open in figure viewer Analysis 1.3Comparison 1 Rapid versus slow antiepileptic drug (AED) withdrawal, Outcome 3 Seizure freedom after 5 years of AED withdrawal.
| https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005003.pub3/references/es |
IJMS | Free Full-Text | Lipidomic Approaches to Study HDL Metabolism in Patients with Central Obesity Diagnosed with Metabolic Syndrome
The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors characterised by central obesity, atherogenic dyslipidaemia, and changes in the circulating lipidome; the underlying mechanisms that lead to this lipid remodelling have only been partially elucidated. This study used an integrated & ldquo;omics& rdquo; approach (untargeted whole serum lipidomics, targeted proteomics, and lipoprotein lipidomics) to study lipoprotein remodelling and HDL composition in subjects with central obesity diagnosed with MetS (vs. controls). Compared with healthy subjects, MetS patients showed higher free fatty acids, diglycerides, phosphatidylcholines, and triglycerides, particularly those enriched in products of de novo lipogenesis. On the other hand, the & ldquo;lysophosphatidylcholines to phosphatidylcholines& rdquo; and & ldquo;cholesteryl ester to free cholesterol& rdquo; ratios were reduced, pointing to a lower activity of lecithin cholesterol acyltransferase (LCAT) in MetS; LCAT activity (directly measured and predicted by lipidomic ratios) was positively correlated with high-density lipoprotein cholesterol (HDL-C) and negatively correlated with body mass index (BMI) and insulin resistance. Moreover, many phosphatidylcholines and sphingomyelins were significantly lower in the HDL of MetS patients and strongly correlated with BMI and clinical metabolic parameters. These results suggest that MetS is associated with an impairment of phospholipid metabolism in HDL, partially led by LCAT, and associated with obesity and underlying insulin resistance. This study proposes a candidate strategy to use integrated & ldquo;omics& rdquo; approaches to gain mechanistic insights into lipoprotein remodelling, thus deepening the knowledge regarding the molecular basis of the association between MetS and atherosclerosis.
Lipidomic Approaches to Study HDL Metabolism in Patients with Central Obesity Diagnosed with Metabolic Syndrome
by
Simona D’Amore 4,5 ,
Benjamin Jenkins 6 ,
Richard Kay 6 ,
Antonio Murgia 1 ,
Luis Vicente Herrera-Marcos 7 ,
Stefanie Neun 1 ,
Alice P. Sowton 8 ,
Zoe Hall 1,9 ,
Giuseppe Palasciano 5 ,
Frank Reimann 6 ,
Andrew Murray 8 ,
Patrizia Suppressa 2 ,
Carlo Sabbà 2 ,
Antonio Moschetta 2 ,
Albert Koulman 6 ,
Julian L. Griffin 1,9,10,*,† and
Michele Vacca 1,2,3,6,*,†
1
Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK
2
Department of Interdisciplinary Medicine, Clinica Medica “C. Frugoni”, Aldo Moro University of Bari, 70124 Bari, Italy
3
Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
4
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
5
Clinica Medica “A. Murri”, “Aldo Moro” University of Bari, 70124 Bari, Italy
6
Welcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK
7
8
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
9
Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK
10
Rowlett Institute, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, UK
*
Authors to whom correspondence should be addressed.
These authors equally contributed to this work.
Int. J. Mol. Sci. 2022 , 23 (12), 6786; https://doi.org/10.3390/ijms23126786
Received: 9 April 2022 / Revised: 10 June 2022 / Accepted: 13 June 2022 / Published: 17 June 2022
(This article belongs to the Special Issue Lipids Metabolism and Cardiometabolic Diseases )
Abstract
The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors characterised by central obesity, atherogenic dyslipidaemia, and changes in the circulating lipidome; the underlying mechanisms that lead to this lipid remodelling have only been partially elucidated. This study used an integrated “omics” approach (untargeted whole serum lipidomics, targeted proteomics, and lipoprotein lipidomics) to study lipoprotein remodelling and HDL composition in subjects with central obesity diagnosed with MetS (
vs.
de novo
lipogenesis. On the other hand, the “lysophosphatidylcholines to phosphatidylcholines” and “cholesteryl ester to free cholesterol” ratios were reduced, pointing to a lower activity of lecithin cholesterol acyltransferase (LCAT) in MetS; LCAT activity (directly measured and predicted by lipidomic ratios) was positively correlated with high-density lipoprotein cholesterol (HDL-C) and negatively correlated with body mass index (BMI) and insulin resistance. Moreover, many phosphatidylcholines and sphingomyelins were significantly lower in the HDL of MetS patients and strongly correlated with BMI and clinical metabolic parameters. These results suggest that MetS is associated with an impairment of phospholipid metabolism in HDL, partially led by LCAT, and associated with obesity and underlying insulin resistance. This study proposes a candidate strategy to use integrated “omics” approaches to gain mechanistic insights into lipoprotein remodelling, thus deepening the knowledge regarding the molecular basis of the association between MetS and atherosclerosis.
Keywords:
obesity
;
lipoprotein metabolism
;
LC-MS
;
lipidomics
;
lecithin cholesterol acyltransferase (LCAT)
1. Introduction
The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors defined by the co-existence of central obesity, systemic hypertension, impaired glucose metabolism, and/or atherogenic dyslipidaemia (decreased high-density lipoprotein (HDL) and increased apolipoprotein (apo) B containing lipoproteins: very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL)) [ 1 ]. As a result of the obesity epidemic, MetS has rapidly become a public health burden, with the prevalence in European countries estimated between 10% and 30% [ 2 ]. Furthermore, MetS leads to increased mortality due to its association with type 2 diabetes mellitus (T2DM), fatty liver, cardiovascular disease (CVD), and cancer [ 1 , 3 ]. MetS is a multifactorial condition whose pathophysiology is still under investigation. It has been demonstrated that obesity and insulin resistance (IR) profoundly reshape the lipoprotein profile and alter the quantity and quality of atherogenesis-affecting triglycerides (TG), cholesterol transport, and lipoprotein oxidation while promoting low-grade chronic inflammation [ 4 , 5 ]. Much less, however, is known about the contribution of other key structural lipids, such as phospholipids (PL), to this process [ 6 ].
The main circulating phospholipids phosphatidylcholines (PC) and lysophosphatidylcholines (LysoPC) are biochemically interconvertible species, and their metabolism can be modulated both intracellularly (e.g., in the liver, intestine, adipose tissue, or macrophages) and extracellularly. In the blood, PC can be remodelled into LysoPC by two enzymes: (i) lipoprotein-associated phospholipase A2 (Lp-PLA 2), an enzyme with pro- and anti-inflammatory capabilities [
7
] that catalyses the hydrolysis of fatty acids at the sn-2 position of oxidised phospholipids, ultimately generating a fatty acid and a LysoPC, and (ii) lecithin cholesterol acyltransferase (LCAT), a key player in the formation of large and mature HDL [
8
] that transfers 18:1 or 18:2 fatty acids from PC to free cholesterol (FC), thus generating cholesteryl esters (CE) and LysoPC [
9
]. Lipoprotein lipid remodelling is also ensured by (iii) phospholipid transfer protein (PLTP), which mediates the net transfer of PL from TG-rich lipoproteins into HDL particles alongside transferring several lipids, such as diglycerides, phosphatidic acids, sphingomyelins, cerebrosides, phosphatidylethanolamines, and α-tocopherol [
10
] (thus rendering this protein a non-specific transporter), and (iv) cholesteryl ester transfer protein (CETP), which is capable of transferring TG from ApoB lipoprotein to HDL in exchange for CE.
By thoroughly phenotyping lipid/lipoprotein metabolism, this study aims to expand the characterisation of lipid/HDL remodelling in early-stage and pharmacologically naïve MetS patients with central obesity.
Due to advances in mass spectrometry, it is now possible to characterise a plethora of circulating lipids with unprecedented throughput. Lipidomics has already proven to be a valuable tool in shedding light on metabolic disorders (including IR and non-alcoholic fatty liver disease) and cancer [ 11 , 12 , 13 ]. As recently highlighted in a systematic review of the literature, to date, only a few studies have investigated the lipidomic features of non-diabetic patients with MetS in whole serum [ 6 ], and even fewer have examined their HDL lipidome. Findings from the latter have been particularly challenging to harmonise because the pioneering studies investigated the major lipid classes (i.e., PL, CE, and TG) [ 14 ] with no information on single lipid species, while more recent studies differed in the way that lipids were normalised. Indeed, while Khan et al. reported the HDL lipidome as a function of HDL-PC content [ 15 ], Denimal et al. reported HDL lipidomic data as a percentage (mol%) of total lipids [ 16 ] along with the differences in the HDL subpopulation investigated. Further investigation is therefore warranted to understand how absolute changes in the HDL lipidome are associated with the disease and correlate with the cardio-metabolic risk.
Here, we employed state-of-the-art liquid chromatography coupled with mass spectrometry (LC-MS)-based lipidomics and proteomics, as well as lipoproteins lipidomics and biochemical analyses, to describe changes in HDL remodelling occurring in patients with central obesity and MetS. Overall, our results suggest that central obesity and MetS are associated with an impairment of HDL phospholipid metabolism and composition, which is partially driven by the lower activity of LCAT, with major changes correlating with the metabolic impairment of the patients.
2. Results
2.1. Clinical Characteristics of the Study Cohort
Compared with controls, MetS patients were older, showed higher body mass index (BMI) and waist circumference, alongside higher insulin resistance, as assessed by the Homeostasis Model Assessment 2 of Insulin Resistance (HOMA2-IR) ( Supplementary Table S1 ). They also displayed mixed dyslipidaemia: remarkably higher TG and lower high-density lipoprotein cholesterol (HDL-C) (with an expected significant effect of sex on these parameters), alongside a higher ApoB-100/ApoA-1 ratio. MetS patients did not show significant differences in total cholesterol, low-density lipoprotein cholesterol (LDL-C), or blood pressure (BP) compared to control subjects ( Supplementary Table S1 ). Regarding BP, 29% of the patients with increased BP were already receiving appropriate medical treatment.
2.2. Whole Serum Lipidomics of Healthy Participants and MetS Patients
In keeping with the definition of MetS and the widely established literature pointing to hyperinsulinemia and adipose tissue insulin resistance (AT-IR) as drivers of MetS in overweight/obese subjects [ 17 , 18 ], patients with MetS showed higher levels of total TG, diglycerides (DG), and free fatty acids (FFA) ( Figure 1 a–c) as compared with controls. Not surprisingly, the most significant differences in TG were observed in those containing saturated and monounsaturated fatty acids (differences in single lipid species are detailed in Supplementary Figure S1 and Supplementary Table S2 ) that our group and others previously linked to de novo lipogenesis (DNL) [ 19 , 20 , 21 ]. However, MetS patients also displayed significantly higher levels of total PC along with lower LysoPC when compared with controls ( Figure 1 d–e), while total sphingomyelins (SM), CE, and FC ( Figure 1 f–h) did not differ between the two groups.
Figure 1.
The whole serum levels of major lipid classes in healthy and MetS participants.
TG (
a
), DG (
b
), FFA (
c
), and PC (
d
) were higher in MetS (
n
= 14), whereas LysoPC (
e
) were lower as compared with controls (
n
= 11). SM, FC, and CE (
f
–
h
) were not significantly different. Data are expressed as mean ± standard deviation. Statistical significance was assessed using two-way ANOVA using the disease state and sex as covariates; a
p
-value < 0.05 was considered significant. Detailed differences in the lipid species are described in
Supplementary Figure S1 and Supplementary Table S2
. (
i
) Heatmap representing a correlation matrix between metabolic features and lipidomic data in the whole cohort: colour represents the Pearson correlation coefficient (red: positive; blue: negative), and the size of the circle represents significance (red bold borders highlight correlations with
p
< 0.01; black bold borders highlight correlations with
p
< 0.05). All lipid species were analysed by liquid chromatography–mass spectrometry except for FC and CE, which were analysed colorimetrically, as reported in the method section. Abbreviations: TG, triglycerides; DG, diglycerides; FFA, free fatty acids; PC, phosphatidylcholines; LysoPC, lysophosphatidylcholines; SM, sphingomyelins; FC, free cholesterol; CE, cholesteryl esters; BMI, body mass index; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HOMA2-IR, Homeostasis Model Assessment 2 of Insulin Resistance.
Some of the key drivers of the aforementioned differences were (1) lower levels of LysoPC containing polyunsaturated fatty acids (including LysoPC 20:5, 20:4, and 18:2); (2) lower abundance of CE 18:2; and (3) higher levels of different polyunsaturated PC (such as PC 40:9 and 42:9) in MetS compared to controls ( Supplementary Table S2 ).
The correlation matrix between lipid classes and clinical data highlighted a negative correlation between HDL-C and PC and a positive correlation between LysoPC and HDL-C ( Figure 1 i). These results point to a possible impairment in phospholipid lipoprotein metabolism occurring in MetS, associated with the severity of the metabolic impairment and possibly secondary to imbalances in HDL formation and/or remodelling.
2.3. Whole Serum Apolipoprotein Profile of Healthy Participants and MetS Patients
As apolipoproteins are key regulators of circulating lipid metabolism we studied the apolipoprotein profile of our cohort. In agreement with the low levels of HDL-C, MetS patients had significantly lower levels of ApoA-I and ApoD ( Figure 2 a,b), while ApoA-IV, ApoM, ApoE, ApoC-I, and ApoB-100 did not show significant differences between groups ( Figure 2 c–g). On the other hand, ApoC-II and ApoC-III were remarkably higher in MetS patients as compared with controls ( Figure 2 h,i). High levels of ApoC-III are known to contribute to hypertriglyceridemia via the inhibition of (a) the activity of lipoprotein lipases (LPL) and (b) the uptake of TG by the liver [ 22 ], thus resulting in an increased half-life of TG-rich lipoproteins; elevated levels of ApoC-II have already been reported in patients with T2DM and obesity [ 23 , 24 ]; however, the biological meaning of differences in ApoC-II levels is yet to be fully elucidated, as this apolipoprotein seems to have LPL-promoting activity [ 25 ]. The correlation analysis ( Figure 2 j) confirmed the expected positive correlations of ApoA-I with HDL-C (while being negatively correlated with BMI and HOMA2-IR) and of ApoC-II/ApoC-III with TG. Moreover, we also found interesting correlations between lipidomic and proteomic data ( Figure 2 k): in addition to the expected positive correlations between TG/DG and ApoC-II/ApoC-III (in light of the biological functions of these lipoproteins), PC and LysoPC positively correlated with ApoA-I, thus further suggesting that differences in whole serum phospholipid concentrations could be due to modifications in HDL composition.
Figure 2.
Serum levels of major apolipoproteins in healthy and MetS participants.
In MetS (
n
= 14), ApoA-I (
a
) and ApoD (
b
) were lower, ApoA-IV, ApoM, ApoE, ApoC-I and ApoB-100 (
c
–
g
) were not significantly different, whereas ApoC-II (
h
) and ApoC-III (
i
) were higher as compared with controls (
n
= 11). All apolipoproteins were analysed by liquid chromatography–mass spectrometry, as reported in the method section. Statistical significance was assessed using two-way ANOVA using the disease state and sex as covariates; a
p
-value < 0.05 was considered significant. Data are mean ± standard deviation. (
j
) Heatmap representing a correlation matrix among significantly different apolipoproteins and metabolic features in MetS and healthy controls: colour represents the Pearson correlation coefficient (red: positive; blue: negative), and the size of the circle represents significance (red bold borders highlight correlations with
p
< 0.01; black bold borders highlight correlations with
p
< 0.05). (
k
) Heatmap representing a correlation matrix among significantly different lipidomic and apolipoprotein species in MetS and healthy controls: colour represents the Pearson correlation coefficient (red: positive; blue: negative), and the size of the circle represents significance (red bold borders highlight correlations with
p
< 0.01; black bold borders highlight correlations with
p
< 0.05). Abbreviations: ApoA-I, apolipoprotein A-I; ApoD, apolipoprotein D; ApoA-IV, apolipoprotein A-IV; ApoM, apolipoprotein M; ApoE, apolipoprotein E; ApoC-I, apolipoprotein C-I; ApoB-100, apolipoprotein B-100; ApoC-II, apolipoprotein C-II; ApoC-III, apolipoprotein C-III; BMI, body mass index; TC total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HOMA2-IR, Homeostasis Model Assessment 2 of Insulin Resistance.
2.4. LCAT, but Not Lp-PLA2, Activity Is Reduced in MetS
Apart from the anticipated lipidomic and apolipoprotein features characterising the MetS, our results point to the remodelling of the circulating lipidome. To gain insights into the biology of lipoprotein’s remodelling, we determined the activity levels of circulating lipoprotein remodelling enzymes.
While Lp-PLA2 and CETP were not significantly different between the two groups (data not shown), PLTP was significantly higher in MetS compared with controls ( Supplementary Figure S2 ).
As our group recently showed in an independent cohort of patients with increased visceral obesity [ 26 ], we found LCAT activity to be significantly lower in the MetS group as compared with controls ( Figure 3 a). Here, by assessing different product/substrate ratios (proposed as indirect proxies of LCAT activity [ 27 , 28 , 29 ]) using lipidomics, we went a step further in showing that the lower LCAT activity has functional implications in the lipidome. While the LysoPC/PC ratio can be affected by both LCAT and Lp-PLA2 activity (the latter not being different in our cohort), the conversion of FC to CE in plasma can only be catalysed by LCAT [ 30 ]. As shown in Figure 3 b,c, both CE/FC and LysoPC/PC ratios were significantly lower in MetS patients. This was even more evident ( Figure 3 d) when combining the information from cholesterol and phospholipids using a recently proposed formula, called the “non-equilibrium reaction quotient” (Q’; formula: (CE*LysoPC)/(FC*PC)) [ 27 ]. Furthermore, in support of the notion that the differences in the aforementioned lipid species (product/substrate ratios) reflect LCAT activity, we found significant positive correlations amongst these indirect proxies and the enzymatic assay ( Figure 3 e–g).
Figure 3.
Direct and indirect assessment of LCAT activity in healthy and MetS
participants
.
The direct measurement of LCAT activity (
a
) and its lipidomic predictors (
b
–
d
) were significantly lower in MetS (
n
= 14) when compared with controls (
n
= 11). The latter (
e
–
g
) positively correlated with LCAT activity. All lipid species were analysed by liquid chromatography–mass spectrometry except for FC and CE, which were analysed colorimetrically, as reported in the method section. LCAT activity was measured with a fluorometric assay in kinetic measurements. Statistical significance was assessed using two-way ANOVA using the disease state and sex as covariates; a
p
-value < 0.05 was considered significant. Data are mean ± standard deviation. The correlation between variables was assessed with Pearson’s correlation coefficient; the statistical significance was calculated using multiple regression to control for the effect of sex; a
p
-value < 0.05 was considered significant. Abbreviations: LCAT, lecithin–cholesterol acyltransferase; CE, cholesteryl esters; FC, free cholesterol; LysoPC, lysophosphatidylcholines; PC, phosphatidylcholines; Q’, (CE*LysoPC)/(FC*PC).
Taken together, these data suggest that the differences in the whole serum lipidome likely reflect, at least in part, suppressed LCAT activity.
2.5. LCAT Activity and Its Lipidomic Proxies Show an Inverse Correlation with Metabolic Risk Factors and Positively Correlate with HDL-C
The role of LCAT in the pathophysiology of atherosclerosis is highly debated, with conflicting results coming from pre-clinical and clinical studies [ 30 ]. Contradictory findings have also been reported in patients with metabolic risk factors [ 26 , 31 , 32 , 33 , 34 ], further highlighting the intricate nature of the LCAT function. Because of the coherent reduction in LCAT activity and its product-to-substrate ratios in MetS, we sought to understand the extent to which these parameters correlated with characteristic metabolic risk factors linked to MetS, such as BMI, HOMA2-IR, and HDL-C.
LCAT activity and/or all of the lipidomic indices predicting its activity showed remarkable negative correlations with BMI ( Figure 4 a,d,g,j) and HOMA2-IR ( Figure 4 b,e,h,k) and positive correlations with HDL-C ( Figure 4 c,f,i,l). Q’ showed the highest correlation (R = 0.57) and significance ( p = 0.0008) with HDL-C, further strengthening our hypothesis that the observed lipidomic differences were driven by HDL remodelling, which might go beyond the lower HDL cholesterol content that has been well described in MetS.
Figure 4.
Correlation between direct/indirect measurements of LCAT activity and metabolic risk factors.
Lipidomic predictors and direct measurement of LCAT activity (
a
–
l
) were negatively correlated with BMI and HOMA2-IR and positively correlated with HDL-C. All measurements were performed on MetS (
n
= 14) and controls (
n
= 11). Lipid species were analysed by liquid chromatography–mass spectrometry except for FC and CE, which were analysed colorimetrically, as reported in the method section. The correlation between variables was assessed with Pearson’s correlation coefficient; the statistical significance was calculated using multiple regression to control for the effect of sex; a
p
-value < 0.05 was considered significant. Abbreviations: LCAT, lecithin–cholesterol acyltransferase; CE, cholesteryl esters; FC, free cholesterol; LysoPC, lysophosphatidylcholines; PC, phosphatidylcholines; Q’, (CE*LysoPC)/(FC*PC); BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; HOMA2-IR, Homeostasis Model Assessment 2 of Insulin Resistance.
Taken together, these data suggest that LCAT activity and its lipidomic proxies display a strong relationship with cardio-metabolic risk factors, this being partially attributable to lower HDL-C levels in the MetS group compared with controls. Moreover, together with an impairment of cholesterol efflux (associated with reduced ABCA1/G1 monocyte/macrophage expression) that we and others reported in MetS [
35
,
36
], these data point to a possible impairment in HDL metabolism at multiple levels, which might affect not only HDL concentration and function (reverse cholesterol transport, RCT) but also the composition of HDL lipids.
2.6. HDL Composition in Central Obesity and MetS
Lastly, to gain insights into the functional implications in terms of HDL composition led by the impairment in HDL formation [ 26 , 37 ] and remodelling, we characterised the differences in the HDL lipidome occurring in MetS. As shown in Figure 5 , when compared with those of controls, MetS HDL showed significantly higher total TG and saturated very long chain SM (SM 48:0). Increased HDL-TG reduce HDL stability, rendering them more prone to the dissociation of ApoA-I and thus potentially increasing their catabolism [ 38 ]. On the other hand, several lipids belonging to PC, LysoPC, CE, and SM showed lower abundance in MetS compared with controls ( Figure 5 ). Specifically, within HDL, both the product and substrates of LCAT (i.e., CE 18:2, LPC 18:2, and PC 34:2) alongside several MUFA SM were lower in MetS compared with controls. Reduced levels of PC and SM within HDL have been associated with the decreased efflux capacity of HDL particles, both in vitro and in observational studies [ 39 , 40 , 41 , 42 , 43 ]. Moreover, reduced PC and SM in HDL have been reported in patients with CVD [ 44 ], while the data in MetS cohorts are more debated [ 15 , 16 ]. The cluster of PC and SM that were identified as being most significantly reduced ( p < 0.01) in MetS compared with controls also correlated negatively with BMI, TG, and glycaemia ( Figure 6 ), therefore highlighting their importance as targets of future mechanistic studies to better characterise their biological importance.
Figure 5. Differences in the HDL lipidome in healthy and MetS participants. The HDL lipidome of MetS participants ( n = 14) showed lower levels of specific sphingomyelins (SM), phosphatidylcholines (PC), lysophosphatidylcholine (LysoPC) 18:2, and cholesteryl ester (CE) 18:2 and higher total triglycerides (TG) along with TG 52:3 and SM 48:0 when compared with healthy subjects ( n = 11). Statistical significance was assessed by Student’s two-sided T-Test; a p -value < 0.05 was considered significant. Lipid species were analysed by liquid chromatography–mass spectrometry, as reported in the method section. The mean values of each lipid in healthy and MetS participants, along with unadjusted and adjusted false discovery rates (FDRs) and p -values, are reported in Supplementary Table S5 .
Figure 6. HDL lipid species correlate with clinical features of metabolic impairment. Heatmap representing a correlation matrix among highly significantly different HDL lipid species ( p < 0.01) and metabolic parameters in MetS ( n = 14) and healthy controls ( n = 11): colour represents the Pearson correlation coefficient (red: positive; blue: negative), and the size of the circle represents significance (red bold borders highlight correlations with p < 0.01; black bold borders highlight correlations with p < 0.05). Abbreviations: PC, phosphatidylcholines; SM, sphingomyelins; BMI, body mass index; TC total cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; HOMA2-IR, Homeostasis Model Assessment 2 of Insulin Resistance.
The presence of odd-chain fatty acids among some of the most significantly reduced lipids within the HDL fractions suggests a potentially novel role for HDL as a carrier of health-promoting lipids, as odd-chain fatty acids have been previously associated with a reduced incidence of T2DM [ 45 , 46 ]. The provenience of these lipids requires further investigation, as dietary sources [ 47 ], gut microbiota [ 48 ], alpha-oxidation [ 49 ], and mitochondrial catabolism of BCAA [ 50 ] can potentially contribute to the pool of circulating odd-chain fatty acids.
Overall, our data highlight that whole serum lipidomics is highly influenced by lipoprotein’s metabolism and can provide useful insights into these processes; however, lipoproteins lipidomics offers a more detailed picture of the biology underlying systemic lipid metabolism.
3. Discussion
Central obesity and MetS are characterised by mixed dyslipidaemia: its treatment is a cornerstone for primary and secondary prevention of CVD. Beyond the traditional lipid markers (e.g., HDL-C and TG), several studies have characterised the lipidomic signature of abdominal obesity and MetS, but knowledge around the biological meaning of these signatures in disease and the underlying mechanisms remains limited.
In this study, we were able to confirm multiple previously described MetS-associated lipidomic changes related to IR and hyperinsulinemia (DG and TG, specifically enriched in DNL products) [ 6 , 19 ] and to describe novel findings that correlate with the metabolic burden of central obesity and MetS.
The phospho-lipidomic signature of MetS patients is more debated in the literature, probably because it is more influenced by differences in study design (recruitment criteria, normalisation of lipid species, lipids detected, and lipoprotein separation method). We confirmed higher levels of total PC in MetS vs. controls, as shown previously by others [ 51 , 52 , 53 ], although conflicting results have also been published [ 54 , 55 ]. We considered the higher levels of PC in MetS vs. controls unexpected, considering that, at least in healthy subjects, PCs are predominantly contained in HDL particles [ 56 ] and that HDL-C and ApoA-1 were significantly lower in our cohort of MetS participants.
Investigating HDL composition in more detail, we were indeed able to show that HDL-PC concentrations are lower, as expected, and this correlated with cardio-metabolic risk factors. While reduced SM levels within HDL are associated with decreased RCT (in vitro), some in vitro and pre-clinical studies showed an inhibitory effect of SM on LCAT [ 57 ]. This suggests that, in MetS, other pathways (e.g., reduced ApoA-1) might explain the lower LCAT activity levels but not HDL-SM levels. A deeper look into HDL lipidomics therefore suggested that (1) whole serum lipidomics can be misleading when lipoprotein fractions are under metabolic pressure, altering lipid physiology; (2) differentially studying the lipid composition of lipoprotein fractions can be more informative in cardio-metabolic studies than whole serum lipidomics, also clarifying some apparent conflicting results; (3) there is an urgent need to deepen the knowledge of PL metabolism and function, as it might help to better understand the role of HDL in cardio-metabolic disease; and (4) last, a consensus in lipoprotein lipidomic data analysis is currently needed: we suggest that apparently conflicting results in the literature are partly due to the different methods used to isolate the lipoproteins and process the data (lipid normalisation) [ 14 , 15 , 16 , 58 ]. Indeed, the expression of data as percentages is very common in lipidomic studies; however, because this normalisation is influenced by the abundance of other lipids (and different laboratories have different arrays of lipids detected by their assays), the use of absolute values should be preferred, as recommended by a recent position paper for the standardisation of lipidomic human blood samples [ 59 ].
Another result that attracted our attention was the differential regulation between LysoPC (lower) and PC (higher) in whole serum lipidomics: since PC and LysoPC are biochemically interconvertible species, we checked if our data could help to study disease-associated changes in the activity of lipid-remodelling enzymes. Here, we described a reduction in LCAT activity in patients with central obesity and MetS that leads to functional PL/cholesterol remodelling, and we investigated the association of multiple lipidomic ratios with standard enzymatic activity assays as valuable predictors of LCAT activity (as confirmed by a strong correlation among direct/indirect measurements). Moreover, Q’ has been shown to be reduced in patients with CVD [
27
]: intriguingly, assessing LCAT activity either directly or with lipidomic ratios, we found that it was reduced in our early-stage naïve MetS patients with mild cardiovascular risk and without organ damage; and correlated with metabolic features: these findings therefore suggest that reduced LCAT activity is an early event associated with central obesity and insulin resistance, and that lipidomic ratios might serve in the future as potential predictive biomarkers of HDL function and/or cardiovascular risk.
Last, although it was beyond the scope of this work to describe the mechanisms by which LCAT activity was reduced, the proteomics data allow us to speculate that contributors to the reduced activity might be the lower levels of ApoA-I (the main activator of LCAT) [
30
] and elevated ApoC-III levels (an inhibitor of LCAT) [
60
]. These data coherently point toward reduced LCAT activity in our cohort. Reduced LCAT activity, together with reduced cholesterol efflux and lipoprotein oxidation [
61
], might contribute to the close association between MetS, impaired RCT, and atherosclerosis. However, it is important to underline that, although the crucial role of LCAT in the maturation of HDL has been elucidated by intensive investigation over the last 50 years, its role in CVD is still debated [
62
], and larger studies are needed to stratify patients against cardio-metabolic risk.
This study has some limitations. First, we used data from the highest number of available participants: although multiple layers of evidence support our findings, non-significant results must be interpreted with caution in light of the small sample size (all variables with an effect size < 1.1 were not sufficiently powered in the post hoc power analysis). Second, this study might suffer from a bias of recruitment: the presence of atherogenic dyslipidaemia (high TG; low HDL-C) is one of the MetS-defining criteria [ 63 ], potentially explaining some differences in the lipidomic results shown by others. Third, the Q index does not account for endothelial and hepatic lipase activities, which are able to remodel circulating phospholipids; however, the robust correlation with LCAT activity reassures that most of the changes in the Q index observed in MetS were due to LCAT activity per se. Fourth, while LCAT is the only enzyme capable of converting FC to CE in circulating blood, their ratio might be impacted by the altered transfer of FC from peripheral tissues to lipoproteins [ 64 ]. Last, our results (despite finding multiple lines of validation in the literature [ 18 , 19 , 26 , 27 , 44 , 65 , 66 ]) will require validation in a larger study cohort to prove the transferability of our main findings to clinical practice.
In conclusion, our results suggest that central obesity and MetS are associated with an impairment of phospholipid remodelling and HDL composition, partially led by reduced LCAT activity and correlating with obesity and insulin resistance. This study also suggests the need for a candidate strategy to use integrated lipidomic and proteomic approaches to gain mechanistic insights into lipoprotein remodelling in order to deepen the knowledge regarding the molecular basis of the association between MetS and atherosclerosis.
4. Materials and Methods
4.1. Ethics and the MetS Study Cohort
Eleven healthy volunteers and fourteen patients with central obesity, at the first diagnosis of MetS, with no evidence of organ damage, were included in this study. The presence of MetS was defined when at least 3 (out of 5) criteria for MetS were present according to the National Cholesterol Education Program Third Adult Treatment Panel (ATP III) [
63
]: all (100%) patients showed increased WC and were overweight/obese (21% had ≥ 25 BMI < 30; 79% had BMI ≥ 30). The other MetS criteria were: reduced HDL-C (93%); increased glucose (57%); increased triglycerides (42%); and increased BP (or in treatment for hypertension—43%). Exclusion criteria were: the presence of diseases that could have influenced participants’ metabolism (i.e., autoimmune disease, cancer, endocrine disorders, and acute and chronic kidney failure), smoking, alcohol intake of over 25 g/day, and pharmacological treatment (hypertension drugs in MetS patients were allowed). None of the participants had documented significant atherosclerosis at the carotid Doppler ultrasound; also, the average intima-media thickness, a marker of subclinical atherosclerosis, of the MetS group was within the normal range (data not shown). The clinical characteristics of the study population are summarised in
Supplementary Table S1
.
4.2. Sample Collection and Clinical Biochemistry Measurements
After overnight fasting, serum was collected from healthy and MetS participants for the assessment of standard clinical biochemistry tests. Serum was separated by centrifugation and stored at −80 °C. Clinical biochemistry, including the full lipid profile, glucose, insulin, and circulating liver enzymes, was performed by The Pathology Partnership (Addenbrooke’s Hospital, Cambridge, UK). Homeostasis Model Assessment 2 (HOMA2-IR) values were calculated using the HOMA Calculator v2.2.3 available at https://www.dtu.ox.ac.uk/homacalculator/ (accessed on 5 May 2019).
4.3. HDL Isolation
The serum HDL separation was performed by size-exclusion chromatography (SEC) using a previously described method [
67
]. Briefly, fractions were determined in 50 μL of serum samples diluted with 50 μL of a PBS solution via SEC, using a Superose 6 increase column (10/300GL, 10 × 300, 24 mL), (GE Healthcare; Uppsala, Sweden). SEC was carried out using an ÄKTA purifier 10 (GE Healthcare; Uppsala, Sweden), equipped with a fraction collector (Frac-950). The system was controlled by a UNICORN control system, version 4.10 (GE Healthcare; Uppsala, Sweden). The SEC flow rate was set at 450 μL/min. Eluting fractions were collected in glass-coated 96-well plates (Eppendorf Protein Low-Bind; Hamburg, Germany). The HDL fractions were combined after fractionation, and samples were dried in a vacuum centrifuge and stored at −80 °C before further processing. Lipids from the selected fractions obtained by Superose-6 SEC were further extracted and investigated by LC-MS, as detailed below.
4.4. Lipid Extraction for Mass Spectrometry Analyses
Lipids were extracted from blood serum and dried HDL fractions, previously stored at −80 °C, using an adaptation of the Folch method [
68
]. Briefly, 10 μL of blood serum was mixed with chloroform/methanol (2:1, 1 mL), and then 10 μL of internal standard mix including the following: cholesteryl-d7 pentadecanoate (15:0d7 CE), heptadecanoic-d33 acid (17:0-d33 FFA), 1-palmitoyl(D31)-2-oleyl-sn-glycero-3-phosphatidylcholine (16:0-d31-18:1 PC), N-palmitoyl(d31)-d-erythro-sphingosylphosphorylcholine (16:0-d31 SM), and glyceryl tri(pentadecanoate-d29) (45:0-d87 TAG) (Avanti Polar Lipids Inc, Alabaster, AL, USA) was added. Samples were sonicated for 10 min, and subsequently, deionised water was added (400 μL). Samples were then centrifuged (13,000×
g
, 10 min). The organic fraction was transferred into a new vial and dried under a stream of nitrogen. Dried samples were then stored at −80 °C until analysis.
4.5. Lipid Analysis by LC-MS
Before analysis, dried samples were reconstituted in 20 μL of 1:1 chloroform/methanol, sonicated for 10 min, and then diluted in isopropyl alcohol/acetonitrile/water (2:1:1, 100 μL). The analysis of intact lipids was performed through LC-MS using a Dionex Ultimate 3000 ultrahigh-performance liquid chromatography system (UHPLC; Thermo Scientific, Hemel Hempstead, UK) coupled to an LTQ Orbitrap Elite Mass Spectrometer (Thermo Scientific, Hemel Hempstead, UK). A 10 μL sample was injected onto a C18 CSH column, 1.7 μm pore size, 2.1 mm × 50 mm (Waters Ltd., Manchester, UK), maintained at 55 °C. A gradient of solvent A, 10 mM ammonium formate in acetonitrile/water 6:4, and solvent B, 10 mM ammonium formate in isopropanol/acetonitrile 9:1, was used for the positive mode acquisition. For the negative mode, the mobile phase remained the same except for the use of 10 mM ammonium acetate instead of ammonium formate. HPLC was coupled to a heated electrospray source held at 365 °C. The data were collected in positive and negative ion modes with a mass range of 100–2000
m/z
. Peaks in the spectra were detected and integrated by XCMS software with an in-house script running under R (version 4.0.0). Lipid peak areas were normalised (divided) to their class-specific stable isotopically labelled internal standard peak areas, leading to semi-quantitative data, here referred to as normalised intensity. With regard to missing values, lipids with missing values higher than 30% were removed from the dataset, whereas the others were imputed with half of the minimum value detected for that specific lipid [
69
].
4.6. Esterified Cholesterol Analysis by LC-MS/MS
The organic lipid-containing layer from the Folch extraction was analysed by targeted LC-MS/MS using a UHPLC+ series coupled to a TSQ Quantiva mass spectrometer (Thermo Fisher scientific, Waltham, MA, USA). Ten microlitres of sample containing isotopically labelled cholesteryl-d7 pentadecanoate (Avanti Polar Lipids Inc, Alabaster, AL, USA) was injected onto an Acquity C18 CSH column (Waters Ltd., Warrington, UK; 100 × 2.1 mm, 1.7 μm) with a column temperature of 45 °C. A gradient separation was used as described for the lipidomics experiments. A heated electrospray ionisation source was operated in positive ion mode; desolvation temperature and gas flow were 270 °C and 45 arbitrary units, respectively. The selected reaction monitoring transitions used are included in
Supplementary Table S3
. Xcalibur software (Thermo Fisher Scientific, Hemel Hempstead, UK)) was used for peak integration. Peak areas of whole serum were normalised to the internal standard, while HDL lipids were further normalised by the total protein content of the HDL fraction (Pierce bicinchoninic acid assay).
4.7. HDL Total Protein Concentration
Total protein concentration in the HDL fraction was determined by bicinchoninic acid assay (Pierce BCA; Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions.
4.8. Whole Serum Protein Digestion for LC-MS/MS Analysis
Serum (10 μL) was diluted by a factor of 10 with 50 mM ammonium bicarbonate in water. Diluted serum (10 μL) was then transferred to 490 μL of 10 mM dithiothreitol in 50 mM ammonium bicarbonate, with 0.5 mg/mL bovine serum albumin (BSA) as an internal standard. Samples were incubated at 60 °C for 1 h and allowed to cool to room temperature, after which 100 μL of 100 mM iodoacetamide in 50 mM ammonium bicarbonate was added and samples were incubated at room temperature in the dark for 30 min. Trypsin (10 μL at 100 μg/mL) was added to a 100 μL aliquot of each sample and incubated for 16 h at 37 °C. After incubation, 20 μL of 1% formic acid was added to halt digestion prior to analysis by LC-MS/MS.
4.9. Apolipoprotein Analysis by LC-MS/MS
LC-MS/MS analysis was performed on an M-Class liquid chromatography system coupled to a XevoTQ-XS triple quadrupole (Waters, Milford, MA, USA). A gradient of solvent A, 0.1% formic acid in water, and solvent B, 0.1% formic acid in acetonitrile, was used to separate digested proteins. The sample (2 µL) was injected onto an HSS T3 50 × 1.0 mm column (Waters) at 25 µL per minute at 15% B, rising to 50% B over 5 min. The column was washed with 85% B for 2.5 min before returning to initial conditions for a total run time of 10 min. Positive electrospray ionisation was performed with a needle voltage of 3 kV, source and desolvation temperatures of 150 °C and 450 °C, respectively, and a cone voltage of 30 V. The selected reaction monitoring transitions used are included in
Supplementary Table S4
. Peptide peaks were integrated using TargetLynxXS (Waters, Milford, MA, USA) and expressed as a ratio of the average peak area to the mean peak area value of two typically digested BSA peptides.
4.10. Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Activity
Lp-PLA2 activity in serum was measured in duplicate using a commercially available kit (Cayman, Europe) following the manufacturer’s instructions. Specifically, samples were incubated for 30 min with Ellman’s reagent at room temperature with the subsequent addition of 2-thio PAF, used as a substrate for Lp-PLA2 activity. The reaction causes an increase in colourimetric absorbance, which was measured once every minute at 405–414 nm. Measurements were obtained using a plate reader (Tecan Infinite 200 PRO) (Tecan, Mannedorf, Switzerland).
4.11. Phospholipid Transfer Protein (PLTP) Activity
PLTP activity in serum was measured in duplicate using a commercially available kit (Merck, St. Louis, MO, USA) following the manufacturer’s instructions. Specifically, the assay uses a proprietary substrate to detect PLTP-mediated transfer of the fluorescent substrate. The transfer activity results in an increase in fluorescence intensity at 465/535 nm. Measurements were obtained using a plate reader (Tecan Infinite 200 PRO) (Tecan, Mannedorf, Switzerland).
4.12. Cholesteryl Ester Transfer Protein (CETP) Activity
CETP activity in serum was measured in duplicate using a commercially available kit (Merck, St. Louis, MO, USA) following the manufacturer’s instructions. Specifically, the assay uses a proprietary substrate to detect CETP-mediated transfer of neutral lipid from the substrate to its acceptor. The transfer activity results in an increase in fluorescence intensity at 465/535 nm. Measurements were obtained using a plate reader (Tecan Infinite 200 PRO) (Tecan, Mannedorf, Switzerland).
4.13. Lecithin–Cholesterol Acyltransferase (LCAT) Activity
LCAT activity in serum was measured in duplicate using a commercially available kit (Merck, St. Louis, MO, USA) following the manufacturer’s instructions. Specifically, samples were incubated with LCAT substrate for 3 h at 37 °C. The fluorescent substrate emits fluorescence at 470 nm. When the substrate is hydrolysed by LCAT, a monomer is released that emits fluorescence at 390 nm. The LCAT activity is expressed as a change in 470/390 nm emission intensity. Measurements were obtained using a plate reader (Tecan Infinite 200 PRO) (Tecan, Mannedorf, Switzerland).
4.14. Statistical Analysis
Data are shown as mean ± standard deviation unless otherwise specified. Normality was visually assessed from plots of the data, and logarithmic transformations were applied to skewed variables. “Post-Hoc” power analyses were performed with the freely available G*power software: all variables with an effect size (e.g., delta/sigma) > 1.1 were sufficiently powered and resulted in significant results. Comparisons of clinical and omics data between healthy and MetS were assessed using two-way ANOVA (with “sex” and “disease state” as covariates), and
p
-value < 0.05 was considered significant. Correlation matrices between omics layers and clinical variables were performed with Pearson correlation coefficients, with
p
-value < 0.05 considered significant, or multiple regression (lm function, in R) with “sex” as a covariate, when relevant; a
p
-value < 0.05 was considered significant. Log2 fold changes in the whole serum and HDL lipidome (volcano plots) were analysed by Student’s two-sided T-Test, with a
p
-value < 0.05 considered significant. The adjusted
p
-value calculated using the false discovery rate (FDR) was also calculated and is reported along with the unadjusted
p
-value in
Supplementary Figures S2 and S5
. Statistical analysis was performed with R version 4.0.0 and Microsoft Excel 2016. Graphs were obtained using R version 4.0.0 and Graph Pad (Graph Pad Prism 7.0, San Diego, CA, USA).
G.M., M.V., S.D. and J.L.G. conceived and designed the study. G.M., M.V. and J.L.G. wrote the manuscript. All the authors provided useful criticism during the study and critically reviewed the manuscript. S.D., M.V., P.S., G.P., A.M. (Antonio Moschetta) and C.S. recruited the patients. G.M., B.J., A.M. (Antonio Murgia), A.K., Z.H. and S.A.P.-D. performed lipidomic analyses. R.K. and F.R. performed proteomic analyses. G.M., A.P.S. and A.M. (Andrew Murray) performed BCA analyses. G.M. and M.V. performed statistical analyses and prepared the figures. G.M. performed enzymatic assays and HDL lipoprotein isolation with support from S.N. and L.V.H.-M. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Comitato Etico Indipendente Locale (Ethics Committee) of the Azienda Ospedaliera Ospedale Policlinico Consorziale di Bari (protocol code PLS/PBMC/09): (initial protocol number) 3479/09; (amended protocol number) 115/13; date of approval: (initial protocol) 29 July 2009; (last amendment) 4 February 2013. Participants were recruited at the Ospedale Policlinico Consorziale di Bari, Italy.
Informed Consent Statement
All participants gave written informed consent.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding authors [M.V., J.L.G.].
Acknowledgments
The authors are indebted to the following colleagues and institutions: (1) Katherine Stott and Matthew Watson (Department of Biochemistry, University of Cambridge) and Damon Parkington and his team (Amanda McKillion and Tabasum Tabasum; NIHR Cambridge BRC Nutritional Biomarker Laboratory) for training, useful conversations, and access to instrumentation; (2) the MRC Metabolic Diseases Unit (MC_UU_12012/5), Amy George (IMS-MRL Peptidomics and Proteomics Core), and the Biochemistry Assay Lab (Keith Burling and collaborators) for serum biochemistry.
The authors declare no conflict of interest for this article. S.D. and has been recently employed by Chiesi (after the development of this manuscript).
Abbreviations
apo Apolipoprotein
BMI Body mass index
CE Cholesteryl esters
DG Diglycerides
FC Free cholesterol
FFA Free fatty acids
HDL High-density lipoprotein
HOMA2-IR Homeostasis Model Assessment 2 of Insulin Resistance
LCAT Lecithin–cholesterol acyltransferase
LDL Low-density lipoprotein
LPC Lysophosphatidylcholines
Lp-PLA2 Lipoprotein-associated phospholipase A2
MetS Metabolic syndrome
SM Sphingomyelins
PC Phosphatidylcholines
TG Triglycerides
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Figure 1. The whole serum levels of major lipid classes in healthy and MetS participants. TG ( a ), DG ( b ), FFA ( c ), and PC ( d ) were higher in MetS ( n = 14), whereas LysoPC ( e ) were lower as compared with controls ( n = 11). SM, FC, and CE ( f – h ) were not significantly different. Data are expressed as mean ± standard deviation. Statistical significance was assessed using two-way ANOVA using the disease state and sex as covariates; a p -value < 0.05 was considered significant. Detailed differences in the lipid species are described in Supplementary Figure S1 and Supplementary Table S2 . ( i ) Heatmap representing a correlation matrix between metabolic features and lipidomic data in the whole cohort: colour represents the Pearson correlation coefficient (red: positive; blue: negative), and the size of the circle represents significance (red bold borders highlight correlations with p < 0.01; black bold borders highlight correlations with p < 0.05). All lipid species were analysed by liquid chromatography–mass spectrometry except for FC and CE, which were analysed colorimetrically, as reported in the method section. Abbreviations: TG, triglycerides; DG, diglycerides; FFA, free fatty acids; PC, phosphatidylcholines; LysoPC, lysophosphatidylcholines; SM, sphingomyelins; FC, free cholesterol; CE, cholesteryl esters; BMI, body mass index; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HOMA2-IR, Homeostasis Model Assessment 2 of Insulin Resistance.
Figure 2. Serum levels of major apolipoproteins in healthy and MetS participants. In MetS ( n = 14), ApoA-I ( a ) and ApoD ( b ) were lower, ApoA-IV, ApoM, ApoE, ApoC-I and ApoB-100 ( c – g ) were not significantly different, whereas ApoC-II ( h ) and ApoC-III ( i ) were higher as compared with controls ( n = 11). All apolipoproteins were analysed by liquid chromatography–mass spectrometry, as reported in the method section. Statistical significance was assessed using two-way ANOVA using the disease state and sex as covariates; a p -value < 0.05 was considered significant. Data are mean ± standard deviation. ( j ) Heatmap representing a correlation matrix among significantly different apolipoproteins and metabolic features in MetS and healthy controls: colour represents the Pearson correlation coefficient (red: positive; blue: negative), and the size of the circle represents significance (red bold borders highlight correlations with p < 0.01; black bold borders highlight correlations with p < 0.05). ( k ) Heatmap representing a correlation matrix among significantly different lipidomic and apolipoprotein species in MetS and healthy controls: colour represents the Pearson correlation coefficient (red: positive; blue: negative), and the size of the circle represents significance (red bold borders highlight correlations with p < 0.01; black bold borders highlight correlations with p < 0.05). Abbreviations: ApoA-I, apolipoprotein A-I; ApoD, apolipoprotein D; ApoA-IV, apolipoprotein A-IV; ApoM, apolipoprotein M; ApoE, apolipoprotein E; ApoC-I, apolipoprotein C-I; ApoB-100, apolipoprotein B-100; ApoC-II, apolipoprotein C-II; ApoC-III, apolipoprotein C-III; BMI, body mass index; TC total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HOMA2-IR, Homeostasis Model Assessment 2 of Insulin Resistance.
Figure 3. Direct and indirect assessment of LCAT activity in healthy and MetS participants . The direct measurement of LCAT activity ( a ) and its lipidomic predictors ( b – d ) were significantly lower in MetS ( n = 14) when compared with controls ( n = 11). The latter ( e – g ) positively correlated with LCAT activity. All lipid species were analysed by liquid chromatography–mass spectrometry except for FC and CE, which were analysed colorimetrically, as reported in the method section. LCAT activity was measured with a fluorometric assay in kinetic measurements. Statistical significance was assessed using two-way ANOVA using the disease state and sex as covariates; a p -value < 0.05 was considered significant. Data are mean ± standard deviation. The correlation between variables was assessed with Pearson’s correlation coefficient; the statistical significance was calculated using multiple regression to control for the effect of sex; a p -value < 0.05 was considered significant. Abbreviations: LCAT, lecithin–cholesterol acyltransferase; CE, cholesteryl esters; FC, free cholesterol; LysoPC, lysophosphatidylcholines; PC, phosphatidylcholines; Q’, (CE*LysoPC)/(FC*PC).
Figure 4. Correlation between direct/indirect measurements of LCAT activity and metabolic risk factors. Lipidomic predictors and direct measurement of LCAT activity ( a – l ) were negatively correlated with BMI and HOMA2-IR and positively correlated with HDL-C. All measurements were performed on MetS ( n = 14) and controls ( n = 11). Lipid species were analysed by liquid chromatography–mass spectrometry except for FC and CE, which were analysed colorimetrically, as reported in the method section. The correlation between variables was assessed with Pearson’s correlation coefficient; the statistical significance was calculated using multiple regression to control for the effect of sex; a p -value < 0.05 was considered significant. Abbreviations: LCAT, lecithin–cholesterol acyltransferase; CE, cholesteryl esters; FC, free cholesterol; LysoPC, lysophosphatidylcholines; PC, phosphatidylcholines; Q’, (CE*LysoPC)/(FC*PC); BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; HOMA2-IR, Homeostasis Model Assessment 2 of Insulin Resistance.
Figure 5. Differences in the HDL lipidome in healthy and MetS participants. The HDL lipidome of MetS participants ( n = 14) showed lower levels of specific sphingomyelins (SM), phosphatidylcholines (PC), lysophosphatidylcholine (LysoPC) 18:2, and cholesteryl ester (CE) 18:2 and higher total triglycerides (TG) along with TG 52:3 and SM 48:0 when compared with healthy subjects ( n = 11). Statistical significance was assessed by Student’s two-sided T-Test; a p -value < 0.05 was considered significant. Lipid species were analysed by liquid chromatography–mass spectrometry, as reported in the method section. The mean values of each lipid in healthy and MetS participants, along with unadjusted and adjusted false discovery rates (FDRs) and p -values, are reported in Supplementary Table S5 .
Figure 6. HDL lipid species correlate with clinical features of metabolic impairment. Heatmap representing a correlation matrix among highly significantly different HDL lipid species ( p < 0.01) and metabolic parameters in MetS ( n = 14) and healthy controls ( n = 11): colour represents the Pearson correlation coefficient (red: positive; blue: negative), and the size of the circle represents significance (red bold borders highlight correlations with p < 0.01; black bold borders highlight correlations with p < 0.05). Abbreviations: PC, phosphatidylcholines; SM, sphingomyelins; BMI, body mass index; TC total cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; HOMA2-IR, Homeostasis Model Assessment 2 of Insulin Resistance.
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Mocciaro, G.; D’Amore, S.; Jenkins, B.; Kay, R.; Murgia, A.; Herrera-Marcos, L.V.; Neun, S.; Sowton, A.P.; Hall, Z.; Palma-Duran, S.A.; Palasciano, G.; Reimann, F.; Murray, A.; Suppressa, P.; Sabbà, C.; Moschetta, A.; Koulman, A.; Griffin, J.L.; Vacca, M. Lipidomic Approaches to Study HDL Metabolism in Patients with Central Obesity Diagnosed with Metabolic Syndrome. Int. J. Mol. Sci. 2022, 23, 6786.
https://doi.org/10.3390/ijms23126786
Mocciaro G, D’Amore S, Jenkins B, Kay R, Murgia A, Herrera-Marcos LV, Neun S, Sowton AP, Hall Z, Palma-Duran SA, Palasciano G, Reimann F, Murray A, Suppressa P, Sabbà C, Moschetta A, Koulman A, Griffin JL, Vacca M. Lipidomic Approaches to Study HDL Metabolism in Patients with Central Obesity Diagnosed with Metabolic Syndrome. International Journal of Molecular Sciences. 2022; 23(12):6786.
https://doi.org/10.3390/ijms23126786
Chicago/Turabian Style
Mocciaro, Gabriele, Simona D’Amore, Benjamin Jenkins, Richard Kay, Antonio Murgia, Luis Vicente Herrera-Marcos, Stefanie Neun, Alice P. Sowton, Zoe Hall, Susana Alejandra Palma-Duran, Giuseppe Palasciano, Frank Reimann, Andrew Murray, Patrizia Suppressa, Carlo Sabbà, Antonio Moschetta, Albert Koulman, Julian L. Griffin, and Michele Vacca. 2022. "Lipidomic Approaches to Study HDL Metabolism in Patients with Central Obesity Diagnosed with Metabolic Syndrome" International Journal of Molecular Sciences23, no. 12: 6786.
https://doi.org/10.3390/ijms23126786
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960, R, 2016-04-20 02:11:41, 2016-04-19 15:14:25.393, 2016-04-19 15:14:25.721, 0.328, 0.000000, 0.000000025596, 0.000000267618, -0.000000349364, -0.3935328423976898, 0.6847963333129883, 0.1360513567924500, 0.5980601310729980, 1, 1, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 100, 100, 0, 0, 0, 0, 0, 0, 33708490335658
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989, R, 2016-04-20 02:11:41, 2016-04-19 19:43:13.406, 2016-04-19 19:43:13.699, 0.293, 0.000000, -0.000000039903, -0.000000105571, 0.000000173465, 0.5950069427490234, 0.3052921891212463, 0.7434169650077820, -0.0097265020012856, 0, 0, 1, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 100, 0, 100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 33709547297962
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| https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20220110T191204/anc/eng/sff/mvn_rec_160416_160420_updated_v03.sff |
The Truth About Lions | Science| Smithsonian Magazine
The world's foremost lion expert reveals the brutal, secret world of the king of beasts
SCIENCE
The Truth About Lions
Biologists long believed that lions band together to hunt prey. But Craig Packer and colleagues have found that's not the main reason the animals team up.
Anup and Manoj Shah / www.shahimages.com
Craig Packer was behind the wheel when we came across the massive cat slumped in the shade beneath a spiny tree. It was a dark-maned male, elaborately sprawled, as if it had fallen from a great height. Its sides heaved with shallow pants. Packer, a University of Minnesota ecologist and the world’s leading lion expert, spun the wheel of the Land Rover and drove straight toward the animal. He pointed out the lion’s scraped elbow and a nasty puncture wound on its side. Its mane was full of leaves. From a distance it looked like a deposed lord, grand and pitiable.
Since arriving in Tanzania’s Serengeti National Park only that morning, I’d gaped at wildebeests on parade, dawdling baboons, gazelles rocketing by, oxpecker birds hitching rides atop Cape buffaloes, hippos with bubblegum-colored underbellies. The Serengeti usually dazzles first-time visitors, Packer had warned, making us giddy with an abundance of idyllic wildlife straight out of a Disney song-and-dance number.
The sublime brute only 15 feet away was my first wild Panthera leo. Male African lions can be ten feet long and weigh 400 pounds or more, and this one appeared to be pushing the limits of its species. I was glad to be inside a truck.
Packer, though, opened the door and hopped out. He snatched a stone and tossed it in the big male’s direction.
The lion raised its head. Its handsome face was raked with claw marks.
Packer threw another stone. Unimpressed, the lion briefly turned its back, showing hindquarters as smooth as cast bronze. The beast yawned and, nestling its tremendous head on its paws, shifted its gaze to us for the first time. Its eyes were yellow and cold like new doubloons.
This was one of The Killers.
Packer, 59, is tall, skinny and sharply angular, like a Serengeti thorn tree. He has spent a good chunk of his life at the park’s Lion House, a concrete, fortress-like structure that includes an office, kitchen and three bedrooms. It is furnished with a faux leopard-skin couch and supplied only sporadically with electricity (the researchers turn it off during the day to save energy) and fresh water (elephants dug up the pipelines years ago). Packer has been running the Serengeti Lion Project for 31 of its 43 years. It is the most extensive carnivore study ever conducted.
He has persisted through cholera outbreaks, bouts of malaria and a 1994 canine distemper epidemic that killed off a third of the 300 lions he’d been following. He has collected lion blood, milk, feces and semen. He has honed his distressed wildebeest calf call to get his subjects’ attention. He has learned to lob a defrosted ox heart full of medicine toward a hungry lion for a study of intestinal parasites. And he has braved the boredom of studying a creature that slumbers roughly 20 hours a day and has a face as inscrutable as a sphinx’s.
Packer’s reward has been an epic kind of science, a detailed chronicle of the lives and doings of generations of prides: the Plains Pride, the Lost Girls 2, the Transect Truants. Over the decades there have been plagues, births, invasions, feuds and dynasties. When the lions went to war, as they are inclined to do, he was their Homer.
“The scale of the lion study and Craig Packer’s vigor as a scientist are pretty unparalleled,” says Laurence Frank, of the University of California at Berkeley, who studies African lions and hyenas.
One of Packer’s more sensational experiments took aim at a longstanding mystery. A male lion is the only cat with a mane; some scientists believed its function was to protect an animal’s neck during fights. But because lions are the only social felines, Packer thought manes were more likely a message or a status symbol. He asked a Dutch toy company to craft four plush, life-size lions with light and dark manes of different lengths. He named them Lothario, Fabio, Romeo and Julio (as in Iglesias—this was the late 1990s). He attracted lions to the dolls using calls of scavenging hyenas. When they encountered the dummies, female lions almost invariably attempted to seduce the dark-maned ones, while males avoided them, preferring to attack the blonds, particularly those with shorter manes. (Stuffing still protrudes from the haunches of Fabio, a focal point of Lion House décor.)
Consulting their field data, Packer and his colleagues noticed that many males with short manes had suffered from injury or sickness. By contrast, dark-maned males tended to be older than the others, have higher testosterone levels, heal well after wounding and sire more surviving cubs—all of which made them more desirable mates and formidable foes. A mane, it seems, signals vital information about a male’s fighting ability and health to mates and rivals. Newspapers across the globe picked up the finding. “Manely, lady lions look for dark color,” one headline said. “Blonds have less fun in the lion world,” read another.
Lately, Packer’s research has taken on a new dimension. Long a dispassionate student of lion behavior and biology, he has become a champion for the species’ survival. In Tanzania, home to as many as half of all the wild lions on earth, the population is in free fall, having dropped by half since the mid-1990s, to fewer than 10,000. Across Africa, up to one-quarter of the world’s wild lions have vanished in little more than a decade.
The reason for the decline of the king of beasts can be summed up in one word: people. As more Tanzanians take up farming and ranching, they push farther into lion country. Now and then a lion kills a person or livestock; villagers—who once shot only nuisance lions—have started using poisons to wipe out whole prides. It is not a new problem, this interspecies competition for an increasingly scarce resource, but neither is it a simple one. Among other things, Packer and his students are studying how Tanzanians can change their animal husbandry and farming practices to ward off ravenous felines.
Scientists used to believe that prides—groups of a few to more than a dozen related females typically guarded by two or more males—were organized for hunting. Other aspects of the communal lifestyle—the animals’ affinity for napping in giant piles and even nursing each others’ young—were idealized as poignant examples of animal-kingdom altruism. But Packer and his collaborators have found that a pride isn’t formed primarily for catching dinner or sharing parenting chores or cuddling. The lions’ natural world—their behavior, their complex communities, their evolution—is shaped by one brutal, overarching force, what Packer calls “the dreadful enemy.”
Other lions.
Early one morning last August, Serengeti Lion Project researchers found Hildur, a Herculean male with a blond mane, limping around near a grassy ditch. He was sticking close to one of the pride’s four females, whose newborn cubs were hidden in a nearby stand of reeds. He was roaring softly, possibly in an effort to contact his darker-maned co-leader. But C-Boy, the researchers saw, had been cornered on the crest of a nearby hill by a fearsome trio of snarling males whom Packer and colleagues call The Killers.
The whole scene looked like a “takeover,” a brief, devastating clash in which a coalition of males tries to seize control of a pride. Resident males may be mortally wounded in the fighting. If the invaders are victorious, they kill all the young cubs to bring the pride’s females into heat again. Females sometimes die fighting to defend their cubs.
The researchers suspected that The Killers, who normally live near a river 12 miles away, had already dispatched two females from a different pride—thus The Killers earned their names.
C-Boy, surrounded, gave a strangled growl. The Killers fell on him, first two, then all three, slashing and biting as he swerved, their blows falling on his vulnerable hindquarters. The violence lasted less than a minute, but C-Boy’s flanks looked as if they’d been flayed with whips. Apparently satisfied their opponent was crippled, The Killers turned and trotted off toward the marsh, almost in lock step, as Hildur’s female companion crept toward a stand of reeds.
None of the Jua Kali lions had been spotted since the fight, but we kept riding out to their territory to look for them. We didn’t know if C-Boy had survived or if the cubs had made it. Finally, one afternoon we found JKM, the mother of the Jua Kali litter, lolling atop a termite mound as large and intricate as a pipe organ.
“Hey there, sweetness,” Packer said to her as we pulled up. “Where are your cubs?”
JKM had her eye on a kongoni antelope a few miles away; unfortunately, it was watching her, too. She was also scanning the sky for vultures, perhaps in the hopes of scavenging a hyena kill. She stood up and ambled off into the hip-high grass. We could see dark circles around her nipples: she was still lactating. Against the odds, her cubs seemed to have survived.
Perhaps the apparent good fortune of the Jua Kali cubs was linked to another recent sighting, Packer speculated: a female from another nearby group, the Mukoma Hill pride, had been seen moving her own tiny bobble-headed cubs. The cubs were panting and mewling pitifully, clearly in distress; normally cubs stay in their den during the heat of the day. The Killers might have forsaken the Jua Kali females to take over the Mukoma Hill pride, which inhabits richer territory near river confluences to the north. The woodlands there, said Packer, were controlled by a series of “dinky little pairs of males”: elderly Fellow and Jell-O; Porkie and Pie; and Wallace, the Mukoma Hill leader, whose partner, William, had recently died.
Packer recalled a similar pattern of invasion in the early 1980s by the Seven Samurai, a coalition of males, several with spectacular black manes, who had once brought down two adult, 1,000-pound Cape buffaloes and a calf in a single day. After storming the north they’d sired hundreds of cubs and ruled the savanna for a dozen years.
It took a while for Packer to tune into such dramas. When he first visited the Serengeti lions in 1974, he concluded that “lions were really boring.” The laziest of all the cats, they were usually collapsed in a stupor, as if they had just run a marathon, when in reality they hadn’t moved a muscle in 12 hours. Packer had been working under Jane Goodall in Tanzania’s Gombe Stream National Park, observing baboons. He slept in a metal structure called The Cage to be closer to the animals. In 1978, when Packer’s plan to study Japanese monkeys fell through, he and a fellow primatologist, Anne Pusey, to whom he was married at the time, volunteered to take over the Lion Project, begun 12 years earlier by the American naturalist George Schaller.
By the time Packer and Pusey installed themselves in the Lion House, scientists were well aware that lions are ambush predators with little stamina and that they gorge at a kill, each one downing up to 70 pounds in a sitting. (Lions eat, in addition to antelope and wildebeest, crocodiles, pythons, fur seals, baboons, hippopotamuses, porcupines and ostrich eggs.) Lion territories are quite large—15 square miles on the low end, ranging up to nearly 400—and are passed down through generations of females. Lions are vigorous when it comes to reproduction; Schaller observed one male mate 157 times in 55 hours.
Packer and Pusey set out not just to document lion behavior but to explain how it had evolved. “What we wanted to do was figure out why they did some of these things,” Packer says. “Why did they raise their cubs together? Did they really hunt cooperatively?”
They kept tabs on two dozen prides in minute detail, photographing each animal and naming new cubs. They noted where the lions congregated, who was eating how much of what, who had mated, who was wounded, who survived and who died. They described interactions at kills. It was slow going, even after they put radio collars on several lions in 1984. Packer was always more troubled by the lions’ sloth than their slavering jaws. Following prides at night—the animals are largely nocturnal—he sometimes thought he would go mad. “I read Tolstoy, I read Proust,” he says. “All the Russians.” Packer and Pusey wrote in one article that “to the list of inert noble gases, including krypton, argon and neon, we would add lion.”
Still, they began to see how prides functioned. Members of a large pride didn’t get any more to eat than a lone hunter, mostly because a solitary animal got the proverbial lion’s share. Yet lions band together without fail to confront and sometimes kill intruders. Larger groups thus monopolize the premier savanna real estate—usually around the confluence of rivers, where prey animals come to drink—while smaller prides are pushed to the margins.
Even the crèche, or communal nursery that is the social core of every pride, is shaped by violence, Packer says. He and Pusey realized this after scrutinizing groups of nursing mothers for countless hours. A lactating female nursed another’s young rarely, usually after an unrelated cub sneaked onto her nipple. An alert lioness reserves her milk for her own offspring. In contrast to the widespread belief that crèches were maternal utopias, Packer and Pusey found that nursing mothers stick together chiefly for defense. During takeovers by outside males, solitary females lost litter after litter, while cooperating lionesses stood a better chance of protecting their cubs and fending off males, which can outweigh females by as much as 50 percent.
Surviving cubs go on to perpetuate the bloody cycle. Juvenile females often join forces with their mother’s pride to defend the home turf. Males reared together typically form a coalition around age 2 or 3 and set out to conquer prides of their own. (Hard-living males rarely live past age 12; females can reach their late teens.) A lone male without a brother or cousin will often team up with another singleton; if he doesn’t, he is doomed to an isolated life. A group of lions will count its neighbors’ roars at night to estimate their numbers and determine if the time is right for an attack. The central insight of Packer’s career is this: lions evolved to dominate the savanna, not to share it.
As we crossed the plains one morning, the Land Rover—broken speedometer, no seat belts, cracked side mirrors, a fire extinguisher and a roll of toilet paper on the dashboard—creaked like an aged vessel in high seas. We plowed through oceans of grasses, mostly brown but also mint green, salmon pink and, in the distance, lavender; the lions we hunted were a liquid flicker, a current within a current. The landscape on this day did not look inviting. Sections of the giant sky were shaded with rain. Zebra jaws and picked-clean impala skulls littered the ground. Bones don’t last long here, though; hyenas eat them.
Packer and a research assistant, Ingela Jansson, were listening through headphones for the ping-ping-ping radio signal of collared lions. Jansson, driving, spotted a pride on the other side of a dry gully: six or seven lions sitting slack-jawed in the shade. Neither she nor Packer recognized them. Jansson had a feeling they might be a new group. “They may never have seen a car before,” she whispered.
The sides of the ditch looked unpromising, but Packer and Jansson couldn’t resist. Jansson found what seemed to be a decent crossing spot, by Serengeti standards, and angled the truck down. We roared across the bed and began churning up the other side. Packer, who is originally from Texas, let out a whoop of triumph just before we lurched to a halt and began to slide helplessly backward.
We came to rest at the bottom, snarled in reeds, with only three wheels on the ground, wedged between the riverbanks as tightly as a filling in a dental cavity. The ditch was 15 feet deep, so we could no longer see the pride, but as we’d slipped downward, a row of black-tipped ears had cocked inquisitively in our direction.
Jansson stepped out of the truck, long blond ponytail whipping around, dug at the wheels with a shovel and spade, and then hacked down reeds with a panga, or straight-blade machete. Earlier I had asked what kind of anti-lion gear the researchers carried. “An umbrella,” Jansson said. Apparently, lions don’t like umbrellas, particularly if they’re painted with large pairs of eyes.
Packer is not afraid of lions, especially Serengeti lions, which he says have few encounters with people or livestock and have plenty of other things to eat. To figure out if a sedated lion is truly down for the count, he’ll get out of the truck to tickle its ear. He says he once ditched a mired Land Rover within ten feet of a big pride and marched in the opposite direction, his 3-year-old daughter on his shoulders, singing nursery school songs all the way back to the Lion House. (His daughter, Catherine, 25, is a student at the Johns Hopkins Bloomberg School of Public Health. Packer never tried such a stunt with son Jonathan, now 22, although Jonathan was once bitten by a baboon. Packer and Pusey divorced in 1997; she returned to studying chimpanzees.)
I’d already taken stock of their carving-knife incisors and Cleopatra eyes, observed their low, rolling, hoodlum swaggers, heard their idling growls and nocturnal bellows. If you live in a mud hut protected by a bramble fence, if your cows are your bank account and your 7-year-old son is a shepherd who sleeps in the paddock with his goats, wouldn’t you want to eliminate every last lion on earth?
“People hate lions,” Packer had told me. “The people who live with them, anyway.”
After more than an hour of reed-whacking, stone-wedging and wrestling with mud ladders placed under the tires to provide traction, the vehicle finally surged onto the far side of the ditch. Incredibly, the lions remained precisely where we’d seen them last: sitting with Zen-like equanimity on their little doily of shade.
Jansson looked through binoculars, taking note of their whisker patterns and a discolored iris here and a missing tooth there. She determined this was the seldom-seen Turner Springs pride. Some of the sun-dazed lions had bloodstains on their milky chins. Though they hadn’t displayed the slightest interest in us, I uttered a silent prayer to go home.
“Let’s go closer,” Packer said.
The first true lion probably padded over the earth about 600,000 years ago, and its descendants eventually ruled a greater range than any other wild land mammal. They penetrated all of Africa, except for the deepest rain forests of the Congo Basin and driest parts of the Sahara, and every continent save Australia and Antarctica. There were lions in Great Britain, Russia and Peru; they were plentiful in Alaska and the habitat known today as downtown Los Angeles.
In the Grotte Chauvet, the cave in France whose 32,000-year-old paintings are considered among the oldest art in the world, there are more than 70 renderings of lions. Sketched in charcoal and ocher, these European cave lions—maneless and, according to fossil evidence, 25 percent bigger than African lions—prance alongside other now-extinct creatures: mammoths, Irish elk, woolly rhino. Some lions, drawn in the deepest part of the cave, are oddly colored and abstract, with hooves instead of paws; archaeologists believe these may be shamans.
The French government invited Packer to tour the cave in 1999. “It was one of the most profound experiences of my life,” Packer says. But the dream-like quality of the images wasn’t what excited him; it was their zoological accuracy. By the light of a miner’s lamp, he discerned pairs, lions moving in large groups and even submissive behavior, depicted down to the tilt of the subordinate’s ears. The artist, Packer says, “doesn’t exaggerate their teeth, he doesn’t make them seem more formidable than I would. This was somebody who was viewing them in a very cool and detached way. This was somebody who was studying lions.”
The lions’ decline began about 12,000 years ago. Prehistoric human beings, with their improving hunting technologies, probably competed with lions for prey, and lion subspecies in Europe and the Americas went extinct. Other subspecies were common in India and Africa until the 1800s, when European colonists began killing lions on safaris and clearing the land. In 1920, a hunter shot the last known member of the North African subspecies in Morocco. Today, the only wild lions outside Africa belong to a small group of fewer than 400 Asiatic lions in the Gir Forest of India.
Lions persist in a handful of countries across southeastern Africa, including Botswana, South Africa and Kenya, but Tanzania’s population is by far the largest. Though devastatingly poor, the nation is a reasonably stable democracy with huge tracts of protected land.
Serengeti National Park—at 5,700 square miles, about the size of Connecticut—is perhaps the world’s greatest lion sanctuary, with some 3,000 lions. In Packer’s study area, comprising the territories of 23 prides near the park’s center, the number of lions is stable or even rising. But the Serengeti is the exception.
Part of the blame for Tanzania’s crashing lion population belongs to the trophy-hunting industry: the government allows the harvest of some 240 wild lions a year from game reserves and other unprotected areas, the highest take in Africa. Safaris charge a trophy fee of as little as $6,000 for a lion; animals are shot while feasting on baits, and many of the coveted “trophy males” have peach fuzz manes and haven’t even left their mother’s pride yet. The use of lion parts in folk medicines is another concern; as wild tigers disappear from Asia, scientists have noticed increasing demand for leonine substitutes.
The central issue, though, is the growing human population. Tanzania has three times as many residents now—some 42 million—as when Packer began working there. The country has lost more than 37 percent of its woodlands since 1990. Disease has spread from village animals to the lions’ prey animals, and, in the case of the 1994 distemper outbreak that started in domestic dogs, to the lions themselves. The lions’ prey animals are also popular in the burgeoning—and illicit—market for bush meat.
And then there is the understandable ill will that people bear lions, which loiter on front porches, bust through thatched roofs, snatch cattle, rip children from their mother’s arms, haul the elderly out of bed and seize women on the way to latrines. In the 1990s, as Tanzanians plowed large swaths of lion territory into fields, lion attacks on people and livestock rose dramatically.
Bernard Kissui, a Tanzanian lion scientist with the African Wildlife Foundation and one of Packer’s former graduate students, met Packer and me in Manyara, a bustling district southeast of Serengeti National Park. Kissui said five lions nearby had recently died after eating a giraffe carcass laced with tick poison.
“Is that one of your study prides?” Packer asked.
“I’m suspecting so,” said Kissui, who works in the nearby Tangire National Park. He wasn’t sure who had poisoned the lions or what had provoked the killings. A month earlier, lions had killed three boys, ages 4, 10 and 14, herding livestock, but that was in a village 40 miles away.
“Africa is not Africa without lions,” Kissui told me, but “human needs precede the wildlife’s. As the number of people increases, we take the land that would have been available to the wildlife and use it for ourselves. Africa has one billion people now. Think about what that one billion implies in terms of the future of lions. We are heading into a very complicated world.”
Young men from pastoral tribes no longer care to tend cattle, Kissui says. “They want to go to Arusha and drive a car.” So their little brothers are sent into the bush instead. Packer and his students have shown that lions tend to target livestock tended by boys during the dry season.
Packer, Kissui and other scientists are experimenting with ways to keep people and lions safe. Special funds repay herders for lost livestock—if no lion is harmed. They have suggested that corn farmers in southern Tanzania hang chili peppers in their fields, which repel the bush pigs that lions relish, or dig ditches around their crops to keep the pigs out. And Packer is assisting Kissui with a program that subsidizes herdsmen who want to replace their bramble-enclosed paddocks with fences of metal and wood.
In Manyara we visited Sairey LoBoye, a study participant. He was attired in stunning blue blankets and talking on his cellphone. LoBoye is a member of the Maasai tribe, whose traditional culture centers on safeguarding cattle: teenagers spear lions as a rite of passage. LoBoye said he simply wanted lions to leave him alone. Two years ago lions devoured one of his precious bulls, but since installing a modern fence, he hasn’t had any problems and his cattle and children are safer. “Now I can sleep at night,” he said.
Packer argues that the Serengeti, like some South African parks, should be surrounded by an electric, elephant-proof, heavily patrolled fence that would encompass the whole wildebeest migration route and keep the lions in and the poachers out. The idea has little support, in part because of the tens of millions of dollars it would cost to erect the barrier.
As hard as it is for Packer to imagine the prides he has followed for so long ending in oblivion in the next few decades, he says that’s the most likely outcome: “Why am I doing this? I feel like I owe this country something. So 100 years from now there will still be lions in Tanzania.”
Before I left the Serengeti, Packer took me to see a fig tree that had served for decades as a lion scratching post. As we drove across the savanna, graduate student Alexandra Swanson fiddled with a radio scanner, searching for signals from radio-collared lions, but we heard only static.
The tree was on a kopje, one of the isolated piles of rocks in the grasslands that are popular lion haunts. Packer wanted to climb up for a better look. Lulled, perhaps, by the silence on the scanner, I agreed to accompany him.
We’d climbed most of the way up the pile when Packer snapped his fingers and motioned for me to crouch down. The world seemed to zoom in and out, as if I was looking through a camera’s telephoto lens, and I imagined hot lion breath on my neck.
Packer, at the top of the kopje, was waving me closer.
“Do you see that lion?” he whispered. “No,” I whispered back.
He pointed at a shadowy crevice beneath the fig tree, about 20 feet away. “You don’t see that lion?”
“There is no lion,” I said, as if my words could make it so.
Then I saw one tiny, yellow, heart-shaped face, and then another, bright as dandelions against the gray rocks. Golden eyes blinked at us.
Mothers often leave their cubs for long stretches to hunt, but this was only the second time in Packer’s long career he’d found an unattended den. Young cubs are almost completely helpless and can starve or be eaten by hyenas if left alone too long. One of the cubs was clearly horrified by our presence and shrank behind its braver sibling, which arranged itself in a princely fashion on the rocks to enjoy these strange, spindly, cringing creatures. The other cub seemed to forget its fear and bit the bold one’s ear. They were perfect fleecy things. Their coats had a faint tiled pattern that would fade away with time.
That night we camped beside the kopje, Swanson and I in the bed of the Land Rover and Packer in a flimsy tent. It wasn’t the most restful evening of my life: in the lion’s last great stronghold, we were outside a mother’s very den.
I kept thinking of the cubs in the crevice. Their mother might return while we slept. I almost hoped she would.
The first true lion probably padded over the earth about 600,000 years ago , and its descendants eventually ruled a greater range than any other wild land mammal. Anup and Manoj Shah / www.shahimages.com
Biologists long believed that lions band together to hunt prey. But Craig Packer and colleagues have found that's not the main reason the animals team up. Anup and Manoj Shah / www.shahimages.com
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Reporting From the Serengeti
Smithsonian staff writer Abigail Tucker came across imperiled zebras, dusty savannahs and perilous roads while researching the Tanzanian lions
A frequent contributor to Smithsonian, Abigail Tucker is the author of The Lion in the Living Room: How House Cats Tamed Us and Took Over the Worldand Mom Genes: Inside the New Science of Our Ancient Maternal Instinct. More information is available at her website:abigailtucker.com
| https://www.smithsonianmag.com/science-nature/the-truth-about-lions-11558237/?page=5&viewAll=y |
Tiny 'lab-on-a-chip' detects pollutants, disease and biological weapons | EurekAlert! Science News
For centuries, animals have been our first line of defense against toxins. A canary in a coalmine served as a living monitor for poisonous gases. Scientists used fish to test for contaminants in our water. Even with modern advances, though, it can take days to detect a fatal chemical or organism. Until now. Working in the miniaturized world of nanotechnology, Tel Aviv University researchers have made an enormous -- and humane -- leap forward in the detection of pollutants.
Tiny 'lab-on-a-chip' detects pollutants, disease and biological weapons
Tel Aviv University scientists develop highly accurate nano-scale biomonitoring solution
American Friends of Tel Aviv University
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IMAGE:This is Yosi Shacham-Diamand of Tel Aviv University.view more
Credit: AFTAU
For centuries, animals have been our first line of defense against toxins. A canary in a coalmine served as a living monitor for poisonous gases. Scientists used fish to test for contaminants in our water. Even with modern advances, though, it can take days to detect a fatal chemical or organism.
Until now. Working in the miniaturized world of nanotechnology, Tel Aviv University researchers have made an enormous -- and humane -- leap forward in the detection of pollutants.
A team led by Prof. Yosi Shacham-Diamand, vice-dean of TAU's Faculty of Engineering, has developed a nano-sized laboratory, complete with a microscopic workbench, to measure water quality in real time. Their "lab on a chip" is a breakthrough in the effort to keep water safe from pollution and bioterrorist threats, pairing biology with the cutting-edge capabilities of nanotechnology.
"We've developed a platform -- essentially a micro-sized, quarter-inch square 'lab' -- employing genetically engineered bacteria that light up when presented with a stressor in water," says Prof. Shacham-Diamand. Equipment on the little chip can work to help detect very tiny light levels produced by the bacteria.
Instead of using animals to help detect threats to a water supply, Prof. Shacham-Diamand says "Our system is based on a plastic chip that is more humane, much faster, more sensitive and much cheaper."
Tiny Lab-on-Chip Boosts Accuracy
"Basically, ours is an innovative advance in the 'lab on a chip' system," says Prof. Shacham-Diamand. "It's an ingenious nano-scale platform designed to get information out of biological events. Our solution can monitor water with never-before-achieved levels of accuracy. But as a platform, it can also be used for unlimited purposes, such as investigating stem cell therapies or treating cancer."
According to published literature, Tel Aviv University is one of the top five universities in the world pioneering the "lab on a chip" concept. The nanolabs can be used to evaluate several biological processes with practical applications, such as microbes in water, stem cells, or breast cancer development. Prof. Shacham-Diamand's active lab group publishes a major paper about once a month in this field, most recently in the journal Nano Letters.
Environmental, Medical and Defense Uses for "Mini-Labs"
Partnering with other Israeli scientists, Tel Aviv University is currently building and commercializing its water-testing mini-labs to measure and monitor how genetically engineered bacteria respond to pollution such as E. coli in water. Cities across Israel have expressed interest in the technology, as has the state of Hawaii.
But other uses are being explored as well. Funded by a $3 million grant from the United States Department of Defense Projects Agency (DARPA), the new lab-on-a-chip could become a defensive weapon that protects America from biological warfare. His system, Prof. Shacham-Diamand says, can be also modified to react to chemical threats and pollution. With some tweaking here and there, it can be updated as new threats are detected.
Prof. Shacham-Diamond's research has also attracted the interest of cancer researchers around the world. He recently addressed 400 physicians at a World Cancer Conference who are seeking new devices to measure and monitor cancer and pharmaceuticals. "They need sensors like Tel Aviv University's lab on a chip. It's a hot topic now," says Prof. Shacham-Diamond.
###
American Friends of Tel Aviv University (www.aftau.org) supports Israel's leading and most comprehensive center of higher learning. In independent rankings, TAU's innovations and discoveries are cited more often by the global scientific community than all but 20 other universities worldwide.
Internationally recognized for the scope and groundbreaking nature of its research programs, Tel Aviv University consistently produces work with profound implications for the future.
| https://archive.eurekalert.org/pub_releases/2009-02/afot-td021709.php |
(PDF) Functional connectome reorganization relates to post-stroke motor recovery and structural disconnection
PDF | Motor recovery following ischemic stroke is contingent on the ability of surviving brain networks to compensate for damaged tissue. In rodent... | Find, read and cite all the research you need on ResearchGate
Functional connectome reorganization relates to post-stroke motor recovery and structural disconnection
DOI: 10.1101/2021.05.27.445834
Abstract and Figures
Motor recovery following ischemic stroke is contingent on the ability of surviving brain networks to compensate for damaged tissue. In rodent models, sensory and motor cortical representations have been shown to remap onto intact tissue around the lesion site, but remapping to more distal sites (e.g. in the contralesional hemisphere) has also been observed. Resting state functional connectivity (FC) analysis has been employed to study compensatory network adaptations in humans, but mechanisms and time course of motor recovery are not well understood. Here, we examine longitudinal FC in 23 first-episode ischemic pontine stroke patients (34-74 years old; 8 female, 15 male) and utilize a graph matching approach to identify patterns of regional functional connectivity reorganization during recovery. We quantified functional reorganization between several intervals ranging from 1 week to 6 months following stroke, and demonstrated that the areas that undergo functional reorganization most frequently are in cerebellar/subcortical networks. Brain regions with more structural connectome disruption due to the stroke also had more functional remapping over time. Finally, we show that the amount of functional reorganization between time points is correlated with the extent of motor recovery observed between those time points in the early to late subacute phases, and, furthermore, individuals with greater baseline motor impairment demonstrate more extensive early subacute functional reorganization (from one to two weeks post-stroke) and this reorganization correlates with better motor recovery at 6 months. Taken together, these results suggest that our graph matching approach can quantify recovery-relevant, whole-brain functional connectivity network reorganization after stroke.
Overview of individuals' stroke lesions, resulting structural disconnection and Fugl-Meyer score trajectories. A. Distribution of lesions across the brain. Colors indicate the number of subjects with a lesion in that voxel. B. Fugl-Meyer scores for all subjects over the five post-stroke sessions. Boxes colored white indicate missing motor scores and diagonal lines within the box indicate missing MRI data for the corresponding time point. …
Regional functional remapping frequencies are related to mean estimated structural connectivity disruptions due to the lesion. A. Regional remap frequencies plotted on a glass brain, averaged across 4 inter-session comparisons. Inset figures display a lateral view (top row) and medial view (bottom row). B. Regional remap frequencies plotted on a glass brain, displayed separately for each inter-session comparison. C. Network-level sum of remaps, averaged across all 4 comparisons, and normalized by the number of regions in each network. Remaps are separated based on their position relative to the lesion (contralesional vs. ipsilesional). D. Network-level sum of remaps, displayed separately for each inter-session comparisons, normalized by the number of regions in each network. Ipsilesional = in the same hemisphere as the lesion, contralesional = in the opposite hemisphere as the lesion. …
Remapping preferentially occurs in regions with greater structural connectivity disruption A. Correlations between average ChaCo scores and regional remap frequencies across all 23 stroke subjects. Regions are colored by network assignment. B. ChaCo scores of regions that remap are significantly greater than ChaCo scores of regions that do not remap. …
The amount of early functional remapping is related to baseline motor impairment and eventual motor recovery; functional remapping is related to change in motor recovery between subsequent time points. A. Pearson correlation between individuals' total number of early remaps (between 1 week FC and 2 week FC) and their change in Fugl-Meyer scores between 1 week and 6 months post-stroke (Spearman correlation: 0.549, p(FDR)=0.022). B. Pearson correlation between individuals' total number of early remaps (between 1 week FC and 2 week FC) and 1 week Fugl-Meyer scores, controlling for subjects' average scan lengths between 1 week post-stroke and session 2 (Spearman correlation: -0.654, p(FDR) = 0.002). C. Results from linear mixed effects analysis; colors indicate different individuals' longitudinal time points. D. Pearson correlation between the total remaps observed between each pair of time points and the change in Fugl-Meyer scores between time points, controlling for average fMRI scan length. P-values are corrected for multiple comparisons (Spearman correlations: Corr. 1 week-2 weeks = 0.456, p(FDR)=0.0575, Corr. 2 weeks -1 month = 0.566, p(FDR)=0.03, Corr. 1 month -3 months = 0.533, p(FDR)=0.03, Corr. 3 months -6 months = -0.09, p(FDR)=0.714) …
Figure S6: Average framewise displacement between scans does not correlate with the sum of remaps observed between scans. …
Figures - available via license: Creative Commons Attribution-NonCommercial 4.0 International
Functional connectome reorganization relates to post-str oke motor
recovery and structural disruption
Emily R Olafson 1 , Keith W Jamison 1 , Elizabeth M Sweeney 2 , Hesheng Liu 3 , Danhong W ang 3 , Joel E Bruss 4 ,
Aaron D Boes 4 , Amy Kuceyeski 1
1 Department of Radiology, W eill Cornell Medical College, New Y ork City, Ne w Y ork, USA, 10021
2 Department of Population Health Sciences, Weill Cornell Medical Colle ge, New Y ork City, New Y ork, USA, 10021
3 Department of Radiology, Harv ard Medical School, Boston, Massachusetts, USA, 02115
4 Department of Neurology, Uni versity of Iowa, Iowa City , IA, USA, 52242
Abstract
Motor recovery following ischemic stroke is contingent on the ability of survi ving brain networks to com-
pensate for damaged tissue. In rodent models, sensory and motor cortical representations have been shown to
remap onto intact tissue around the lesion site, but remapping to more distal sites (e.g. in the contralesional hemi-
sphere) has also been observed. Resting state functional connectivity (FC) analysis has been employed to study
compensatory network adaptations in humans, but mechanisms and time course of motor recovery are not well
understood. Here, we examine longitudinal FC in 23 first-episode ischemic pontine stroke patients (34-74 years
old; 8 female, 15 male) and utilize a graph matching approach to identify patterns of regional functional connec-
tivity reorganization during recov ery. W e quantified functional reorganization between several interv als ranging
from 1 week to 6 months following stroke, and demonstrated that the areas that undergo functional reorganization
most frequently are in cerebellar/subcortical networks. Brain regions with more structural connectome disruption
due to the stroke also had more functional remapping over time. Finally, we show that the amount of functional
reorganization between time points is correlated with the extent of motor recovery observ ed between those time
points in the early to late subacute phases, and, furthermore, individuals with greater baseline motor impairment
demonstrate more extensive early subacute functional reorganization (from one to tw o weeks post-stroke) and this
reorganization correlates with better motor recovery at 6 months. Tak en together, these results suggest that our
graph matching approach can quantify recovery-relev ant, whole-brain functional connectivity network reorganiza-
tion after stroke.
Introduction
Motor deficits are among the most common and disruptive symptoms of ischemic stroke. Spontaneous
recovery of motor function occurs for most patients (Duncan et al., 2000), and largely depends on the ability of
brain networks to functionally reorganize and compensate for lost function (Corbetta et al., 2005). As demonstrated
by animal models, the functionality of damaged motor regions may be remapped to surviving tissue around the
lesion (Winship and Murphy, 2009). However, brain areas distant to the lesion that have similar function and/or
1
connectivity as the damaged area have also been sho wn to compensate for lost function (Winship and Murphy,
2009; Adam et al., 2020; Murata et al., 2015; Brown et al., 2009).
In humans, functional reorganization has been studied with functional magnetic resonance imaging (fMRI).
T ask fMRI studies have demonstrated that cortical reorganization related to motor recov ery can be characterized
by task-based activation of survi ving ipsilesional cortex, contralesional areas, and even in regions not classically
activated by motor tasks in healthy subjects (Park et al., 2011). Recently, resting-state fMRI has emerged as a
means to study connectivity changes after stroke in subjects who are sev erely impaired and cannot perform motor
tasks (Park et al., 2011). Resting-state fMRI has been used to identify recovery-related changes in functional
connectivity (FC) between specific brain regions, reflecting network-lev el changes. However, few studies to date
have attempted to capture longitudinal network-lev el reorganization using resting-state fMRI.
Prior studies investigating neural correlates of motor reco very have also focused almost exclusiv ely on
supratentorial strokes that impact the internal capsule and surrounding areas. Infratentorial pontine strokes may
impact the corticospinal tract directly or the connections between motor cortex and the cerebellum (Lu et al.,
2011), they account for roughly 7 percent of all ischemic strokes (Saia and Pantoni, 2009), and may have dif ferent
mechanisms of recovery-related reorganization from those of supratentorial strokes.
Remote brain areas anatomically connected to the lesion undergo structural and functional changes through
a process known as diaschisis (Carrera and T ononi, 2014). Remapping of areas anatomically connected to the
lesion may be an important component of the recovery process that has not been deeply explored. In this study, we
propose a novel measure to capture adaptive functional plasticity after pontine strok e, outlined below , and relate it
to patterns of regional stroke-related structural connectome disruption and measures of motor recovery .
Connectivity to the rest of the brain is one aspect of a brain region’ s functional role in the network. We pro-
pose that instances of functional reorganization over time, as in the case of adjacent/distal surviving tissue adopting
the functional role of lost tissue, may be captured by identifying brain regions whose pattern of FC with the rest
of the brain is more closely matched by a different brain region at a later date. Considering functional connec-
tomes as a graph, the task of identifying similar nodes (gray matter regions, in this case) between two functional
connectomes can be considered a graph matching problem (Conte et al., 2004). Conceptually, the process of graph
matching exchanges the labels of regions in a network when doing so results in increased similarity of the two
networks. When two regions exchange FC profiles, the regions are said to have been ‘remapped’. We hypothesize
that graph matching, applied recently to brain networks for the first time to assess the relationship between func-
tional and structural connectivity networks (Osmanlıo ˘
glu et al., 2019), will allow accurate quantification of whole
brain, network-level, recov ery-relevant functional reorganization after stroke.
As far as we know , no work has attempted to detect connectivity network-level functional reorganization in
post-stroke recovery with longitudinal MRI, much less correlate it with measures of recovery or patterns of struc-
tural connectome damage. We hypothesize that 1) brain regions with more structural damage due to the stroke will
more frequently functionally reorganize, 2) more impaired subjects will have more early functional reor ganization
in the sub-acute stages, 3) the amount or early reorganization will be correlated with long-term recovery , and 4)
the amount of functional reorganization over time will correlate with the change in motor impairment between
subsequent sessions.
2
Materials and methods
Data description
The data consist of twenty-three first-episode stroke patients (34-74 years old; mean age 57 years; 8 female)
with isolated pontine infarcts previously described in (Lu et al., 2011). Fourteen subjects had right brainstem
infarcts, nine had left brainstem infarcts (Figure 1A). Patients were scanned five times o ver a period of 6 months,
specifically, MRIs were obtained at 7, 14, 30, 90 and 180 days after stroke onset on a 3T TimTrio Siemens
using a 12-channel phase-array head coil. Fugl-Meyer motor scores were obtained twice at each session, and
later averaged and normalized to a range of 0-100 (Figure 1B). Anatomical images were acquired using a sagittal
MP-RAGE three-dimensional T1-weighed sequence (TR, 1600ms; TE 2.15ms; flip angle, 9°, 1.0 mm isotropic
voxels, FOV 256 x 256). Each MRI session involved between two and four runs of resting-state fMRI at 6 mins
each. Subjects were instructed to stay awake with their eyes open; no other task instruction was provided. Images
were acquired using the gradient-echo echo-planar pulse sequence (TR, 3000ms; TE, 30ms; flip angle, 90°, 3 mm
isotropic voxels).
Structural data processing
Preprocessing of the longitudinal structural data included affine registration of each subject’ s T1 scans to
the baseline T1 scan, collapsing co-registered files to an average T1 and creation of a skull-stripped brain mask
followed by manual editing and binarization of the hand-edited mask. The brain mask was then transformed back
to each of the follow-up T1s in native space using the in verse registration acquired from the first step. This was
followed by bias field correction of all the T1 scans, transformation of native-space bias field-corrected data back
to baseline space, and the creation of an average bias field-corrected scan for each subject. Stroke lesion masks
were hand-drawn on these transformed T1 scans by ADB and JEB. Structural normalization was performed with
the CONN toolbox (Whitfield-Gabrieli and Nieto-Castanon, 2012).
Functional data processing
Preprocessing of the longitudinal functional data was performed using the CONN toolbox (Whitfield-
Gabrieli and Nieto-Castanon, 2012), including functional realignment of volumes to the baseline volume, slice
timing correction for alternating acquisition, segmentation and normalization, and smoothing with a 4mm FWHM
kernel. This was followed by a denoising protocol (CompCor) (Behzadi et al., 2007) which regressed out the
cerebrospinal fluid and white matter signal, as well as 24 realignment parameters (added first-order derivativ es and
quadratic effects). Temporal band pass filtering (0.008 - 0.09Hz), despiking and global signal remo val regression
were also performed. The first four frames of each BOLD run were removed. Frame censoring was applied to scans
with a framewise displacement threshold of 0.5 mm along with its preceding scan (Power et al., 2012). Regional
time series were acquired by parcellating the scans into 268 non-overlapping brain regions using a functional atlas
derived from healthy controls (Shen et al., 2013) and av eraging the time course of all voxels within a given region.
V oxels identified as lesioned were excluded from regional timeseries calculations. Regions were assigned to one
of 8 functional networks, identified by (Finn et al., 2015) using spectral clustering in healthy subjects (Figure S1).
3
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(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
Figure 1: Overview of individuals’ stroke lesions, resulting structural disconnection and Fugl-Meyer score trajec-
tories. A. Distribution of lesions across the brain. Colors indicate the number of subjects with a lesion in that
voxel. B. Fugl-Meyer scores for all subjects ov er the five post-stroke sessions. Boxes colored white indicate miss-
ing motor scores and diagonal lines within the box indicate missing MRI data for the corresponding time point.
C. Group average structural disconnection scores for each brain region calculated as the number of streamlines
connected to each region that intersect with the lesion, normalized by the total number of streamlines connecting
to that region (only displaying regions with disconnection scores > 0.005). Top row of each subject inset sho ws a
lateral view of the brain, bottom row of each inset shows a medial vie w.
4
Functional connectivity calculation
Functional connectivity (FC) matrices were calculated as the regularized in verse of precision matrices.
Calculating FC using precision minimizes the effect of indirect connections and has been shown to result in FC
that are more similar to structural connectivity (W odeyar et al., 2020; Li ´
egeois et al., 2020). To compute the
precision FC, we first calculated the full Pearson correlation-based FC ( Σ i ) for each individual i by correlating
region-pair time series. We then took the unregularized in verse of Σ i , denoted P
i , and averaged them over the
i subjects to obtain the population-level precision FC matrix P
avg . We then calculated the individual precision
FC matrices using Tikhonov regularization, which adds a full-rank regularization term (scaled identity) to the
correlation matrix before inversion (Li ´
egeois et al., 2020):
P reg
i = ( Σ i + λ · I ) − 1
where I is the identity matrix and λ ∈ [ 0 , 1 ] is the regularization parameter. The regularization parameter
λ was chosen via a grid search to be the value that minimized the root mean squared error of the Frobenius norm
of the difference in regularized subject precision matrices P re g
i and the population-level unregularized precision
matrix P
avg , which was found to be λ = 0 . 73 (Fig S2). The values along the diagonal were set to 0 prior to graph
matching.
Estimated structural disconnection
Deficits from subcortical stroke may be related to functional alterations at distant sites via metabolic di-
aschisis (Hillis et al., 2002; Corbetta et al., 2015) or remote degeneration that spreads along the white matter
connectivity network (Duering et al., 2015; Cheng et al., 2015). In order to account for the impact of lesions on the
structural connectome, the extent of regional structural connectivity (SC) disruption due to the lesion was assessed
for each stroke subject with the Network Modification (NeMo) T ool (Kuceyeski et al., 2013). The NeMo Tool
v2 requires only an individual’ s lesion mask in MNI space, which was obtained as described above, to produce
an estimate of structural disconnection to each brain voxel, or to each region in a user-defined atlas. The newest
version of the NeMo T ool, originally published in 2013, includes a reference database of SC from 420 unrelated
individuals from the Human Connectome Project’ s (HCP) 1200 release (50 percent female, aged 25-35). The
NeMo T ool begins by mapping the lesion mask into this healthy database’s collection of tractography streamlines
that quantify likely white matter pathways. It then identifies streamlines that pass through the lesion mask and
records the gray matter voxels/regions that are at the ends of that streamline. The NeMo Tool produces the re-
gional structural disconnection vector (ChaCo score, Change in Connectivity) that is an estimate of the percent of
damaged streamlines at each voxel or region in the atlas (Figure 1C).
Graph matching
W e used a graph matching algorithm to capture FC network reorganization over time (2). Graph matching
is an algorithmic process that maximizes the similarity between two networks by identifying an optimal map-
ping between nodes in the networks. One approach to identifying this optimal mapping is with a combinatorial
optimization problem known as linear assignment.
5
Figure 2: Overview of the graph matching procedure used to identify brain regions whose FC is more similar to a
different region’ s FC in the subsequent imaging session, i.e. regions that ”remap” functional profiles. A. Example
of a pair of regions that remap. Region i at 1 week post-stroke and region j at 2 weeks post-stroke hav e highly
similar FC with the rest of the brain (moreso than region i at 1 week to region i at 2 weeks). The cost to remap i to
j is low , and these regions would likely be remapped in the graph matching algorithm. B. The cost of remapping
each region pair is used as input to the graph matching algorithm; the output of graph matching is the assignment
of each region in one imaging session to a single corresponding region in the subsequent imaging session. If this
assignment is to a different region, then it said to have ”remapped”. C. Three examples of cost matrices of three
subjects with varying amounts of remapping.
6
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T ake two n × n networks A and B and a cost function c : A × B → R that determines the cost of assigning each
node in A to each node in B . Here, our cost function is the sum of the entries in the cost matrix C = c i j , whose
entries c i j are defined by the Euclidean distance between row i in A and row j in B , i.e. c i j ( A , B ) = || A i • − B j • || 2
2 .
In our application, the rows A i • and B j • represent region i and region j ’s FC to the rest of the brain, or FC profile,
respectively . The linear assignment problem aims to construct the permutation matrix P = p i j that minimizes the
sum of the elements in cost matrix, i.e. min P ∑ n
i = 1 ∑ n
j = 1 c i j p i j . The matrix P is a permutation matrix with exactly
one entry equal to 1 in each row and column, the rest being zero. Ones in the diagonal of P indicate the same node
in the two networks were mapped to one another, while ones in the of f-diagonal indicate a node was “remapped”
to another node.
Here, we use the Hungarian algorithm to solve this minimization problem and find the corresponding op-
timal permutation matrix P . Figure 2 illustrates how the graph matching is applied to subsequent longitudinal FC
networks in the same individual (either post-stroke or control) and depicts an instance of remapping in a single
subject. In Figure 2A, the FC profile of brain region i (green region) at 1 week post-stroke is more closely matched
by the FC profile of region j (blue region) at 2 weeks post-stroke than it is to itself at 2 weeks post-stroke. Ex-
ample cost matrices for three stroke subjects (one with high amount of remapping, one with an average amount
of remapping and one with a low amount of remapping) are also provided. Unsurprisingly, the lo west costs are
along the diagonal (the same region mapping to itself between time points) and across left-right homologues (in
the prominent super and sub diagonals).
Quantification of functional reorganization
The permutation matrices calculated for each pair of time points for each individual were used to quan-
tify functional reorganization. To assess the spatial pattern of reorg anization across the brain, we calculated each
region’s ’ remap frequency’, i.e. the proportion of individuals that had that brain region remap between two subse-
quent time points. To assess the e xtent of functional reorganization for an individual, the number nodes that were
remapped (sum of the off-diagonal in P ) over time was also calculated.
Regularization to reduce noise
W e performed graph matching in two control datasets in order to identify brain regions which may remap
more often due to noise or other factors. We observed remapping in controls in areas of the brainstem and cerebel-
lum, possibly related to the low signal-to-noise ratio of these areas (Figure S3). We aimed to reduce the number of
noise-related remaps by adding a regularization term to the cost matrices prior to the graph matching calculation.
T o do this, we added a regularization parameter to each region-pair based on the Euclidean distance between their
centroids; this results in an increased cost of remapping two regions that are further apart. A Euclidean distance
regularization was chosen due to the fact that remaps in control subjects were primarily between region pairs that
were spatially close to each other, and because prior animal work suggests that functional remapping more often
occurs in areas proximal to the lesion site. We e xpect that stroke-related remapping will be robust to the same
amount of regularization that eliminates or minimizes remapping in controls.
Specifically, the scaled Euclidean distance matrix, whose entries E ij contain distance between centroids for
two regions i and j , was added to the graph matching cost matrix c i j . Therefore, the new, penalized cost matrix
7
is c i j = || A i • − B • j || 2
2 + β E i j , where β is the parameter that scales the regularization term. We varied β to be 0,
1e-4, 2e-4, and 3e-4 and identified the value at which remapping was minimized in controls, which was β = 1e-4
(Figure S4A). The few nodes that remapped in the cast-plasticity and 28andme dataset at a regularization of β =
1e-4 were removed in all analyses in the stroke subjects to further reduce noise.
Statistical analyses
T o test the hypothesis that brain regions more impacted by the stroke lesion would have more frequent
remapping, we calculated the correlation between each region’s remapping frequenc y (proportion of individuals in
which that region was remapped) and the sample average log-transformed ChaCo scores that quantify the re gional
amount of structural (white matter) connectivity disruption due to the stroke lesion. The statistical significance
of the correlation was assessed with permutation testing. There are four measures of remapping frequencies that
represent remapping between the four pairs of subsequent time points post-stroke (1 week - 2 weeks, 2 weeks - 1
month, 1 month - 3 months and 3 months - 6 months). Because there was a statistically significant correlation be-
tween scan length and remapping for the time point from 1 week - 2 weeks post-stroke (corr = -0.57, p(FDR)=0.01),
average fMRI scan length was included as a cov ariate in analyses concerning remapping over time (no other time
point had a significant relationship between scan length and remapping). To test the hypothesis that indi viduals
with more remapping from one time point to another have better motor improvement, we calculated the Pearson
correlation between change in Fugl-Meyer motor scores and number of remapped regions (controlling for mean
fMRI scan length between sessions) from one time point to the next for all four pairs of subsequent time points.
In order to leverage the repeated subject measurements, a linear mixed effects re gression model was employed to
determine the relationship between the amount of remapping between sessions and the change Fugl-Meyer score
between sessions, including age, sex, and scan length as covariates. Let i index a subject and t index a time point.
Our model is then:
changeFM it = β 0 + β 1 rema pping it + β 2 scanl ength it + β 3 age i + β 4 sex i + b i + ε it (1)
where b i ∼ N ( 0 , σ 2
1 ) and ε it ∼ N ( 0 , σ 2
2 ) . We include the random ef fect b i to account for correlation within a subject
at different time points. To test the hypothesis that more impaired indi viduals would have more early remapping,
Pearson’s correlation was computed between motor scores at 1 week post-stroke with the amount of remapping
from 1 to 2 weeks post-stroke, controlling for the two sessions’ average fMRI scan lengths. To test if functional
remapping in the early post-stroke period would be correlated with overall motor recov ery, Pearson’ s correlation
was computed between the number of regions that remapped from 1 week to 2 weeks post-stroke and the change
in Fugl-Meyer scores from 1 week to 6 months post-stroke, controlling for the two sessions’ average fMRI scan
length. For the last analysis, p-values were corrected for multiple comparisons using the Benjamimi-Hochberg
FDR procedure.
Code availability
The code for to replicate this analysis is available on GitHub: https://github.com/emilyolafson/stroke-graph-
matching
8
Results
Remapping in control subjects
W e performed the same graph matching analysis in two separate datasets of control individuals: 1) a single
female individual sampled for 30 continuous days as part of the 28andMe study (Pritschet et al., 2020) and 2)
three separate individuals sampled daily for between 10 and 14 sessions as a part of a cast-induced plasticity
study (Newbold et al., 2020). Several non-ov erlapping windows of imaging obtained 7 days apart (replicating 1
week vs 2 week comparisons) and 16 days apart (replicating 2 week vs 1 month comparisons) were extracted (see
Supplementary Methods).
The 28andMe dataset had a total of 7 non-overlapping one-week and 16-day intervals; remaps were ob-
served in both the one-week and 16-day interval comparison (Figure S4B), with around 8% of nodes remapping
without any regularization, and 0.5% of nodes remapping with a regularization level of β = 1e-4. The cast-
plasticity dataset, with a total of 15 non-overlapping 1-week windows (3, 5, and 7 windo ws for subjects, 1, 2, and
3, respectively), also had remaps (Figure S4B), with about 6% of nodes remapping without regularization, and
0.2% of nodes remapping with a regularization level of β = 1e-4.
Functional reorganization is primarily observed in the subcortical/cerebellar netw ork
Functional remapping in stroke subjects was observed in about 18-23% of nodes (across 4 session compar-
isons) without regularization, and in 3-4% of nodes after imposing regularization at a level of β = 1e-4 (Figure
S4C). Remapping occurred most often in the brainstem and cerebellum (Figure 3A,B), similar to the spatial dis-
tribution of ChaCo scores (amount of structural disconnection), which were also highest in the brainstem and
cerebellum (Figure 1C). W e also assessed patterns of remapping within 8 functional networks by calculating the
total number of swaps across subjects that involv e regions in those networks, normalized by the number of regions
in each network. The most remaps occur between regions in the subcortical-cerebellum network (Figure 3C,D).
Regions with greater structural connectivity network disruption have mor e functional reorganization over
time
For each pair of subsequent time points, there was a significant, positive correlation between sample-average
regional ChaCo scores and functional remapping frequency , indicating those regions with more structural connec-
tivity disruption across the stroke subjects also had more remapping over time (Figure 4A). Furthermore, across
subjects, the brain regions that remap have significantly higher ChaCo scores compared to those that do not remap
(assessed with permutation testing with 10000 permutations) (Figure 4B).
Functional reorganization is related to impairment and recov ery
W e observed a significant positive correlation between the number of early post-stroke remaps (between 1
weeks and 2 weeks post-stroke) and the 6 month improvement in motor scores, as measured by the difference in
Fugl-Meyer scores at 6 months and 1 week post stroke (controlling for average scan length). This result indicates
that individuals with more early functional remapping had better long-term recovery (Figure 5A). There was also
a significant negative relationship between the number of early post-stroke remaps (between 1 week and 2 weeks)
9
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
Figure 3: Regional functional remapping frequencies are related to mean estimated structural connectivity disrup-
tions due to the lesion. A. Regional remap frequencies plotted on a glass brain, averaged across 4 inter-session
comparisons. Inset figures display a lateral view (top row) and medial view (bottom ro w). B. Regional remap
frequencies plotted on a glass brain, displayed separately for each inter-session comparison. C. Network-level sum
of remaps, averaged across all 4 comparisons, and normalized by the number of regions in each network. Remaps
are separated based on their position relative to the lesion (contralesional vs. ipsilesional). D. Network-le vel sum
of remaps, displayed separately for each inter-session comparisons, normalized by the number of regions in each
network. Ipsilesional = in the same hemisphere as the lesion, contralesional = in the opposite hemisphere as the
lesion.
10
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
Figure 4: Remapping preferentially occurs in regions with greater structural connectivity disruption A. Correlations
between average ChaCo scores and regional remap frequencies across all 23 stroke subjects. Regions are colored
by network assignment. B. ChaCo scores of regions that remap are significantly greater than ChaCo scores of
regions that do not remap.
and baseline Fugl-Meyer scores, such that more impaired subjects had more remapping at baseline (Figure 5B).
The linear mixed effects model demonstrated a statistically significant relationship between ‘remapping’ (remap)
and a change in Fugel-Meyer score. For every one unit increase in ‘remapping’, there is an average increase of 0.46
units in the change in Fugl-Meyer scores, holding all other factors constant (Figure 5C)(p-value = 0.0037). The
amount of recovery between subsequent sessions was significantly significant positiv e associated with the number
of remaps between sessions for the two comparisons between 2 weeks and 1 month post-stroke (Figure 5D), but
only a trend for significance existed at the 1 month to 3 months time points and there was no significant correlation
for the 3 and 6 months comparison.
Robustness of results
The impact of lesions introducing noise into the BOLD signal of underlying gray matter is likely not driving
remapping, as the maximum overlap of the lesions with each ROI is no more than 30 percent (Figure S5) and,
importantly, lesioned v oxels were excluded from FC calculations. We also found that the number of remaps was
not related to differences in in-scanner motion between scans, as measured by framewise displacement (Fig S6).
Additionally, there is one free parameter in the graph matching, which was the amount of re gularization (value of
β ). The main results we present here based on a value that reduced the amount of remapping in controls to a level
of < 1% (see Figure S4). However , we also replicated the main results across an increasing value of β to show
robustness of the findings to this parameter choice (Figure S8, S9, S10).
11
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The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.445834 doi: bioRxiv preprint
Figure 5: The amount of early functional remapping is related to baseline motor impairment and eventual mo-
tor recovery; functional remapping is related to change in motor recovery between subsequent time points. A.
Pearson correlation between individuals’ total number of early remaps (between 1 week FC and 2 week FC)
and their change in Fugl-Meyer scores between 1 week and 6 months post-stroke (Spearman correlation: 0.549,
p(FDR)=0.022). B. Pearson correlation between individuals’ total number of early remaps (between 1 week FC
and 2 week FC) and 1 week Fugl-Meyer scores, controlling for subjects’ average scan lengths between 1 week
post-stroke and session 2 (Spearman correlation: -0.654, p(FDR) = 0.002). C. Results from linear mixed effects
analysis; colors indicate different individuals’ longitudinal time points. D. Pearson correlation between the total
remaps observed between each pair of time points and the change in Fugl-Meyer scores between time points, con-
trolling for average fMRI scan length. P-values are corrected for multiple comparisons (Spearman correlations:
Corr. 1 week-2 weeks = 0.456, p(FDR)=0.0575, Corr. 2 weeks - 1 month = 0.566, p(FDR)=0.03, Corr. 1 month -
3 months = 0.533, p(FDR)=0.03, Corr. 3 months - 6 months = -0.09, p(FDR)=0.714)
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Discussion
In this paper, we proposed a measure of functional connectome reorganization based on graph matching, and
evaluated its relationship to structural disconnection and motor impairment/recov ery in a set of 23 individuals with
pontine stroke. We observed instances of functional reorganization over the 1 week to 6 months post-strok e period,
and demonstrated that the areas that undergo functional reorganization most frequently are in cerebellar/subcortical
networks. Furthermore, regions more impacted by stroke via disruption to their structural connections had more
functional remapping over time. Finally, we show that functional reor ganization one week post-stroke is highly
related to both baseline impairment and the extent of motor recovery at 6 months, and, finally , that the extent of
functional reorganization between 2 weeks and 1 month post-stroke is correlated with the extent of motor recovery
observed in this same subacute time period.
Motor recovery following stroke is supported by acti ve functional and structural remodelling in the area
bordering the stroke, including increases in excitability , increases in dendritic spine turnover, and the formation of
new axonal projections (Murphy and Corbett, 2009). This remodelling can entail surviving cortical areas remap-
ping functionally to compensate for post-stroke impairment (Brown et al., 2009). The dynamic reorganization of
resting-state functional connectivity , observed in this stroke cohort in cerebellum and subcortical areas, may reflect
longitudinal compensatory changes in representations of motor functions. Interestingly, we showed correlations
between amount of functional remapping and amount of motor improvement but only in the period of time in
which most post-stroke recovery occurs (within 3 months after stroke) (Lee et al., 2015). However, resting-state
functional connectivity , though related to task-based responses, may not be fully representative of brain activ ation
patterns underlying specific behaviors, and has shown to be constrained by the structural connectome (Kuceyeski
et al., 2019; Honey et al., 2009). Thus, it is possible that the remapping observed is not a functional remapping per
se (in the sense of remapping a region’s role in a specific task), b ut a shift in balance of a brain area’s functional
connectivity profile at rest, which could reflect task-based functional compensations, changes in network topology ,
and/or underlying structural remodelling.
W e also show that more remapping between sessions is associated with better motor recovery between
those same sessions, and that more remapping in the early phase of stroke is related to both amount of baseline im-
pairment and the degree of motor recovery at 6 months. Functional reorganization measured with this remapping
technique may be interpreted as reflecting a compensatory, beneficial process that is proportional to the e xtent of
motor recovery . On the other hand, this approach may also be capturing phenomena that occurs during the first
6 months after stroke that are unrelated to recovered functionality , but that correlate with measures of recovery
nonetheless. For instance, stroke-related increases in noise in the subcortical/cerebellar may result in more remap-
ping which could be the result of a random or pathological process concomitant with a recovery mechanism. Thus,
more densely-sampled fMRI studies should be performed to identify other elements of this reorganization process.
The most remaps were observed in the subcortical/cerebellum network, suggesting that remapping is likely
reflecting a process of functional reorganization that is spatially constrained (Figure 3). This network-level reorga-
nization is consistent with prior task-based studies showing remapping of motor-based activ ations to premotor and
homologous areas, and with studies of resting-state FC that demonstrate specific spatial patterns of FC changes
after stroke, like changes in resting state FC within motor networks (Zhang et al., 2016), and contralesional func-
13
. CC-BY-NC 4.0 International license made available under a
tional connectivity changes that are concentrated in a small set of brain regions (Y ourganov et al., 2021).
W e now understand that deficits arising from stroke are not only related to the damage inflicted at the
stroke core, but also to remote cortical areas structurally connected to the lesion, due to retro- and anterograde
degeneration (Guggisberg et al., 2019). For instance, several studies have shown that there are local reductions
in cortical thickness in areas directly connected to subcortical lesions (Duering et al., 2015; Cheng et al., 2015).
Here, we show that the amount of structural disconnection from a stroke lesion is associated with greater functional
reorganization after stroke, suggesting that indirect damage to region’ s structural connections may also trigger its
functional remapping.
Plasticity is frequently observed in the area bordering the stroke (Brown et al., 2009), where tissue may
have a similar function to the area damaged by stroke. To incorporate the a priori hypothesis that recov ery-related
remapping would be observed between adjacent regions, we added a penalty to the graph matching algorithm pro-
portional to the distance between region-pairs. This penalty term did not substantially alter our results, suggesting
that the relationships we observed between remapping and recovery were driv en, in part, by remapping between
areas that were closer together. Long-range functional reorganization has been observed in animal models, partic-
ularly when the lesion is large. However , most studies of ’smaller’ strokes in rodent models resemble the relati ve
size of a survivable human stroke (Murphy and Corbett, 2009), so we assume that the strok e subjects we observed
had relatively smaller strokes that would more likely ha ve remapping between adjacent regions.
Limitations
There are several limitations to this study . The first is that the impact of noise cannot be completely ac-
counted for due to a lack of sufficient controls with the same acquisition and processing methods. It is possible
that the nodes that remap more frequently are in brain areas that have lower SNR and that remaps observed as
indicative of noisy signal. Indeed, the SNR of HCP subjects is lowest in medial structures such as the thalamus,
cortical midsurface, and most consequentially to this study, the anterior cerebellum (see S3).Howe ver, the SNR
of the subcortical/cerebellum network was not sufficient to cause substantial remapping in the longitudinal data
in healthy individuals after regularization. Finally, the control analyses used data from two different studies with
varying scanners and processing pipelines but minimal remapping was observed, supporting the hypothesis that
fMRI noise is not driving remapping.
Conclusions
In this study we proposed a measure of functional connectome reorganization, called remapping, and ap-
plied it to longitudinal resting-state fMRI data in a cohort of pontine stroke patients. Remapping was observed in
all stroke subjects and was correlated with recovery ov er the early to late subacute phases. Areas impacted by the
lesion through structural disconnection were more likely to remap than those areas not impacted by the lesion. Two
independent analyses showed that little to no remapping is observed in healthy individuals. This work expands our
understanding of functional processes related to recovery after stroke. If we can identify subjects who have more
potential for functional reorganization, or can devise therapeutics to boost this remapping mechanism, we may be
able to improve patient outcomes after stroke.
14
. CC-BY-NC 4.0 International license made available under a
Acknowledgements
W e thank Dr. Daniel Tranel, Dr. Zhou Fan, and Chang Su for their valuable and constructive suggestions
during the development of this research work.
Funding
This work was funded by the following grants: R01 NS102646 (AK), RF1 MH123232 (AK) and R21
NS104634 (AK).
Competing interests
None to disclose
Supplementary Methods
Supplementary control analyses
28andMe data: The 28andMe dataset (Pritschet et al., 2020 consists of densely sampled anatomical
and functional MRI on a female participant (23 y.o.) who underwent imaging for 30 consecutive days. fMRI
preprocessing is detailed in (Pritschet et al., 2020; details do not deviate significantly from the processing described
in this paper. Because the TR for the resting state fMRI obtained for this subject was much lower than the TR of
stroke subjects (720ms vs 3000ms, respectively), the 28andMe data was do wnsampled to an equivalent TR. Initial
scans contained 820 frames at a TR of 720ms, equating to roughly 10 minutes of acquisition. Resampling to
1/4th of the frequency was performed using MA TLAB’s resample() function which performs do wnsampling as
well as filtering to account for aliasing, which reduced the number of frames to 206 for each of the 30 scans.
GSR was then performed on the regional timeseries data.The 28andMe analyses were completed using functional
connectivity derived from the linear correlation between re gion time series. Seven sets of scans were extracted (day
1, 8, 24; day 2, 9, 25; day 3, 10, 26; day 4, 11, 27; day 5, 12, 28; day 6, 13, 29; and 1 week, 14, 30), with intervals
between the days selected to replicate the interval between scanning in the stroke subject’ s first three visits (7, 14
and 30 days post-stroke). Graph matching was applied to each of the 7 sets of scans for both pairs of subsequent
time points within the set, and the resulting remapping frequencies calculated over the 14 total sets of FCs.
Cast-induced plasticity data: Each of three adult subjects were scanned daily for a cast-induced plasticity
study by Newbold et al. (Newbold et al., 2020), two were males (35 y.o. and 27 y.o.) and one was a 25 y.o. female.
Subjects underwent structural and functional MRI scanning for 10-14 days before their dominant arm was covered
in a medical cast, and were scanned for a period of time during the cast and after the cast was removed. Because
significant resting-state functional connectivity changes were observed during the cast period, we did not use this
data, nor did we use the data following the cast removal because a dif ferent scanner was used. Participants were
scanned for 30 minutes using a 3T Siemens Trio MRI scanner; we only used 14 minutes of scan data (first 380 TRs)
in order to match the mean scan length of our stroke subjects. BOLD data were acquired at a spatial resolution
of 4mm, single-band, with a TR of 2.2s. Subject 1 had 10 pre-cast scans, subject 2 had 12, and subject 3 had 14.
These subjects were used to investigate remapping in controls in the 1-week windo w that replicates the difference
15
. CC-BY-NC 4.0 International license made available under a
between 1 and 2 weeks post-stroke in the stroke subjects. For each subject, we obtained several non-overlapping
windows. Specifically for subject 1, we compared: day 1 and day 8, day 2, 9, and day 3, 10. For subject 2, we
compared: day 1, 8, day 2, 9, day 3, 10, day 4, 11, day 5, 12. For subject 3, we compared: day 1, 8, day 2, 9, day
3, 10, day 4, 11, day 5, 12, day 6, 13, 1 week, 14. Raw data was downloaded from Datalad and processed with the
same pipeline as the stroke subjects. Graph matching was applied to the resulting scans.
16
Supplementary Figures
Figure S1: 8 functional networks identified by (Finn et al., 2015) by clustering healthy functional connectivity
matrices.
17
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(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
Figure S2: Lambda parameter that minimizes the error of precision matrices
18
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(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
Figure S3: SNR calculations on the test-retest HCP BOLD data: temporal signal-to-noise ratio:
TSNR=MEAN/stdev(non-artifact thermal noise)
Figure S4: A. Average remap frequency (average across nodes) of the control datasets (cast and 28andme) relati ve
to stroke subjects, with varying levels of re gularization. The amount of regularization that minimized remapping in
controls (1e-4) was used to regularize stroke subjects. B. Remapping of cast-induced plasticity controls (top row)
and of 28andme subject (bottom 2 rows) with varying le vels of euclidean distance regularization. C. Remapping
of stroke subjects with varying regularizaiton.
19
Figure S5: Average overlap between each gray matter regions and lesions; calculated for each subject as the total
volume of the lesion inside each region divided by the total re gion volume. Displaying only regions with an average
overlap with the lesion above zero.
Figure S6: A verage framewise displacement between scans does not correlate with the sum of remaps observed
between scans.
20
Figure S7: The amount of early functional remapping is related to baseline motor impairment and eventual mo-
tor recovery; functional remapping is related to change in motor recovery between subsequent time points. A.
Spearman correlation between individuals’ total number of early remaps (between 1 week FC and 2 week FC)
and their change in Fugl-Meyer scores between 1 week and 6 months post-stroke. B. Spearman correlation be-
tween individuals’ total number of early remaps (between 1 week FC and 2 week FC) and 1 week Fugl-Meyer
scores, controlling for subjects’ average scan lengths between 1 week post-stroke and session 2. C. Results from
linear mixed effects analysis. D. Spearman correlation between the total remaps observed between each pair of
time points and the change in Fugl-Meyer scores between time points, controlling for average fMRI scan length.
P-values are corrected for multiple comparisons.
21
(a) β = 0 (b) β = 1e-3
(c) β = 2e-3 (d) β = 3e-3
(e) Legend
Figure S8: V arying β does not impact the significance of the correlation between regional number of remaps and
ChaCo scores. P-values are corrected for multiple comparisons.
22
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(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
(a) β = 0 (b) β = 1e-3
(c) β = 2e-3 (d) β = 3e-3
Figure S9: V arying β does not change the significance of the relationship between total number of remaps between
1 and 2 weeks post-stroke and a) baseline Fugl-Meyer scores or b) 6-month follow-up Fugl-Meyer scores.
23
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.445834 doi: bioRxiv preprint
Figure S10: Varying β generally does not alter the relationships observ ed between session-specific changes in
Fugl-Meyer motor scores and the number of regions that functionally remap between sessions. Corrected p-values
are reported.
24
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| https://www.researchgate.net/publication/351965445_Functional_connectome_reorganization_relates_to_post-stroke_motor_recovery_and_structural_disconnection |
HB357
Health insurance; premium contribution rates
Description:
Provides direct temporary economic relief for a period of two years by allowing private employers the flexibility to implement up to a 60/40 cost sharing for their employees’ health insurance premiums. Sets the maximum employee contribution at forty per cent of the total premium.
HOUSE OF REPRESENTATIVES H.B. NO. 357 TWENTY-SECOND LEGISLATURE, 2003 STATE OF HAWAII
A BILL FOR AN ACT
RELATING TO HEALTH INSURANCE PREMIUM CONTRIBUTIONS.
BE IT ENACTED BY THE LEGISLATURE OF THE STATE OF HAWAII:
SECTION 1. The September 11, 2001, terrorist attacks on the United States have severely impacted Hawaii’s economy. Businesses experienced catastrophic revenue losses as a result of the decrease in the number of visitors to Hawaii. Our State’s continuing economic stagnation has hurt other sectors of our economy not dependent on tourism.
Furthermore, Hawaii’s employers, particularly small businesses, have not had economic relief and continue to experience lagging sales, increasing health insurance premiums, and the high costs of workers’ compensation and general liability coverages. As the primary source of income for a majority of Hawaii’s workers, small businesses face some of the most formidable obstacles in remaining competitive and profitable. By directly addressing the issue of who pays for health insurance, the legislature is seeking to increase the awareness of health care in general and the role of society as a whole in containing costs and sharing the burden. While this measure shifts health costs from one payee to another, it is only meant to be a short-term solution to the current crisis. The Prepaid Health Care Act of 1974 should be reviewed in its entirety so that long-term solutions may be appropriately proposed in future legislative sessions.
The purpose of this Act is to provide direct temporary economic relief for a period of approximately two years by allowing employers more flexibility in how much they are required to contribute to their employees’ health insurance premiums.
SECTION 2. Chapter 431, Hawaii Revised Statutes, is amended by adding a new section to article 10A to be appropriately designated and to read as follows:
"
§431:10A- Liability for payment of premium; withholding.
Unless an applicable collective bargaining agreement specifies differently, every employer shall contribute at least sixty per cent of the premium for coverage required by chapter 393 and the employee shall contribute the balance.
The employer shall withhold the employee's share of the premium from the employee's wages as specified by the director.
SECTION 3. All laws inconsistent with this Act shall be suspended during the effective period of this Act and to the extent that the suspension is necessary to effectuate the purposes of this Act.
SECTION 4. Upon the repeal of this Act, all statutes that were suspended under this Act shall be reinstated in the form that existed on the day before the effective date of this Act.
SECTION 5. If any provision of this Act, or the application thereof to any person or circumstance is held invalid, the invalidity does not affect other provisions or applications of the Act, which can be given effect without the invalid provision or application, and to this end the provisions of the Act are severable.
SECTION 6. New statutory material is underscored.
SECTION 7. This Act shall take effect on the beginning of the fiscal year after the enactment of legislation by the Congress of the United States permitting the State of Hawaii to amend chapter 393, Hawaii Revised Statutes (the Prepaid Health Care Act) without loss of exemption from the Employment Retirement Income Security Act and shall be repealed two years after the beginning of the fiscal year in which this Act is effective.
INTRODUCED BY: ___________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
| https://www.capitol.hawaii.gov/sessions/session2004/bills/HB357_.htm |
Bolometers for infrared and millimeter waves
Download Citation | Bolometers for infrared and millimeter waves | This review describes bolometric detectors for infrared and millimeter waves. The introduction sketches the history of modern bolometers,... | Find, read and cite all the research you need on ResearchGate
Article
Bolometers for infrared and millimeter waves
August 1994
Journal of Applied Physics76(1):1 - 24
DOI: 10.1063/1.357128
Source
IEEE Xplore
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
P. L. Richards
P. L. Richards
Abstract
This review describes bolometric detectors for infrared and millimeter waves. The introduction sketches the history of modern bolometers, indicates how they fit into the more general class of thermal detectors, and describes the types of applications for which they are the optimum solution. Section I is a tutorial introduction to the elementary theories of bolometer response, of thermal radiation, and of bolometer noise. Important results are derived from the laws of thermal physics in the simplest possible way. The more rigorous theories of bolometer response and noise that are required for quantitative understanding and optimization are then summarized. This material is intended to provide the background required by workers who wish to choose the appropriate bolometer technology for a given measurement, or to evaluate a novel technology. Section II, then describes the various components of an efficient bolometer and gives details of the fabrication and performance of modern bolometers. This discussion focuses on composite bolometers with semiconducting thermometers for operation at and below liquid helium temperatures. The tradeoffs involved in using superconducting thermometers at low temperatures are discussed. Finally, a discussion is given of bolometers for operation at liquid nitrogen temperature which use the new high‐T c superconductors as thermometers.
... To ensure sufficient saturation power and dynamic range, a TES is typically biased at 10-50% of its normal state resistance, with the bath temperature maintained at B ∼ 50-70% C , within the capabilities of the available cryogenic refrigeration. Noise-equivalent power, NEP, is a figure of merit in bolometer sensitivity, corresponding to the incident power giving a signal-to-noise ratio of unity in a 1 Hz bandwidth
[30]
. Expressed in units of W Hz −1/2 , NEP is defined as the square root of the spectral density of the power-referred detector noise, P ( ) (W 2 Hz −1 ), as ...
... where I ( ) is the current-referred noise spectral density (A 2 Hz −1 ) and I is the power-tocurrent responsivity (A W −1 ), which allows measured current noise to be referred back to an effective power noise at the bolometer input [10,
30]
. The total noise power spectral density is the sum of various contributions including thermal fluctuation noise, Johnson noise in the bolometer and bias resistors, and amplifier noise. ...
... where the first term on the right hand side represents classical bunched noise, and the second shot noise. The form of this expression is the same as that used to describe fluctuations in the number of photons absorbed from an optical beam, and derives from the average variance in the number of bosons per mode, ⟨(Δ ) 2 ⟩ = ⟨ ⟩(1 + ⟨ ⟩)
[30,
31]. The Noise Power Spectral Densities (NPSDs) associated with classical noise and shot noise at a given temperature may be defined as the square roots of the respective integrands of Eq. 5.11, and the combined NPSD as their quadrature sum. ...
Transition Edge Sensors for Far-Infrared Space Science
Thesis
Oct 2021
Emily Williams
Superconducting Transition Edge Sensors (TESs) are an outstanding candidate detector technology for the next generation of far-infrared space observatories. Future missions will seek to achieve unprecedented background-limited sensitivities by combining large (>1 m) cold (<4 K) aperture telescopes with many thousands of detectors having Noise Equivalent Power (NEP) of only 10^{-19} WHz^{-1/2}. However, very few TES arrays have so far been developed for these wavelengths, ∼30-200 μm, characterised by an NEP two orders of magnitude lower than necessary in TESs for ground-based microwave astronomy, few-moded optical behaviour and saturation powers of only ∼10 fW. In this thesis, I seek to advance far-infrared TES technology first by demonstrating cryogenic characterisation techniques fundamental to understanding physical behaviour and performance, then by exploring promising innovations in device design. I first describe a cryogenic optical test facility in which TESs are cooled to <100 mK and illuminated with a few-mode infrared field. I implement techniques to shield detectors from stray light, stray magnetic fields and electromagnetic interference, critical to realising optimal performance both in ground-based test systems and ultimately in space, with a particular emphasis on thermal design to eliminate stray light. I demonstrate successful TES operation through the thermal, optical and electrical characterisation of the first TESs for 60-110μm wavelengths, integrated with reflective backshorts and few-mode lightpipes. I then present a new technique for generating a rapidly modulated optical field using a fast infrared source, allowing response rates to changes in illumination to be measured for the first time in these devices. Achieving NEP∼10^{-19} WHz^{-1/2} currently requires long (>600 μm), narrow (≤1.5 μm) TES support legs to limit thermal conductance by diffusive phonon scattering, preventing tight optical packing in arrays. Incorporating elastic filters into shorter legs offers an attractive means to reach low NEP in compact structures with increased performance uniformity. I present the first experimental study of TES supported by phononic interferometers and resonators, patterned into legs only 0.5 μm wide and up to 25 μm long, demonstrating NEPs as low as 5×10^{-19} WHz^{-1/2} suitable for a range of ultra-low-noise TES applications. I conclude by developing elastic travelling wave simulations of a new family of lattice support structures, exploring their potential for enhanced thermal isolation.
... TES bolometers have superconducting thermistors that are voltage biased to operate precisely in their superconducting transition; thus, a small change in temperature yields a large change in resistance, enabling the detectors to be highly sensitive even to weak signals.
1,
2 The experiments enabled by TES bolometers touch on some of the largest questions in cosmology and particle physics today. For example, experiments such as SPT-3G (the current receiver on the South Pole Telescope [SPT]), BICEP Array, Advanced ACTPol (the current receiver on the Atacama Cosmology Telescope [ACT]), POLARBEAR/Simons Array, and Simons Observatory use TES bolometers to precisely map the temperature and polarization anisotropies of the cosmic microwave background (CMB), the relic radiation leftover from the early universe. ...
... Ntrees is the number of trees in the random forest; choices were [10, 50, 100, 500, 1000]. d is the maximum allowed depth of each tree; choices were
[1,
2,3,4,5,6]. s is the minimum number of bolometers necessary to split a node on the tree; choices were [2,3,4]. ...
... Ntrees is the number of trees in the random forest; choices were [10, 50, 100, 500, 1000]. d is the maximum allowed depth of each tree; choices were
[1,
2,3,4,5,6]. s is the minimum number of bolometers necessary to split a node on the tree; choices were[2,3,4]. ...
Correlating Visual Characteristics and Cryogenic Performance of Superconducting Detectors
Jul 2022
K. R. Ferguson
<here is a image ff3c224a867cdc5a-102e4596bbfcacad> Thomas Cecil
A. N. Bender
N. Whitehorn
Cryogenic characterization of transition-edge sensor (TES) bolometers is a time- and labor-intensive process. As new experiments deploy larger and larger arrays of TES bolometers, the testing process will become more of a bottleneck. Thus it is desirable to develop a method for evaluating detector performance at room temperature. One possibility is using machine learning to correlate detectors' visual appearance with their cryogenic properties. Here, we use three engineering-grade TES bolometer wafers from the production cycle for SPT-3G, the current receiver on the South Pole Telescope, to train and test such an algorithm. High-resolution images of these TES bolometers were captured and relevant features were calculated from the images. Cryogenic performance metrics, including a detector's ability to tune and superconducting parameters such as normal resistance, critical temperature, and transition width, were also measured. A random forest algorithm was trained to predict these performance metrics from the visual features. Analysis of the images proved highly successful. While the ability of the random forest algorithm to predict cryogenic features was limited with the chosen set of input image features, it is possible that an increase in data volume or the addition of more image features will solve this problem.
... This variable can represent the Coatings 2023, 13, 1088 3 of 24 photogenerated voltage (V Ph ) or generated by irradiation with a certain power density [43], while R can be expressed as R V = V ph P in or R i = I ph P in (1) where P denotes the irradiated light power of a laser. R is wavelength-dependent due to the sensitive material layer's light absorption and energy gap [44][45]
[46]
[47]. ...
... The on/off ratio denotes the quantity ratio between light current and I dark . Generally speaking, due to the photovoltaic effect, I dark is suppressed by rectification effects to obtain a high I ph and achieve a high on/off ratio [43][44][45]
[46]
[47]. ...
Multiplier Effects of Photodetectors—Source of Gain
Jun 2023
Haoliang Chang
Jinhuan Chen
Xinyu Zhu
Ming Yang
A photodetector is a type of optoelectronic device with excellent photoelectric conversion abilities, which has especially important applications in many fields such as optical communication, image sensing, aerospace/environmental detection, and military safety. Among these applications, the multiplier effect of optoelectronic devices has been widely explored because photodetectors can convert a very weak optical signal into electrical signal output and offer amazing electron multiplication abilities. To date, hundreds of multiplier effects of photodetectors have been reported. However, there are few reviews on the multiplier effects of such devices. Here, a review of the multiplier effects of photodetectors covering detection spectra from ultraviolet to infrared is presented, including photodetectors based on inorganic materials, organic materials, and organic/inorganic materials. First, we provide brief insights into the detection mechanisms of multiplier effects of photodetectors and introduce the merits that represent key factors for a reasonable comparison of different photodetectors. Then, the multiplier effect on different types of material photodetectors is reviewed. Notably, we summarize the optimization directions of the performance of the multiplier photodetectors, including improving the external quantum efficiency, reducing the dark current, and increasing the response speed and spectral regulation. Finally, an outlook is delivered, the challenges and future directions are discussed, and general advice for designing and realizing novel high-performance photodetectors with multiplier effects is given to provide a guideline for the future development of this fast-developing field. The bottlenecks of existing multiplier technology are also analyzed, which has strong reference significance for the future development of this field.
... With an emphasis on silicon and other semiconductor materials, we introduce five common physical mechanisms in the following: (i) In the photovoltaic effect [4], we observe the generation of photocurrent resulting from the separation of electronhole pairs by the built-in electric field in the p-n metallurgical junction. (ii) In photothermoelectric (PTE), the generation of hot electrons produces a VPTE voltage based on the Seebeck effect [5]. (iii) The bolometer method refers to changing the electrical conductance and carrier transport properties of an illuminated material due to absorption heat
[6]
This type of photodetection considers the thermal resistance of Rh and ΔR creation by ΔT. (iv) The photogating method [7] with light illumination results in the creation of Δn, and the photogenerated electron-hole pair density and trapping of one type of these carriers under the light-sensitive layer provide the channel required for carrier recirculation under an external bias voltage. ...
... Aα and Ãα represent the spectral function and the spectral reverse time function of the α terminal, respectively. Formula
(6)
describes the electron-photo coupling matrix: ...
Ab initio Calculation for Photocurrent in Silicon p-n Junction: the First-Order Perturbation Theory
A computational study based on first-principles calculations by supercomputers for nanoelectronic devices sometimes leads to results that can rarely be obtained in experimental laboratories with measuring tolerances. In this paper, therefore, we obtained the electronic, electrical, and optoelectrical properties of silicon p-n junction nanostructures by solving Non-Equilibrium Green's Function (NEGF) using the first-order perturbation theory. We extracted the density of states (DOS), quantum carrier transport coefficient, IV-curve, and optoelectrical behavior by calculating the photocurrent and then plotted the light absorption spectrum. In the studied silicon nanostructure, light absorption is negligible for incident photon energy below 1 eV, and peak absorption occurs at 4 eV. In this research, the developed computational model paves the way for the study of nano-opto-electronic devices.
... It is the measurement of this modification which allows the measurement of the incident flux. A change in electrical resistance, thermoelectric or pyroelectric effects can be used for this measurement
[104]
. This fundamental concept was used to design the first micro-bolometers for infrared cameras in the late 70's [105], but was not published until the early 90's [105,106]. ...
... Due to the absorbed energy, the temperature of the heated element T B rises over time at rate dT B /dt = P/C and approaches the limit value T B = T S + P/G with the thermal time constant τ = C/G. Once the radiation is turned off, this temperature relaxed back to its initial value with the same time constant τ
[104]
.The exploded schematic presentation of a microbolometer is presented inFig. 5.5 (b). ...
Novel concepts for theoretical and applied problems of electromagnetism. Part 1 : Absolute representation of the fields in the spacetime map. Part 2 : Low-volume optical antennas for bolometer applications
This work consists of two parts which, although very different from each other, both belong to the same field: electromagnetism and its modern problems. In the first part, an absolute geometrization of the electromagnetic field in spacetime is presented, challenging the claim that the only way to present electromagnetic field is abstraction. It is demonstrated that with the absolute topology in spacetime, two scalar invariants are sufficient to describe the electromagnetic field. Particular attention is paid to the case of y-invariant p-polarised field, the topology of which can be represented in 3D spacetime by lines (electric spaghetti), the two scalar invariants then being reduced to one. Unlike the world lines of particles, which are always time-like, these lines transcend the boundary between space and time. This new approach of the electromagnetic field opens up new perspectives both for teaching and for research, in particular the analysis of the topological properties of these absolute structures in spacetime. The second part is dedicated to a more applied problem, that of the development of nano-absorbers which could become the basis for a new generation of bolometers. In this work, it is demonstrated that thanks to the exceptional properties of plasmonic antennas (total absorption and strong confinement of the electromagnetic field), it is possible to design infrared absorbers whose volume is greatly reduced (several orders of magnitude) compared to those used in current microbolometers. These results pave the way for a major technological breakthrough which, by greatly reducing the thermal capacity of the absorbent, leads to a new sensitivity - speed compromise for bolometers whose performance should then be close to that of cooled photo-detectors.
... NEP is used to characterize the sensitivity of MEMS bolometers, which is defined as the power that generates a signal output that is equal to the root-mean-square (RMS) noise output in a 1 Hz bandwidth
[98]
. In terms of responsiveness in FM detection, the NEP is as ...
Terahertz Detectors Using Microelectromechanical System Resonators
The doubly clamped microelectromechanical system (MEMS) beam resonators exhibit extremely high sensitivity to tiny changes in the resonance frequency owing to their high quality (Q-) factors, even at room temperature. Such a sensitive frequency-shift scheme is very attractive for fast and highly sensitive terahertz (THz) detection. The MEMS resonator absorbs THz radiation and induces a temperature rise, leading to a shift in its resonance frequency. This frequency shift is proportional to the amount of THz radiation absorbed by the resonator and can be detected and quantified, thereby allowing the THz radiation to be measured. In this review, we present an overview of the THz bolometer based on the doubly clamped MEMS beam resonators in the aspects of working principle, readout, detection speed, sensitivity, and attempts at improving the performance. This allows one to have a comprehensive view of such a novel THz detector.
... Multiple important devices use THz detection technologies such as microbolometers
[3,
4], Golay cells, and Superconducting Tunneling Junctions (STJ) [5]. However, field-effect transistors (FETs) are one of the promising candidates for THz detection. ...
Review on Physics and Modelling of THz Radiation Detection Using Field-effect Transistors
... Infrared sensors are broadly classified into two types according to their detection principle: quantum type and thermal type. [1][2][3][4]
[5]
The quantum type is based on the principle that a semiconductor material absorbs infrared rays and excites electrons, thereby detecting infrared rays as a current signal. 4 Since wavelength of the infrared rays that can be absorbed depends on the bandgap of the semiconductor material, the quantum type exhibits an extremely high sensitivity only in a specific wavelength range. ...
Nanostructured Si–Ge thermoelectric material for 1200 V/W highly sensitive infrared thermopile sensor device
In this paper, we report the characteristics of a thermopile infrared sensor in which a nanostructured Si–Ge thermoelectric material is used. Although the thermopile infrared sensor is capable of being operated without power consumption, a challenge has been improving its sensitivity. With the aim of improving its sensitivity, we have realized a nanostructured Si–Ge thermoelectric material with low thermal conductivity (0.8 W/m K or less) by forming nanocrystals through heat treatment of amorphous Si–Ge. The thermopile infrared sensor composed of this material exhibited a high sensitivity of 1200 V/W at a pressure of 1.0 × 10 ⁻¹ Pa or less.
... Responsivity and noise equivalent power (NEP) are the two main parameters in analyzing the bolometer performance, which are the ratio of the voltage output to the input power and the smallest measurable power by the bolometer, respectively
[9]
. Recent studies on the scaling of antenna-coupled bolometer suggested the importance of higher heater resistance to improve the responsivity and NEP simultaneously [10]. ...
Folded-Dipole Antenna Geometrical Analysis for THz Microbolometer
To improve the responsivity of terahertz (THz) antenna-coupled bolometer, heater (load) resistance has to be increased to suppress the thermal conduction and realize larger temperature rise of the thermistor. Proper design of antenna is therefore essential to assure the impedance matching between antenna and heater. From this viewpoint, a high-impedance folded-dipole antenna (FDA) has been studied numerically by the finite element simulation. The effect of FDA structural parameters such as number of arms, antenna width, and arm spacing are discussed with the lumped port and resistive heater coupled to the antenna gap for the cases of radiating and receiving modes, respectively. The product of resonant resistance and area efficiency is used to predict the improvement made by FDA as a figure of merit (FOM) correlated to the bolometer responsivity. This study revealed that the optimum FOM in FDA-coupled bolometer operating at 1 THz was obtained with three arms, 1-μm antenna width and 4-μm arm spacing. A comparison was made with the result from a half-wave dipole antenna and revealed that FDA could enhance the bolometer responsivity by a factor of 15. This research demonstrated the effectiveness of the FDA to improve the performance of THz antenna-coupled bolometer for applications such as imaging for non-destructive inspection.
... On the one hand, single photon detectors [1-6] accurately detect single photons, but saturate as soon as two photons arrive simultaneously. On the other hand, more linear watt meters, such as bolometers
[7]
[8][9], are too noisy to accurately detect single microwave photons. Linear amplifiers [10-12] probe non-commuting observables of a signal so that they must add noise [13] and cannot be used to detect single photons, either. ...
Microwave photon-number amplification
So far, quantum-limited power meters are not available in the microwave domain, hindering measurement of photon number in itinerant quantum states. On the one hand, single photon detectors accurately detect single photons, but saturate as soon as two photons arrive simultaneously. On the other hand, more linear watt meters, such as bolometers, are too noisy to accurately detect single microwave photons. Linear amplifiers probe non-commuting observables of a signal so that they must add noise and cannot be used to detect single photons, either. Here we experimentally demonstrate a microwave photon-multiplication scheme which combines the advantages of a single photon detector and a power meter by multiplying the incoming photon number by an integer factor. Our first experimental implementation achieves a n = 3-fold multiplication with 0.69 efficiency in a 116 MHz bandwidth up to a input photon rate of 400 MHz. It loses phase information but does not require any dead time or time binning. We expect an optimised device cascading such multipliers to achieve number-resolving measurement of itinerant photons with low dark count, which would offer new possibilities in a wide range of quantum sensing and quantum computing applications.
... This time dependent equation can be written for the temperature changes, ΔT 5 T 2 T 0 as: where G eff 5 G 2 I 2 αR 0 is called effective thermal conductance. The (voltage) responsivity of the bolometer S 5 ΔV=P which is voltage drop per watt of absorbed signal power can be found from the Eqs (12.3) and (12.7) as
(Richards, 1994)
S 5 ηIαR 0 G eff ð1 1 ðjwC=G eff ÞÞ (12.8) ...
Plasmonic photodetectors
... The first experimental measurement of spontaneous temperature fluctuations was observed in a paramagnetic salt in cryogenic conditions by magnetometry [16]. Temperature fluctuations are of prime importance in various phenomena in condensed matter as for example they limit the sensitivity of bolometers
[17]
, generate dynamical phase transitions [18] and are at the origin of non-Gaussian fluctuations in metals [19,20]. Micro-scale and nano-scale thermoelectric thermometry is of increasing interest for scanning thermal microscopy [21], cellular-level thermometry [22][23][24][25], semiconductor circuit thermometry [26], and wearable sensors [27,28], further motivating the understanding of fluctuations in thermoelectrics. ...
Fluctuation-dissipation in thermoelectric sensors
Thermoelectric materials exhibit correlated transport of charge and heat. The Johnson-Nyquist noise formula 4 k B TR for the spectral density of voltage fluctuations accounts for fluctuations associated solely with Ohmic dissipation. Applying the fluctuation-dissipation theorem, we generalize the Johnson-Nyquist formula for thermoelectrics, finding an enhanced voltage fluctuation spectral density 4 k B TR (1 + Z D T ) at frequencies below a thermal cut-off frequency f T , where Z D T is the dimensionless thermoelectric device figure of merit. The origin of the enhancement in voltage noise is thermoelectric coupling of temperature fluctuations. We use a wideband ( f T ∼ 1 kHz), integrated thermoelectric micro-device to experimentally confirm our findings. Measuring the Z D T enhanced voltage noise, we experimentally resolve temperature fluctuations with a root mean square amplitude of 0.8 μK Hz −1/2 at a mean temperature of 295 K. We find that thermoelectric devices can be used for thermometry with sufficient resolution to measure the fundamental temperature fluctuations described by the fluctuation-dissipation theorem.
... A TES bolometer can be modeled as a coupled electrothermal system (Mather 1982;
Richards 1994;
Irwin & Hilton 2005), as depicted in Figure 1. At equilibrium, the sum of the TES bias power (P J ) and optical signal (P γ ) dissipated on the TES island equals the phonon power (P j ) that flows from the hot island to the cold bath through the silicon beam connecting them. ...
Calibration of Transition-edge Sensor (TES) Bolometer Arrays with Application to CLASS
The current and future cosmic microwave background (CMB) experiments fielding kilopixel arrays of transition-edge sensor (TES) bolometers require accurate and robust gain calibration methods. We simplify and refactor the standard TES model to directly relate the detector responsivity calibration and optical time constant to the measured TES current I and the applied bias current I b . The calibration method developed for the Cosmology Large Angular Scale Surveyor (CLASS) TES bolometer arrays relies on current versus voltage ( I – V ) measurements acquired daily prior to CMB observations. By binning Q -band (40 GHz) I – V measurements by optical loading, we find that the gain calibration median standard error within a bin is 0.3%. We test the accuracy of this I – V bin detector calibration method by using the Moon as a photometric standard. The ratio of measured Moon amplitudes between the detector pairs sharing the same feedhorn indicates a TES calibration error of 0.5%. We also find that, for the CLASS Q -band TES array, calibrating the response of individual detectors based solely on the applied TES bias current accurately corrects TES gain variations across time but introduces a bias in the TES calibration from data counts to power units. Since the TES current bias value is set and recorded before every observation, this calibration method can always be applied to the raw TES data and is not subject to I – V data quality or processing errors.
... Phonons follow Bose-Einstein statistics, meaning that the noise considerations relevant to single-photon detectors should also be applicable to the single-phonon detector proposed here. Following Ref.
[51]
, we can estimate the NEP due to the Johnson-Nyquist noise contribution as a ratio of Johnson noise √ 4k b T R and voltage responsivity, where R = L/(W enµ) is the resistance of the device. The voltage responsivity can be estimated as V drag /( ω ph /τ tr ), where the transient time τ tr ∼ 1 ns. ...
Quantum Sensing of Single Phonons via Phonon Drag in Two-Dimensional Materials
The capacity to electrically detect phonons, ultimately at the single-phonon limit, is a key requirement for many schemes for phonon-based quantum computing, so-called quantum phononics. Here, we predict that by exploiting the strong coupling of their electrons to surface-polar phonons, van der Waals heterostructures can offer a suitable platform for phonon sensing, capable of resolving energy transfer at the single-phonon level. The geometry we consider is one in which a drag momentum is exerted on electrons in a graphene layer, by a single out-of-equilibrium phonon in a dielectric layer of hexagonal boron nitride, giving rise to a measurable induced voltage ($V_{\rm drag}$). Our numerical solution of the Boltzmann Transport Equation shows that this drag voltage can reach a level of a few hundred microvolts per phonon, well above experimental detection limits. Furthermore, we predict that $V_{\rm drag}$ should be highly insensitive to the mobility of carriers in the graphene layer and to increasing the temperature to at least 300 K, offering the potential of a versatile material platform for single-phonon sensing.
... To evaluate the minimum detectable power of the photodetector, we determined its noise equivalent power (NEP). This value provides the amount of excitation power that generates a photocurrent equal to the noise current (NEP = i n /R, where, i n is noise current and R is the responsivity)
[56]
. Typically, the noise consists of three sources: 1/f noise, shot noise, and Johnson noise. ...
Hybrid Integration of Multilayers GeP on a Silicon Photonics Platform for Optoelectronic Application
Conference Paper
<here is a image 357cc73a087c5269-2ea7351ed5fb340f> Juan Villegas
<here is a image 2582af05cecf7755-0282dc33ed963ddb> Mahmoud Rasras
https://opg.optica.org/abstract.cfm?uri=CLEO_SI-2022-JW3A.33
... For millimeter to sub-millimeter wavelengths (electromagnetic radiation between approximately 100 GHz and 1 THz), bolometers are exceptionally sensitive and able to achieve performance limited primarily by photon shot noise.
39
In this regime, the bolometer is operated at sub-Kelvin temperature and the noise from the detector itself is subdominant to photon noise from incident light. ...
Review of Radio Frequency Interference and Potential Impacts on the CMB-S4 Cosmic Microwave Background Survey
CMB-S4 will map the cosmic microwave background to unprecedented precision, while simultaneously surveying the millimeter-wave time-domain sky, in order to advance our understanding of cosmology and the universe. CMB-S4 will observe from two sites, the South Pole and the Atacama Desert of Chile. A combination of small- and large-aperture telescopes with hundreds of thousands of polarization-sensitive detectors will observe in several frequency bands from 20-300 GHz, surveying more than 50 percent of the sky to arcminute resolution with unprecedented sensitivity. CMB-S4 seeks to make a dramatic leap in sensitivity while observing across a broad range of largely unprotected spectrum which is increasingly being utilized for terrestrial and satellite transmissions. Fundamental aspects of CMB instrument technology leave them vulnerable to radio frequency interference (RFI) across a wide range of frequencies, including frequencies outside of their observing bands. Ground-based CMB instruments achieve their extraordinary sensitivities by deploying large focal planes of superconducting bolometers to extremely dry, high-altitude sites, with large fractional bandwidths, wide fields of view, and years of integration time. Suitable observing sites have historically offered significant protection from RFI, both naturally through their extremely remote locations as well as through restrictions on local emissions. Since the coupling mechanisms are complex, safe levels or frequencies of emission that would not interfere with CMB measurements cannot always be determined through straightforward calculations. We discuss models of interference for various types of RFI relevant to CMB-S4, mitigation strategies, and the potential impacts on survey sensitivity.
... However, owing to the small photon energies involved, THz photodetectors that use intersublevel transitions in low-dimensional nanostructures [9,10] or impurities [11] in semiconductors cannot operate at room temperature. The thermal sensor [12,
13]
is another type of THz sensor that converts the input light into heat and detects the induced rise in temperature by using a thermistor to determine the input lightinduced power. Commonly used thermal sensors include pyroelectric sensors, vanadium oxide (VOx) bolometers [14][15][16], and MEMS bolometers [17][18][19][20]. ...
Thermal and Optical Properties of Porous Nanomesh Structures for Sensitive Terahertz Bolometric Detection
Terahertz (THz) electromagnetic waves are attractive for use in nondestructive and biocompatible sensing applications. Thermal sensors are widely used for THz detection owing to the small photon energies of THz radiation, where this requires materials with low thermal conductivity and a small heat capacity to ensure the sensitive and fast operation of the sensors. In this study, we investigated the thermal and optical properties of porous nanomesh structures for sensitive THz bolometric detection. Nanometer (nm)-scale hole array structures were formed on gallium arsenide (GaAs) microelectromechanical system (MEMS) beams to improve their thermal properties. The thermal conductance of the porous MEMS beams was obtained by measuring their thermal bandwidths; it was found to decrease by as much as ~90% when the porosity (P) of the porous nanostructure was increased to ~0.69. We also measured the THz absorptance of the porous hole array structure. The results show that although the porous nanostructure has a much smaller area than the bulk material, it maintained a high coefficient of THz absorptance because the featured size was much smaller than the THz wavelength. The measured absorptance agreed well with that calculated by using the Drude model. These results demonstrate that the porous nanomesh structure is promising for developing highly sensitive THz thermal sensors.
... This method also accounts for photon-bunching of the wideband signal. Because the fluctuations in energy in different spectral bins are uncorrelated,
47
Методом компьютерного моделирования исследованы процессы распространения тепла в термоэлектрических чувствительных элементах, протекающие после поглощения одиночных УФ фотонов с энергией 3.1–7.1 эВ (400–175 нм). Рассмотрены конструкции чувствительного элемента с поверхностью 10×10 мкм2, состоящие из последовательно расположенных на сапфировой подложке (Al2O3) слоев вольфрамового теплоотвода (W), термоэлектрического сенсора FeSb2, вольфрамового поглотителя и антиотражающего слоя SiO2. Компьютерное моделирование проводилось на основе уравнения распространения тепла из ограниченного объема с использованием трехмерного матричного метода для дифференциальных уравнений.
Terahertz Photoconductivity in Bilayer Graphene Transistors: Evidence for Tunneling at Gate-Induced Junctions
Photoconductivity of novel materials is the key property of interest for design of photodetectors, optical modulators, and switches. Despite the photoconductivity of most novel 2d materials having been studied both theoretically and experimentally, the same is not true for 2d p-n junctions that are necessary blocks of most electronic devices. Here, we study the sub-terahertz photocoductivity of gapped bilayer graphene with electrically induced p-n junctions. We find a strong positive contribution from junctions to resistance, temperature resistance coefficient, and photoresistivity at cryogenic temperatures T ∼ 20 K. The contribution to these quantities from junctions exceeds strongly the bulk values at uniform channel doping even at small band gaps of ∼10 meV. We further show that positive junction photoresistance is a hallmark of interband tunneling, and not of intraband thermionic conduction. Our results point to the possibility of creating various interband tunneling devices based on bilayer graphene, including steep-switching transistors and selective sensors.
Carbon Nanotube-Based Uncooled Bolometers: Advances and Progress
Introduction and Motivation
Energy resolving, single photon counting detectors sensitive to light in the ultraviolet to near-infrared wavelength range are useful in a variety of different fields. In bio-analysis research, there is demand for detectors that can measure fast, low-light biological processes with energy sensitivity (Niwa et al., Sci Rep 7:45660, 2017). Axion and hidden photon dark matter searches, too, could benefit from these kinds of detectors by expanding the searchable parameter space into the 0.1 eV∕c2 to 10 eV∕c2 mass range (Baryakhtar et al., Phys Rev D 98:035006, 2018). Here, we specialize to a particular astrophysical application for these detectors, exoplanet direct imaging, to emphasize the usefulness of this technology and since it is the current focus of our research group. However, the improvements discussed within have a broader significance to any photon-starved application requiring a fast, wide field of view detector with energy resolution in this wavelength range.Exoplanets—planets orbiting stars other than our own—are the primary motivator for this dissertation. Studying them provides us with a way to understand our own solar system. Through the distribution of observed exoplanets, we can gauge how common or unique our home is. By looking at similar systems at different stages after their formation, we can understand their evolution. Ultimately, we are interested in the signatures of life and determining the prevalence of conditions conducive to it. This chapter will introduce the rest of this dissertation by further discussing the science goals of exoplanet astronomy and how they inform the kinds of instrumentation we use to study these systems.KeywordsExoplanetImagingHigh contrastLow lightTransition edge sensorKinetic inductance detectorSuperconducting tunnel junctionResolving powerSpectroscopyIntegral field spectrograph
Effect of Cyano Substitution on Non‐Fullerene Acceptor for Near‐Infrared Organic Photodetectors above 1000 nm
Near‐infrared organic photodetectors (NIR OPDs) comprising ultra‐narrow bandgap non‐fullerene acceptors (NFA, over 1000 nm) typically exhibit high dark current density under applied reverse bias. Therefore, suppression of dark current density is crucial to achieve high‐performance of such NIR OPDs. Herein, cyano (CN) with a strong electron‐withdrawing property is introduced into alkoxy thiophene as a π‐bridge to adjust its optoelectronic characteristics, and the correlation between dark current density and charge injection barrier is investigated. Compared with their motivated NFA (COTH), the novel CN‐substituted NFAs, COTCN and COTCN2, exhibited deeper‐lying highest occupied molecular orbital energy levels and narrower optical bandgap (<1.10 eV), owing to the strong inductive and resonance effect of CN. The dark current and total noise currents are minimized as the number of substituted CN increases because of the larger hole injection barrier. Consequently, PTB7‐Th:COTCN2 exhibited the best shot‐noise limited detectivity (D*sh, 1.18 × 10¹² Jones) and total noise detectivity (D*n, 1.33 × 10¹¹ Jones) compared with those of PTB7‐Th:COTH (D*sh, 2.47 × 10¹¹ Jones and D*n, 1.96 × 10¹⁰ Jones).
Gate-tunable bolometer based on strongly coupled graphene mechanical resonators
Bolometers based on graphene have demonstrated outstanding performance with high sensitivity and short response time. In situ adjustment of bolometers is very important in various applications, but it is still difficult to implement in many systems. Here we propose a gate-tunable bolometer based on two strongly coupled graphene nanomechanical resonators. Both resonators are exposed to the same light field, and we can measure the properties of one bolometer by directly tracking the resonance frequency shifts, and indirectly measure the other bolometer through mechanical coupling. We find that the sensitivity and the response bandwidth of both bolometers can be independently adjusted by tuning the corresponding gate voltages. Moreover, the properties of the indirectly measured bolometer show a dependence on the coupling between the two resonators, with other parameters being fixed. Our method has the potential to optimize the design of large-scale bolometer arrays, and open new horizons in infrared/terahertz astronomy and communication systems.
Boron-doped hydrogenated mixed-phase silicon as thermo-sensing films for infrared detectors
Silicon materials have been widely used as thermo-sensing layers in infrared detectors or uncooled micro-bolometers. Parameters such as a large thermal coefficient of resistance (TCR), low sheet resistance (Rs), and low 1/f noise are important for high performance of these devices. However, there is always a trade-off between these parameters. For example, the crystalline silicon materials typically exhibit low Rs and 1/f noise, and significantly low TCR, while the amorphous silicon materials generally have large TCR, and considerably high Rs and 1/f noise. Consequently, the best trade-off can be achieved by using a mixed-phase structure of silicon materials, i.e. an intermediate form between the crystalline and amorphous structures. Herein we report the important characteristics of hydrogenated mixed-phase silicon films, deposited by the plasma-enhanced chemical vapour deposition process, for infrared detectors. The films in the mixed-phase structure showed high TCR values in the range of 2–3% K–1 and moderate sheet resistances in range of 10–40 MΩ sq⁻¹. These results indicate that the mixed-phase silicon films are potential alternatives to conventional boron doped hydrogenated amorphous and microcrystalline silicon films for use as thermo-sensing layers in infrared detectors.
High‐Speed Photodetectors on Silicon Photonics Platform for Optical Interconnect
A photodetector (PD) converts optical signals into electrical ones and is widely used in optical interconnect. High‐speed PDs are in high demand as they are necessary to meet requirements of large‐capacity optical interconnect. Many high‐performance PDs with various absorption materials and structures are demonstrated on silicon photonics platform, including germanium (Ge) PDs, germanium tin (GeSn) PDs, heterogeneous integrated III–V PDs, all silicon (Si) PDs, 2D material PDs, etc. These kinds of PDs continue to set new records of speed and open an era of ultrahigh‐speed optical interconnect. A comprehensive summary of the state‐of‐the‐art high‐speed PDs on silicon photonics platform is necessary and meaningful. In this review, the basic metrics and key process technologies for the PDs are introduced, and various types of high‐speed PDs based on silicon photonics platform are reviewed and discussed. Furthermore, the summary and perspectives are provided. It is hoped that this review can provide readers more insights into recent advances in high‐speed PDs on silicon photonics platform and contribute to the further development. High‐speed photodetectors (PDs) are in high demand as they are necessary to meet requirements of large‐capacity optical interconnect. Many high‐performance PDs with various absorption materials and structures are demonstrated on silicon photonics platform, which opens an era of ultrahigh‐speed optical interconnect. In this review, a comprehensive summary of the state‐of‐the‐art high‐speed PDs on silicon photonics platform is discussed.
Detection of single phonons via phonon drag in two-dimensional materials
The capacity to electrically detect phonons, ultimately at the single-phonon limit, is a key requirement for many schemes for phonon-based quantum computing; so-called quantum phononics. Here, we predict that by exploiting the strong coupling of their electrons to surface-polar phonons, van der Waals heterostructures can offer a suitable platform for phonon sensing, capable of resolving energy transfer at the single-phonon level. The geometry we consider is one in which a drag momentum is exerted on electrons in a graphene layer, by a single out-of-equilibrium phonon in a dielectric layer of hexagonal boron nitride, giving rise to a measurable induced voltage (Vdrag). Our numerical solution of the Boltzmann transport equation shows that this drag voltage can reach a level of a few hundred microvolts per phonon, well above experimental detection limits. Furthermore, we predict that Vdrag should be highly insensitive to the mobility of carriers in the graphene layer and to increasing the temperature to at least 300 K, offering the potential of a versatile material platform for single-phonon sensing.
Biodegradación de láminas de polietileno de baja densidad LDPE pretratadas por radiación UV, en humus de lombriz y Aspergillus brasiliensis
The degradation of polyethylene presents a series of difficulties as it doesn´t have efficient mechanisms that promote the deterioration of the material, for example, in the city of Bogotá around 428 tons of this material are produced annually. In this sense, it´s relevant to focus attention on this type of solid waste, generating a possibility of biodegradation of low-density polyethylene (LDPE), by means of an experimental matrix that favors the degradation of organic matter and LDPE sheets pretreated with UV
radiation, in kinenergic action with worm humus and biomass of Aspergillus brasiliensis. The evidence found of opaque coloration in the LDPE sheets, decreased flexibility, corrugations, colonization of theinoculum and cracks, proves the ability of an Aspergillus brasiliensis strain conserved in the research laboratory of the Fundación Universidad de América, to biodegrade LDPE with 1,5276% and 1,5186% weight loss after three months.
Silicon-based all-electronic quasi-optical pairs for THz frequency range
Simulation of Heat Propagation Processes in Thermoelectric Detection Pixels
Laser-induced graphene based visible and near-infrared radiation detector
A broadband fast detector of electromagnetic radiation in the visible and near-infrared spectral range is prepared from laser-induced graphene (LIG) obtained by thermal decomposition of a polyimide film. The thermal resistance coefficient of the LIG and resistive responsivity of LIG detector to 532 nm laser power of reach up to ~ 0.05%K-1 and ~ 0.16 %mW-1, respectively, at ambient conditions. The working frequency of LIG detector is spread over 10 kHz, which is explained by the contributions of two different mechanisms: the thermal heating of the graphene and the photogating effect. The photoresponse spectral characteristic of the LIG detector is similar to that of black body radiation with the exception of the tiny peculiarities associated with absorption of light by the optical setup, as well as with the processes of photoelectron generation in the LIG.
An Optical Parametric Amplifier via $ \chi ^{(2)}$ in AlGaAs Waveguides
We report parametric gain by utilizing
$ \chi ^{(2)}$
non-linearities in a semiconductor Bragg Reflection Waveguide (BRW) waveguide chip. Under the two-mode degenerate type II phase matching, it can be shown that more than 18 dBs of parametric gain for both TE and TM modes is tenable in 100 s of micrometers of device length. Polarization insensitive parametric gain can be attained within the 1550 nm region of the spectrum. These AlGaAs BRW waveguides exhibit sub-photon per pulse sensitivity. This is in sharp contrast to other types of parametric gain devices which utilize
$ \chi ^{(3)}$
, where the pump wavelength is in the vicinity of the signal wavelength. This sensitivity, which reached 0.1 photon/pulse, can usher a new era for on-chip quantum information processing using compact, micrometer-scale devices.
Colossal Room‐Temperature Terahertz Topological Response in Type‐II Weyl Semimetal NbIrTe4
The electromagnetic spectrum between microwave and infrared light is termed the “terahertz (THz) gap”, of which there is an urgent lack of feasible and efficient room‐temperature (RT) THz detectors. Type‐II Weyl semimetals (WSMs) have been predicted to host significant RT topological photoresponses in low‐frequency regions, especially in the THz gap, well addressing the shortcomings of THz detectors. However, such devices have not been experimentally realized so far. Herein, we demonstrate a type‐II WSM‐based THz detector, i.e., a NbIrTe4‐based device, which exhibits a photoresponsivity of 5.7×104 V/W, a detectivity of 2.9×109 Jones, and a 1‐year air stability at RT, comparable to the best RT THz detectors. Such excellent THz‐detection performance can be attributed to the topological effect of the type‐II WSM in which the effective mass of photogenerated electrons can be reduced by the large tilting angle of the Weyl cones to further improve mobility and photoresponsivity. Impressively, this device shows a giant intrinsic anisotropic conductance ( σmax/σmin= 339) and THz response ( Iph max/Iph min = 40.9), both of which, to the best of our knowledge, are record values. Our findings open a new avenue for the realization of uncooled and high‐sensitive THz detectors by exploring type‐II WSM‐based devices. This article is protected by copyright. All rights reserved
Thermally Isolated Ruthenium Nanobolometer for Room-Temperature Operation
We propose a bolometer intended for room-temperature operation and based on a 100-nm-wide ruthenium (Ru) strip fabricated on a thin layer of cross-linked polymethyl methacrylate (XPMMA). This layer provides thermal isolation between the silicon substrate and the Ru nanostrip for increasing the nonlinearity of the bolometer
${I}-{V}$
curve due to more intensive self-heating by the biasing and an ac current. A number of bolometers with Ru strips of different dimensions and different thicknesses of XPMMA layer were fabricated and tested at dc. An estimate based on the dc tests gives the electrical voltage responsivity to radio frequency (RF) signal as much as 250 V/W, which makes the proposed bolometer attractive as a sensing element for a simple and low-cost microwave and terahertz detector. Numerical simulations of temperature distribution along the Ru strip and analysis of the bolometer noise performance are also presented.
Terahertz Spectrum in Biomedical Engineering
In recent years, terahertz radiation (THz = 1012 Hz) has attracted much attention due to its exceptional non-invasive and non-ionizing sensing capabilities. The sub-THz band (0.1–0.3 THz) and the THz band (0.3–10 THz) lie between millimeter waves (mm-waves) and light waves with the ability to harness their advantages. The capacity for these sub-THz and THz waves to penetrate deeply into dielectric materials combined with their high spatial resolution makes them well suited for biomedical applications, including in-vivo and ex-vivo experiments. The purpose of this chapter is to discuss how the sensors based on these frequency spectra can be used in various biomedical applications, classified into three major domains, i.e., diagnostics, imaging, and treatment, where they provide many advantages over the existing devices. Next, we will discuss the appropriateness of using photonics and electronics THz instruments in THz applications and the suitability of using electronics in the sub-THz regime. Finally, we'll look at artificial intelligence's function in enhancing the technology's versatility.
Real‐Time THz Beam Profiling and Monitoring via Flexible Vertically Aligned Carbon Nanotube Arrays
In terahertz (THz) quasi‐optical systems, the real‐time profiling and visualization of THz beams is of great importance for beam focusing and collimation applications. Herein, a cost‐effective and room‐temperature‐operated THz imaging device for this purpose is demonstrated experimentally using a flexible and broadband THz absorber based on a vertically aligned carbon nanotube (VACNT) array. Excellent THz absorption performances with an average power absorptance >96.8% are achieved within 0.1 and 2.5 THz. The energy of the incident THz wave is absorbed by the THz absorber and converted into heat that will re‐radiate and can be detected by an infrared (IR) camera as a result of the THz‐to‐IR conversion mechanism. Real‐time THz beam imaging and monitoring applications are demonstrated by a series of experiments at both 0.1 and 0.3 THz, providing an alternative approach for real‐time beam profiling and monitoring of THz waves. The THz beam profiling and visualization is demonstrated experimentally via a cost‐effective and room‐temperature‐operated THz absorber based on the vertically aligned carbon nanotube array. Real‐time THz beam profiling and monitoring experiments are demonstrated at 0.1 THz and 0.3 THz utilizing the THz‐to‐IR conversion mechanism, providing an alternative approach for THz wave imaging using the mature IR techniques.
Simons Observatory Focal-Plane Module: Detector Re-biasing With Bias-step Measurements
The Simons Observatory is a ground-based cosmic microwave background survey experiment that consists of three 0.5 m small-aperture telescopes and one 6 m large-aperture telescope, sited at an elevation of 5200 m in the Atacama Desert in Chile. SO will deploy 60,000 transition-edge sensor (TES) bolometers in 49 separate focal-plane modules across a suite of four telescopes covering 30/40 GHz low frequency (LF), 90/150 GHz mid frequency (MF), and 220/280 GHz ultra-high frequency (UHF). Each MF and UHF focal-plane module packages 1720 optical detectors spreading across 12 detector bias lines that provide voltage biasing to the detectors. During observation, detectors are subject to varying atmospheric emission and hence need to be re-biased accordingly. The re-biasing process includes measuring the detector properties such as the TES resistance and responsivity in a fast manner. Based on the result, detectors within one bias line then are biased with suitable voltage. Here we describe a technique for re-biasing detectors in the modules using the result from bias-step measurement.
Topological Insulators Photodetectors: Preparation, Advances and Application Challenges
In photoelectric device era, topological insulators (TIs) are considered very promising candidates due to their superior features, including remarkable properties, full components, and compatibility with traditional complementary metal-oxide semiconductor processing technologies. Indeed, TIs have been shown to display abundant unparalleled optoelectronic properties, including extremely wide spectral response, fast relaxations in the flexible nanoscale, instance special band-gap structures, and topological surface states (TSS) effect. TIs, combined with optical platforms such as gratings, resonators and optical waveguides, has inspired a variety of military and civilian applications. The photoelectric characteristics of TIs as well as their design and fabrication of derivative heterostructures are comprehensively reviewed, discussed and implemented. This review summarizes the developmental progress of TIs-based photodetectors as well as their working mechanisms, preparation methods, progress and performance indicators. Finally, the future development trend, challenges and important research directions are prospected, which provides a promising approach for the new concept and high performance photodetection applications of TIs.
Revealing the Thermal Properties of Superconducting Magic-Angle Twisted Bilayer Graphene
The allegedly unconventional superconducting phase of magic-angle twisted bilayer graphene (MATBG) has been predicted to possess extraordinary thermal properties, as it is formed from a highly diluted electron ensemble with a record-low carrier density (n) of ∼1011 cm-2 and electronic heat capacity (Ce) of <100kB. While these attributes position MATBG as a ground-breaking material platform for revolutionary calorimetric applications, these properties have so far not been experimentally shown. Here, we reveal the thermal properties of superconducting MATBG by monitoring its temperature dependent critical current (Ic) under continuous laser heating at 1550 nm. From the bolometric effect, we extract the temperature dependence of the electronic thermal conductance (Gth), which has a value of Gth = 0.2 pW/K at 35 mK and in the low temperature limit is consistent with a power law dependence, as expected for nodal superconductors. Our work lays the foundation for future thermal transport studies on this system.
An Open-Circuit Voltage Pixel for Low-Light Visible Imaging in a Standard CMOS Process
Closed cycle 4 K nanowatt meter for hectogram payloads
Superconducting computing research is motivated by fast energy-efficient computing, which creates the challenge of developing components with low-power dissipation requirements. In support of this research, we demonstrate a system that measures heat dissipated by electrical and absorbed optical power in packaged cryogenic devices at a temperature of 4 K. In our system, the device under test resides on a stage that is maintained at a constant 4 K using a feedback heater circuit. The sample stage is cooled via a passive weak thermal link to a stabilized 3 K bath of a closed-cycle pulsed-tube refrigerator. With a maximum device payload of 300 g and a weak thermal link of 13 800 K/W, the empirically determined minimum measurable dissipated power is 300 pW. With a very strong thermal link of 53 K/W, the maximum measurable dissipated power is 30 mW.
Correspondence between microwave and submillimeter absorptivity in epitaxial thin films of YBa_ {2} Cu_ {3} O_ {7}
Phys Rev B
D. Miller
S. Etemad
P. L. Richards
B. F. Cole
We have measured the low-temperature loss in six epitaxial ab-plane films of the high-Tc superconductor YBa2Cu3O7 over a factor of 2000 in frequency. Submillimeter measurements from 25 to 700 cm-1 were made at 2 K by a direct absorption technique in which the film acts as the absorbing element in a composite bolometric detector. Microwave measurements near 10 GHz (0.3 cm-1) were made on five of the same films by resonance techniques at 4 K. The ∼0.4-μm-thick films were grown epitaxially on SrTiO3, LaAlO3, and MgO by off-axis sputtering and laser deposition. The absorptivities measured for all films studied are qualitatively similar, increasing smoothly with frequency, with no gaplike features below the well-known absorption edge at 450 cm-1. A successful three-parameter fit is obtained for all of our films. This fit can be interpreted either in terms of a weakly coupled grain model or a homogeneous two-fluid model with residual normal conductivity. The fitting parameters correspond to a grain-penetration depth λg equal to the muon-spin-relaxation value of 140 nm, and to reasonable grain properties. They also give carrier densities in reasonable agreement with optically determined plasma frequencies and conductivities in agreement with a Kramers-Kronig analysis of the absorptivity data.
Fabrication And Measurement of High Tc Superconducting Microbolometers
IEEE T MAGN
B. F. Cole
M. Nahum
<here is a image b5f2f21ed6c99fd8-15349ceca7d2a8f8> Qing Hu
P. L. Richards
The authors fabricated and measured the performance of
antenna-coupled microbolometers based on the resistive transition of a
high- T <sub>c</sub> superconducting film for use as detectors of
far-infrared and millimeter waves. A planar lithographed antenna
(log-periodic or log-spiral) is used to couple the radiation to a thin
YBCO film with dimensions (≈6×13 μm<sup>2</sup>) which are
smaller than the wavelength to be measured. This film acts both as the
resistor to thermalize the RF currents and as a transition edge
thermometer to measure the resulting temperature rise. Because of its
small size, both the thermal conductance from the film into the bulk of
the substrate and the heat capacity of the thermally active region are
small. Consequently, the microbolometer has low noise, fast response,
and a high voltage responsivity. A phonon-limited electrical NEP of
4.5×10<sup>-12</sup> WHz<sup>-1/2</sup> at a 10-kHz modulation
frequency and a responsivity of 478 V/W at a bias of 550 μA were
measured. Measurements of the optical efficiency are discussed
Thermal detectors as X-ray spectrometers
Article
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> John C Mather
<here is a image 7f5fbeea6015cfb4-f809b9af01155cad> Dan Mccammon
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Samuel Moseley
We show that sensitive thermal detectors should be useful for measuring very small energy pulses, such as those produced by the absorption of x‐ray photons. The measurement uncertainty can be very small, making the technique promising for high resolution nondispersive x‐ray spectroscopy. We derive the limits to the energy resolution of such thermal detectors. We use these to find the resolution to be expected for a detector suitable for x‐ray spectroscopy in the 100–10 000 eV range. If there is no noise in the thermalization of the x‐ray, resolution better than 1 eV full width at half maximum (FWHM) is possible for detectors operating at 0.1 K. Energy loss in the conversion of the photon energy to heat is a potential problem. Statistical fluctuations of lost energy would reduce the energy resolution of the detector. The loss mechanisms may include emission of photons or electrons, or the trapping of energy in long‐lived metastable states. Fluctuations in the phonon spectrum could also limit the resolution if phonon relaxation times are very long. We give conceptual solutions for each of these possible problems.
Thermal boundary resistance for YBa2Cu3O7-δ films
APPL PHYS LETT
M. Nahum
<here is a image af4e8d857ce80a9f-c7854687e668ae89> Simon Verghese
K. Char
P. L. Richards
We have made direct measurements of the thermal boundary resistance, R bd , between high quality epitaxial films of YBa 2 Cu 3 O 7-δ and a variety of substrates with and without buffer layers. The boundary resistance was deduced from measurements of the electrical resistance changes in three parallel strips of YBa 2 Cu 3 O 7-δ when one was electrically heated. Our measurements indicate that R bd is weakly dependent on temperature and, for all the measured samples, has a value of 0.8–1.4×10<sup>-3</sup> K cm<sup>2</sup>/W between 90 and 200 K, which is a factor of ≊80 larger than the prediction of the acoustic mismatch model at 100 K. The thermal response time of ≊1 ns which results from the heat capacity of the film and R bd is observed in many experiments with pulsed laser sources.
A Bolometric Millimeter-Wave System for Observations of Anisotropy in the Cosmic Microwave Background-Radiation on Medium Angular Scales
M. L. Fischer
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> David C Alsop
E. S. Cheng
<here is a image a13ab64dd8946169-54106407145f5f28> George Smoot
We report the performance of a bolometric system designed to measure the anisotropy of the cosmic microwave background (CMB) radiation on angular scales from 0 deg 3 min to 3 deg. The system represents a collaborative effort combining a low-background 1 m diameter balloon-borne telescope with new multimode feed optics, a beam modulation mechanism with high stability, and a four-channel bolometric receiver with passbands centered near frequencies of 3 (90), 6 (180), 9 (270), and 12 (360) cm(exp -1) (GHz). The telescope was flown three times with the bolometric receiver and has demonstrated detector noise limited performance capable of reaching sensitivity levels of Delta(T)/T(sub CMB) is approximately equal to 10(exp -5) with detectors operated at T = 0.3 K.
Electrical self-calibration of nonideal bolometers
Article
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> John C Mather
Photon noise in photometric instruments at far-infrared and submillimeter wavelengths
Article
<here is a image 65ab9d06af91623c-d0c69e0fc72c3827> Jean-Michel Lamarre
Photon noise in photometric instruments is computed using two different methods. A first expression, derived from quantum physics, corresponds to the most widely used formulas and is applicable when diffraction phenomena are negligible. The second one is derived from the semiclassical approach of Hanbury Brown and Twiss. Properties of this expression, including consistency with the former one, asymptotical behavior,andscalepropertiesarederivedanddiscussed. Theeffectofpolarizationisstudied,andpractical examples are given.
Thermal Conductivity of Solids at Room Temperature and Below
Article
G. Childs
L. J. Ericks
R. Powell
YBa2Cu3O7 superconductor microbolometer arrays fabricated by silicon micromachining
Article
IEEE T APPL SUPERCON
B.R. Johnson
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Thomas Ohnstein
C.J. Han
Scott B. Dunham
Linear arrays of YBa2Cu3O7 transition edge microbolometers have been
fabricated on silicon substrates using silicon micromachining to produce
microbolometer structures with good thermal isolation. These bolometers,
which are 85 micron x 115 micron x 1 micron, have a noise equivalent
power (NEP) of 9 x 10 exp -13 W/sq rt Hz (neglecting contact noise) and
a thermal time constant of 24 ms. With contact noise, the NEP is 9 x 10
exp -12 W/sq rt Hz. This performance indicates that a 2D staring focal
plane array of superconductor microbolometers could have a performance
comparable to that of HgCdTe staring arrays without further improvements
in the sharpness of the superconducting transition or reductions in the
YBa2Cu3O7 electrical noise. The use of silicon processing technology to
fabricate the superconductor microbolometers results in a significant
cost advantage over HgCdTe, and there is no long wavelength cutoff
dependence in the sensitivity of a superconductor microbolometer.
SCUBA - Submillimetre common-user bolometer array for the James Clerk Maxwell telescope
Article
Proceedings of SPIE
<here is a image 16959f6308d8945e-00a5b4495d3879af> Colin Richard Cunningham
Walter K. Gear
A submillimeter continuum array instrument being built for the 15-m
James Clerk Maxwell Telescope on Mauna Kea, Hawaii is described. The
instrument contains 2 arrays, one of 91 pixels optimized for 438 microns
and the second of 37 pixels optimized for 855 microns. Both are
hexagonally close-packed, with each pixel having diffraction-limited
angular resolution. Conical horns and single-moded waveguides are used
to couple to the submillimeter beams, minimizing the bolometer
background loading. A filter changing mechanism allows operations of the
arrays at 350 and 750 microns. Single 'photometric' pixels are provided
optimized for operation at 350, 600, 750, 1100, 1400 and 2000 microns.
The instrument will have bolometers sensitive enough to reach the
photon-noise sensitivity limit at both wavelengths, corresponding to an
optical noise equivalent power (NEP) of 1.6 x 10 to the -16th WHz exp
-1/2. This is achieved by cooling to 0.1 K, using a dilution
refrigerator.
High-Temperature Superconducting Microboloineter
Article
APPL PHYS LETT
T.G. Stratton
B.E. Cole
Paul W. Kruse
<here is a image 1fe3b2a50db43788-77a31cbf903aec51> A. M. Goldman
A superconducting microbolometer employing a DyBaCuO film deposited upon a silicon microstructure was found to have a responsivity of 800 V/W at 89 K and a response time of 1 ms.
Electrical self-calibraion of nonideal bolometers
Article
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> John C Mather
The responsivity of an infrared bolometer detector is deduced from electrical measurements, even for cases when the temperature sensor has electrical nonlinearities.
Low-Temperature Germanium Bolometer
Article
J Opt Soc Am
FRANK J. LOW
A bolometer, using gallium-doped single crystal germanium as the temperature-sensitive resistive element, has been constructed and operated at 2°K with a noise equivalent power of 5× 10-13 w and a time constant of 400 µsec. Sensitivities approaching the limits set by thermodynamics have been achieved, and it is shown that the background radiation limited or BLIP condition can be satisfied at 4.2°K. An approximate theory is developed which describes the performance of the device and aids in the design of bolometers with specific properties. The calculated noise equivalent power at 0.5°K, for a time constant of 10-3 sec, is 10-15 w. The detector is suitable for use in both infrared and microwave applications.
Experiments on the Refrangibility of the Invisible Rays of the Sun. by William Herschel, LL. D. F. R. S
Article
Phil Trans Roy Soc Lond
William Herschel
In that section of my former paper which treats of radiant heat, it was hinted, though from imperfect experiments, that the range of its refrangibility is probably more extensive than that of the prismatic colours; but, having lately had some favourable sunshine, and obtained a sufficient confirmation of the same, it will be proper to add the following experiments to those which have been given. I provided a small stand, with four short legs, and covered it with white paper. On this I drew five lines, parallel to one end of the stand, at half an inch distance from each other, but so that the first of the lines might only be ¼ of an inch from the edge. These lines I intersected at right angles with three others; the 2d and 3d whereof were, respectively, at 2½ and at 4 inches from the first.
Cone Channel Condenser Optics
Article
J Opt Soc Am
DONALD E. WILLIAMSON
Conical light pipes to condense radiation are attractive in their simplicity and low cost.In addition, when using detectors having non-uniform surface response, the non-image forming characteristics of such channels are desirable. Through the use of a field lens, channels may be designed which condense the radiation through a given area to the smallest possible size. As viewed from the output end of the channel, this corresponds to achievement of the optimum f/number of 0.6. Reflection losses in the experimental model described increased the f /number to 0.77. The cone channel described has the further advantage that it is not receptive to stray light.
The General Theory of Bolometer Performance
Article
J Opt Soc Am
R. CLARK JONES
A general phenomenological theory of the static and dynamic behavior of bolometers is presented. The theory assumes as given the fundamental relations between the temperature and resistance of the bolometer, and the past history of the power dissipated within it. From these basic properties are derived a number of the properties of more immediate interest, such as electrical impedance, responsivity as a function of frequency, and the static load curve.Several equivalent circuits are developed to represent the behavior of the bolometer as a function of frequency at a single operating point. A two-terminal equivalent circuit is described that represents the electrical impedance as a function of frequency. In order to represent the response of the bolometer to incident radiation as a function of frequency, a four-terminal equivalent circuit is described.An electrical bridge is described that permits one to measure by purely electrical means the electrical response that a bolometer would have to radiation of any given time dependence, including radiation that varies sinusoidally. By purely electrical means and without the need of a radiation source (calibrated or otherwise), the bridge provides a precise measurement of the bolometer’s responsivity (output volts per watt of incident radiation) as a function of frequency. An electrical signal S(t) at the input of the bridge produces the same electrical output as would be produced in the normal use of the bolometer by a radiation signal with the same wave form as S(t).The presentation is in three parts: static performance; stability; and dynamic performance.
The Detectivity of Cryogenic Bolometers
Article
| https://www.researchgate.net/publication/224554517_Bolometers_for_infrared_and_millimeter_waves |
KoreaMed Synapse
Original Article
Korean J Physiol Pharmacol 2010;14(4):229-233.
Published online:18 February 2010
DOI:https://doi.org/10.4196/kjpp.2010.14.4.229
Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice
Hyun Jung Yang
1,
∗
, Yuyoung Joo
2,
∗
, Bo-Hyun Hong
2
, Sung-Ji Ha
2
, Ran-Sook Woo
3
, Sang Hyung Lee
4
, Yoo-Hun Suh
2
, Hye-Sun Kim
2,
5,
1Department of Food and Nutrition, Kookmin University College of Natural Sciences, Seoul 136-702, Korea
2Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Korea
3Department of Anatomy and Neuroscience, College of Medicine, Eulji University, Daejeon 301-746, Korea
4Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-799, Korea
5Department of Pharmacology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Sungnam 463-707, Korea
Corresponding to: Hye-Sun Kim, Departments of Pharmacology, Biomedical Sciences, College of Medicine, Seoul National University, 28, Yeongeon-dong, Jongno-gu, Seoul 110-799, Korea. (Tel) 82-2-740-8298, (Fax) 82-2-741-8298, (E-mail)hyisun@snu.ac.kr
∗These two authors equally contributed to this study.
Received 17 July 2010 Revised 27 July 2010 Accepted 5 August 2010
Copyright © 2010 Korean J Physiol Pharmacol
Abstract
Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of amyloid precursor protein and serves as a bipartite activation enzyme for the ubiquitin-like protein, NEDD8. Previously, it has been reported that APP-BP1 rescues the cell cycle S-M checkpoint defect in Ts41 hamster cells, that this rescue is dependent on the interaction of APP-BP1 with hUba3. The exogenous expression of APP-BP1 in neurons has been reported to cause DNA synthesis and apoptosis via a signaling pathway that is dependent on APP-BP1 binding to APP. These results suggest that APP-BP1 overexpression contributes to neurodegeneration. In the present study, we explored whether APP-BP1 expression was altered in the brains of Tg2576 mice, which is an animal model of Alzheimer's disease. APP-BP1 was found to be up-regulated in the hippocampus and cortex of 12 month-old Tg2576 mice compared to age-matched wild-type mice. In addition, APP-BP1 knockdown by siRNA treatment reduced cullin-1 neddylation in fetal neural stem cells, suggesting that APP-BP1 plays a role in cell cycle progression in the cells. Collectively, these results suggest that increased expression of APP-BP1, which has a role in cell cycle progression in neuronal cells, contributes to the pathogenesis of Alzheimer's disease.
Keywords:Amyloid precursor protein binding protein-1,Amyloid precursor protein,Alzheimer's disease,cell cycle,Tg2576 mice
References
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<here is a image f8c85a5c4642d3af-f84bb78ea24f31ab>
<here is a image 9cd67917bf73eebc-0f8f9852bccebaa0>
Fig. 1.
APP-BP1 protein level was up-regulated in the hippocampus from 12 month-old Tg2576 mice. (A) APP-BP1 protein level was examined by western blotting in the hippocampus from 6-, 12- and 18-month-old Tg 2576 and wild-type mice. This blot is a representative of 4 independent experiments. (B) Densitometric analysis was also performed. Data represent mean±SEM.
∗
p<0.05 compared with 6 month-old wild type mice (n=4) and
#
p<0.05 compared with 12 month-old wild type mice, by one-way ANOVA followed by Duncan's post hoc test.
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<here is a image cbd2f3ee4175deb1-b47b7e563899a88d>
Fig. 2.
APP-BP1 immunoreactivities are increased in the cortex and hippocampus from 12-month-old wild-type and Tg2576 mice. The fixed brains from 12-month-old wild type and Tg2576 mice (n=5) in 10% neutral buffered formalin for 48 h were dehydrated and embedded in paraffin. (A) The fluorescent immunohistochemistry was performed in the cortex with the anti-APP-BP1 antibody for 2 h, which was then visualized using a Cy3-conjugated secondary antibody. DAPI counter staining was performed. Images were collected using the LSM 510 program on a Zeiss confocal microscope. This figure is a representative of 5 independent experiments. Scale bars=25
μ
m. (B) Immunoreactivities of APP-BP1 was examined in the dentate gyrus of 12 month-old wild type and Tg2576 mice. IHC was performed using a Vectastain avidin-biotin complex elite kit. Peroxidase stained sections were examined under a light microscope (BX51TF; Olympus Optical Co., Japan) equipped with an exposure control unit (PM-CB20) and a camera (CPM-C35DX). Scale bars=50
μ
m. (C) Quantative analysis for (B) was performed by calculating APP-BP1 immunoreactive cells per section from 5 independent samples (
∗∗
p<0.01 by Student's
t
-test).
undefined
<here is a image dd876e16aa757cec-b9ce6b1cf74a8f39>
Fig. 3.
APP-BP1 knockdown reduced Cul-1 neddylation in fetal neural stem cells. (A) After treatment of fetal neural stem cells with 10 nM non-targeting and APP-BP1 siRNAs for 72 h, APP-BP1 protein levels were examined by western blotting. Densitometric analysis was also performed. Data represent mean±SEM.
∗
p<0.05 compared with non-treated cells, by one-way ANOVA followed by Duncan's post hoc test. (B) After treatment with siRNAs in fetal neural stem cells (passage 8) for 72 h, neddylated Cul-1 was examined by immunoprecipitation of Cul-1 followed by western blotting for NEDD8.
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| https://synapse.koreamed.org/articles/1025683 |
Amos 8 ESV BSB Parallel
ESV Parallel BSB [BSB CSB ESV HCS KJV ISV NAS NET NIV NLT HEB]
English Standard Version Berean Study Bible
1 This is what the Lord GOD showed me: behold, a basket of summer fruit. 1 This is what the Lord GOD showed me: I saw a basket of summer fruit.
2 And he said, “Amos, what do you see?” And I said, “A basket of summer fruit.” Then the LORD said to me, “The end has come upon my people Israel; I will never again pass by them. 2 “Amos, what do you see?” He asked. “A basket of summer fruit,” I replied. So the LORD said to me, “The end has come for My people Israel; I will no longer spare them.”
3 The songs of the temple shall become wailings in that day,” declares the Lord GOD. “So many dead bodies!” “They are thrown everywhere!” “Silence!” 3 “In that day,” declares the Lord GOD, “the songs of the temple will turn to wailing. Many will be the corpses, strewn in silence everywhere!”
4 Hear this, you who trample on the needy and bring the poor of the land to an end, 4 Hear this, you who trample the needy, who do away with the poor of the land,
5 saying, “When will the new moon be over, that we may sell grain? And the Sabbath, that we may offer wheat for sale, that we may make the ephah small and the shekel great and deal deceitfully with false balances, 5 asking, “When will the New Moon be over, that we may sell grain? When will the Sabbath end, that we may market wheat? Let us reduce the ephah and increase the shekel; let us cheat with dishonest scales.
6 that we may buy the poor for silver and the needy for a pair of sandals and sell the chaff of the wheat?” 6 Let us buy the poor with silver and the needy for a pair of sandals, selling even the chaff with the wheat!”
7 The LORD has sworn by the pride of Jacob: “Surely I will never forget any of their deeds. 7 The LORD has sworn by the Pride of Jacob: “I will never forget any of their deeds.
8 Shall not the land tremble on this account, and everyone mourn who dwells in it, and all of it rise like the Nile, and be tossed about and sink again, like the Nile of Egypt?” 8 Will not the land quake for this, and all its dwellers mourn? All of it will swell like the Nile; it will surge and then subside like the Nile in Egypt.
9 “And on that day,” declares the Lord GOD, “I will make the sun go down at noon and darken the earth in broad daylight. 9 And in that day, declares the Lord GOD, I will make the sun go down at noon, and I will darken the earth in the daytime.
10 I will turn your feasts into mourning and all your songs into lamentation; I will bring sackcloth on every waist and baldness on every head; I will make it like the mourning for an only son and the end of it like a bitter day. 10 I will turn your feasts into mourning and all your songs into lamentation. I will cause everyone to wear sackcloth and every head to be shaved. I will make it like a time of mourning for an only son, and its outcome like a bitter day.
11 “Behold, the days are coming,” declares the Lord GOD, “when I will send a famine on the land— not a famine of bread, nor a thirst for water, but of hearing the words of the LORD. 11 Behold, the days are coming, declares the Lord GOD, when I will send a famine on the land—not a famine of bread or a thirst for water, but a famine of hearing the words of the LORD.
12 They shall wander from sea to sea, and from north to east; they shall run to and fro, to seek the word of the LORD, but they shall not find it. 12 People will stagger from sea to sea and roam from north to east, seeking the word of the LORD, but they will not find it.
13 “In that day the lovely virgins and the young men shall faint for thirst. 13 In that day the lovely young women—the young men as well—will faint from thirst.
14 Those who swear by the Guilt of Samaria, and say, ‘As your god lives, O Dan,’ and, ‘As the Way of Beersheba lives,’ they shall fall, and never rise again.” 14 Those who swear by the guilt of Samaria and say, ‘As surely as your god lives, O Dan,’ or, ‘As surely as the way of Beersheba lives’—they will fall, never to rise again.”
ESV Text Edition: 2016. The ESV® Bible (The Holy Bible, English Standard Version®) copyright © 2001 by Crossway Bibles , a publishing ministry of Good News Publishers. The ESV® text has been reproduced in cooperation with and by permission of Good News Publishers. Unauthorized reproduction of this publication is prohibited. All rights reserved. The Berean Bible ( Berean Study Bible (BSB) © 2016, 2018 by Bible Hub and Berean.Bible . Used by Permission. All rights Reserved.
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My Lords, in moving Amendment 115 I...: 12 Mar 2018: House of Lords debates - TheyWorkForYou
Part of the debate & ndash; in the House of Lords at 1:00 am 12 March 2018
European Union (Withdrawal) Bill - Committee (6th Day) (Continued)
Part of the debate – in the House of Lords at 1:00 am on
12 March 2018
.
Lord Whitty Chair, EU Internal Market Sub-Committee, Chair, EU Internal Market Sub-Committee 1:00,
12 March 2018
My Lords, in movingAmendment115 I will also support Amendment 172, which is about theEuropean Chemicals Agency. Noble Lords may have noticed that, while I normally speak to amendments as a Back-Bencher, I am also representing theFront Benchtonight. I hope the noble Lord, Lord Taylor, theChief Whip, will recognise that this reduces the number of speeches by one—and possibly two if theMinisteragrees with me.
Amendment 115 sets out in some detail a fallback position to deal with the important issue of the management of chemicals. Essentially, it is also a probing amendment in that it asks the Government to clarify their future relationship withREACH, the regime for registering, authorising and controlling the use of chemicals in industry and in everyday life. I note that, since we tabled this amendment, thePrime Ministeris at least in part in support of its objective, in that she wishes to maintain some degree ofUKparticipation in the European Chemicals Agency—which I applaud.
This is a very important area of protection for workers, consumers and the environment, and for ensuring that there is a level playing field in the trade in chemicals across Europe. It deals with more than 20,000 chemicals in an industry which, in British terms, exports 60% of its export produce to the EU, while 75% of our own imports are also from the EU. Having equivalent arrangements is therefore very important: for the industry and the trade; for the protection of people as workers, consumers and the general public; and for the environment and the associated ecosystems of air, water and soil.
The REACH system goes well beyond the point which thePrime Ministermade in relation to the agency. It is a very complex interrelationship between regulating the way that companies operate and market, and the way in which products are handled, traded and transported. It is dependent on a lot of highly intricate, multiple interactions between UK actors and actors within the EU at various levels, and between the institutions of the EU. It is essentially based on a precautionary principle and is a backstop to prevent dangerous chemicals entering the UK. This is a further backstop, were no agreement to be reached along the lines which I hope the Prime Minister is moving towards—in other words, to maintain the present system. Clearly, maintaining the present system is the preferable option. It is one which the chemical industry itself and environmentalists are advocating, and which those who have to deal with the chemicals trade, its products and their incorporation within other products also strongly support.
The Government have been looking at various options and it is right that they should do so. We are given to understand thatMichael Gove, or rather thePermanent Secretaryof his department, has suggested that we should be paying £6 million at the moment to create the capability to enable registration on a UK basis. Amendment 115 attempts to move on from that and to ensure that we have a clear legislative basis for the UK to operate on, which would come as close as possible to maintaining engagement with the REACH process.
We would, however, much prefer it if the REACH process were incorporated in the UK and that we effectively continued in the status quo. If we do not do so, it will not only engage the Government in considerable expenditure but disadvantage UK industry. It will also potentially disadvantage the UK public, in that they will not have the same protections as they had within the EU because we will not have access to the complex database on which the REACH procedure is based.
Incidentally—but to many people quite importantly—it would also increase the number of testing arrangements that would have to be made within the UK, which would be expensive and complex, and would also, among other things, increase the number of animal tests. Therefore, the issue of animal suffering andoppositionto animal testing would be duplicated between the EU and the UK.
So a whole range of issues is involved. An amendment along our lines gives the ability to create an alternative that more or less replicates the REACH provisions, but it is a second-best solution. If the Minister can indicate today that, in the Prime Minister’s words last week, the Government will be seeking full continuing involvement in the REACH process, it would be the best outcome for all of us. It would be the best outcome for those who are potentially exposed to chemical hazards, it would be the best outcome for industry and its operations within Europe and it would also be the best outcome for the Government not to be faced with multiple pressures arising from differential processes and differential regulation.
I therefore hope to hear from the Government not only a clarification but an indication that the maximum interpretation of the Prime Minister’s speech would mean that we would continue to involve ourselves not only in the European Chemicals Agency but in the totality of the REACH process. I hope that the Minister can give me that clarity tonight and share it with the rest of the Committee tonight, in which case we will all be on the same page. If not, it is of such importance to industry, consumers and others that we would need to return if there is a lack of clarity tonight. For the moment, I am encouraged by the Prime Minister’s speech and therefore encourage the Minister to spell out exactly what it means so that we can all go home at some point in the next few hours with at least one advance in the process this evening. I beg to move.
(Citation: HL Deb, 12 March 2018, c1477)
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Us and Them | Stereophile.com
I've known a lot of folks with impressive LP and CD collections who were perfectly content with the sound of the crappiest of hi-fis. This diverse group has included recording engineers, musicians, and owners of record stores. Loving music isn't the same thing as caring about the sound of music, and maybe, in some alternate universe, those folks would-have-been, could-have-been audiophiles. But in this universe, they didn't, and I'm not sure why.
As We See It
Us and Them
I've known a lot of folks with impressive LP and CD collections who were perfectly content with the sound of the crappiest of hi-fis. This diverse group has included recording engineers, musicians, and owners of record stores. Loving music isn't the same thing as caring about the
sound
of music, and maybe, in some alternate universe, those folks would-have-been, could-have-been audiophiles. But in this universe, they didn't, and I'm not sure why.
It's clear that we audiophiles are a different breed. We crave a deeper connection with the sound of music. We also love gear, so we're much more likely to do whatever it takes to accommodate speakers and electronics that take up an inordinate amount of our living space. To us, the gear looks cool. "Civilians" think we're nuts.
My sound obsession began in the 1950s, when I was a small child frequently found pressing my Sony six-transistor AM radio to my ear. Ah, there's Jerry Lee Lewis singing "Breathless"—or Chuck Berry's "Maybellene." I was always searching for that magic mojo.
Many audiophiles credit early exposure to the audio system of a dad, a relative, or a neighbor asthe spark that ignited their passion for sound. My family didn't have a hi-fi, but in 1961 we bought a Wurlitzer jukebox, a refrigerator-sized thing decked out with garishly colored lights that took over the basement den. We'd load it up with 45s and play tunes. The Wurlitzer was my dream machine. There was something about the way its disc-changing mechanism plucked the selected 45 from the rack and the massive tonearm ever-so-gently lowered the stylus into the lead-in groove that I found endlessly fascinating. The whirs and clunks of the machine going through its motions were all part of the intrigue. I spent hours sprawled on the checkerboard linoleum tile in front of the Wurlitzer, feeling the beat, massaged by the low, churning rumble of its mighty woofers.
My pipsqueak six-transistor radio didn't stand a chance. It played the same lyrics, melodies, harmonies, and rhythms, but through the Wurlitzer the sound was completely different—and a whole lot better. I never got over that. I'm still searching for better sound today.
My best friend's dad had a big-rig system that included McIntosh electronics. I can't remember the rest of the gear, but whatever it was, it was impressive, and the Macs' tubes put on a hell of a light show. To me, they looked like rocket ships. My friend's folks didn't play rock'n'roll, just classical music, and I don't recall much about the sound itself—it was background, not foreground, and so no threat to the mighty Wurlitzer.
I began to realize that not all music systems were equally engaging. I was into James Brown, girl groups, and Thelonious Monk, but by the time the Beatles hit I had my own little stereosystem with a Garrard turntable, a plastic amp, and XAM speakers. The sound slammed into high gear when I discovered Jimi Hendrix and Led Zeppelin. Miles Davis's Bitches Brewcame later, and a little further down the road were Brian Eno's Here Come the Warm Jets, Another Green World, and Before and After Science. Those were the albums I'd play when I checked out new gear. The better the hi-fi, the more of the sound I was privy to. The metamorphosis from music lover to audiophile was complete, and there was no turning back.
It wasn't long after that I began a 16-year stint of selling high-end audio in New York City. I demonstrated great-sounding systems to thousands of non-audiophiles, most of whom were unmoved. They didn't get it. Wilson Audio speakers and Krell electronics, orQuad ESL-63s with Conrad-Johnson amps, failed to get a rise out of most high-end virgins. Worse, they looked disappointed—the visual impact of the gear didn't seem to have anything to do with the sound they heard. I learned that exposure to great sound rarely produces instant converts, so it was especially satisfying when a non-audiophile was turned on by the sound.
In the early 1980s, when folks en masse were dumping their LPs for CDs, I began running comparisons of the formats for walk-in customers. Few non-audiophiles had ever heard a great high-end turntable, and through those demos I sold 'tables to folks who were blown away by the difference they heard—and who then began to really listen. The ones who weren'tswayed were much more likely to go for the smallest possible speakers and fuss-free operation. That was all they needed—for them, a hi-fi was an appliance.
One of the things that first attracted me to high-end audio was its human scale. No one knows or cares who designed their iPhone or Samsung flat-screen TV, but owners of Rogue Audio amps can pick up the phone and chat with Mark O'Brien, the man who designs them—or ask John Grado about their 20-year-old Grado Reference cartridge. These guys actually liketo hear from their customers. High-end audio companies are for-profit businesses, but the most successful of them are still run by people who put their blood, sweat, and tears into making the best-sounding products they can. That, more than money, is what drives them. It's all about the sound of the music.
No one needs a high-end system to play tunes, but it sure as hell is a better way to emotionally connect with music. Why we can't be satisfied with the "rich" sound of a Bose SoundLink Bluetooth III speaker is a small mystery. I dunno. Those pint-sized things may be good enough for most music lovers, but audiophiles want more than good enough—a lotmore.— Steve Guttenberg
| https://www.stereophile.com/comment/547837 |
Export Reviews, Discussions, Author Feedback and Meta-Reviews
Paper ID: 1177 Title: Streaming Min-max Hypergraph Partitioning
Current Reviews
Q1
: Comments to author(s). First provide a summary of the paper, and then address the following criteria: Quality, clarity, originality and significance. (For detailed reviewing guidelines, see http://nips.cc/PaperInformation/ReviewerInstructions)
This paper proposes a simple greedy strategy for the min-max hypergraph partitioning problem under the streaming model. This paper defines a stochastic model for generating the input hypergraph and show the sufficient conditions for the asymptotical recovery of the hidden clusters for the hypergraphs generated using this model.
I think the paper studies an interesting and important problem. The proposed stochastic model for graph generation seems interesting and novel. I find it interesting to see that the min-max graph partitioning problem can be almost recovered under certain conditions of the graph.
However, I am mostly concerned about how realistic the stochastic model for generating the graph is: does the hidden co-clustering assumption about how the data is generated realistic in practice? I hope to see more justification of why this model is natural for real-world applications.
I think the authors should also cite a recent but very relevant paper below, which essentially considers the same problem of min-max graph partitioning and proposes an offline greedy algorithm very similar to the one proposed in this work. The offline greedy algorithm is claimed to run with time complexity of O(k|E|) , where k is the number of parts in the resulting partitioning and |E| is the number of edges in the bipartite graph. I am curious to see how the streaming greedy algorithm performs relative to the offline greedy algorithm empirically.
Graph Partitioning via Parallel Submodular Approximation to Accelerate Distributed Machine Learning Mu Li, Dave G. Andersen, Alexander J. Smola, 2015
http://arxiv.org/pdf/1505.04636.pdf
Minor comments:
Line 168-171: It seems that this part of paper is trying to claim that the random partitioning of the graph can yield bad performance, but all it shows is that the random partitioning gives a cost of (1-1/e)m, whereas it is unclear what the global optimal is.
Description of Alg 1 (Line 216-225): The notations used in Alg 1 are a bit confusing. At the beginning of Alg 1, S_i's are defined to be the assignment of the items, which makes me think that S_i should denote the set of items in block i. However, it seems that S_i is used to refer to the set of topics covered by the items in block i in the description of the algorithm. I find it quite confusing.
Q2
: Please summarize your review in 1-2 sentences
This paper proposes a simple greedy strategy for the min-max hypergraph partitioning problem under the streaming model. This paper defines a stochastic model for generating the input hypergraph and show the sufficient conditions for the asymptotical recovery of the hidden clusters.
Submitted by Assigned_Reviewer_2
Q1
: Comments to author(s). First provide a summary of the paper, and then address the following criteria: Quality, clarity, originality and significance. (For detailed reviewing guidelines, see http://nips.cc/PaperInformation/ReviewerInstructions)
The paper proposes a new greedy method for streaming hypergraph clustering, with the goal of minimizing the maximum number of topics covered by a partitioning. The proposed algorithm is simple, and the authors prove the algorithm provably performs well under a balance assumption of the data, asymptotically uncovering the hidden partitioning. The algorithm is then compared against other simple algorithms on real data sets, which it outperforms in terms of normalized maximum load.
It is noted that the new techniques could not be compared against batch methods on real data sets due to their slow computational time. The experiment could be performed on smaller sets (or simply small subsets of the data sets used), and may be interesting (even though the new method cannot necessarily be expected to perform as well as batch techniques, it would be interesting to see what the gap is).
Small typo: Double "the" on line 319.
Q2
: Please summarize your review in 1-2 sentences
The paper proposes a new greedy method for streaming hypergraph clustering, with the goal of minimizing the maximum number of topics covered by a partitioning, proving that it performs well under balance assumptions and demonstrating its efficacy in practice. This problem is typically studies in the batch setting, this makes a natural step and studies it in the streaming model, and the new method seems to work well.
Q1
: Comments to author(s). First provide a summary of the paper, and then address the following criteria: Quality, clarity, originality and significance. (For detailed reviewing guidelines, see http://nips.cc/PaperInformation/ReviewerInstructions)
Overall, I liked the paper. The paper addresses an important problem, and has a nice balance of theoretical results and empirical ones. Some comments:
1) The authors should mention that the problem they consider is a special case of submodular load balancing, studied in 'Submodular approximation: sampling-based algorithms and lower bounds' (Svitkina & Fleicher).
2) The result about arbitrary partitions (Proposition 2) was known for general submodular functions (see, again the above reference). 3) Another related paper -- Graph Partitioning via Parallel Submodular Approximation to Accelerate Distributed Machine Learning (Mu Li et al)
Q2
: Please summarize your review in 1-2 sentences
This paper studies the problem of Min-Max hyper-graph partitioning in a streaming setting. The authors observe that this problem is an instance of min-max subodular data partitioning, a problem also called the submodular load balancing problem. The authors show theoretical results, and demonstrate the algorithm on real world data.
Author Feedback
Author Feedback
Q1
:Author
rebuttal: Please respond to any concerns raised in the reviews. There are
no constraints on how you want to argue your case, except for the fact
that your text should be limited to a maximum of 5000 characters. Note
however, that reviewers and area chairs are busy and may not read long
vague rebuttals. It is in your own interest to be concise and to the
point.
We thank the reviewers for their comments. Answers
below:
Reviewer 1:
- The Stochastic Model:
The intuition
behind the model is that items, e.g. user interests, are drawn from a
hidden mixture distribution across topics. As such, our model is an
instantiation of the classic mixture model [Kleinberg-Sandler, STOC04],
widely used in collaborative filtering. The choice of distribution
follows the line of research on the planted partition / stochastic block
model. Our model is a natural generalization of the stochastic block graph
model to hypergraphs.
We do not claim that our model exactly matches
real data. However, we find it interesting that an algorithm with the
recovery property in the hidden cluster model consistently outperforms
algorithms without this property, on real data. (Our framework can also
show that other partitioning strategies considered, e.g. proportional or
random, do not have the recovery property, as they couple to diverging
Polya urn processes.)
Our work is the first to provide analytic
guarantees for streaming hypergraph partitioning. We hope that it will
spark further research, in particular on generalizing the stochastic input
model.
- The Li, Andersen, Smola [LAS15] paper:
We were
unaware of this work at submission time, given its timing. We plan to
include a complete comparison in the next version of our paper, and
provide a brief overview below.
- The two papers are complementary
in terms of contribution. We consider online arrivals, motivated by
streaming query processing platforms. [LAS15] considers an offline model,
where the entire input is available to the algorithm, and a key component
is a procedure for optimizing the order of examining vertices, and its
efficient implementation. By contrast, we show that, even for random
arrival order, our algorithm performs well.
- We compared our
algorithm with Parsa on a subset of inputs. On a bipartite graph (news20),
compared to random, greedy gives a 20% improvement in memory, 60%
improvement in total traffic, and 71% improvement in max traffic. On a
social graph (livejournal), greedy gives a 67% improvement in memory, and
~100% improvement in (max and total) traffic.
These results put it at
around 50% of Parsa's performance in terms of these parameters, which can
be justified since we stream the input. Running time is less than that of
Parsa (similar to PowerGraph).
- Performance of random
assignment:
Consider an input where m topics form k disjoint
clusters, and each item only subscribes to a single cluster. The optimal
way to distribute onto k partitions would be to place each cluster onto
one partition, with cost m / k. By the Lemma, random partitioning has cost
~2 m / 3. Our point is that the competitive ratio is linear in k, almost
as bad as placing all items onto the same partition.
We will clarify
this part of the discussion.
- We will reword the description to
clarify that S_i's are sets of topics
Reviewer 2:
- Comparison
to offline techniques:
On bipartite data sets, which are our focus,
hMETIS gives better cuts (up to 2x better), but very unbalanced partitions
(>3x difference between min and max size, on the podcast data), since
it is designed to optimize for cut size. Label propagation and spectral
methods had high running times and gave inferior results on sparsified
inputs (even on hidden cluster synthetic inputs).
Comparison with
Parsa (see above), and implicitly Zoltan and PaToH, on bipartite inputs
suggests that performance is between 20-60% relative to these offline
methods.
On social graphs, performance is usually 20-50% of that
of offline techniques such as METIS.
Reviewer 3:
- 1) and
2): Indeed, we are considering a specific instance of submodular load
balancing. We will clarify the connection.
- 3) : Please see response
to Reviewer 1
Reviewer 4:
- Our results are a strict
generalization of [19], as we consider partitioning of hypergraphs. One
key technical distinction is in the reduction to Polya urn processes:
while for graphs the coupling is straightforward, in the case of
hypergraphs the coupling hinges on relating the number of items and the
number of topics on each partition.
Reviewer 5:
- We
erroneously submitted a deprecated version of the additional material, and
were unable to replace it after the deadline. The complete argument is
available in the technical report version of our paper. (Available online,
but not anonymized.) This argument is a significant part of our technical
contribution.
Reviewer 6:
- Indeed, an item subscribing to most
topics forces up the max partition cost. We have not found such items
(users) in the data sets we analyzed. In practice, we believe these items
would get special treatment, i.e. be split up and distributed across
partitions. Extremely popular topics do exist (<20%), and are
duplicated on each partition.
| https://proceedings.neurips.cc/paper_files/paper/2015/file/83f97f4825290be4cb794ec6a234595f-Reviews.html |
Beyond the current means of implementation | Social Watch
Social Watch poverty eradication and gender justice
Beyond the current means of implementation
Goal 17 - Strengthen the means of implementation and revitalize the Global Partnership for Sustainable Development
By Stefano Prato, Society for International Development
The means of implementation (MoI) are the decisive test – one could even say the acid test – of the 2030 Agenda for Sustainable Development, as they reveal the true extent of the commitment by all signatories, and particularly the so-called developed countries, to the aspirations set forward by the Sustainable Development Goals (SDGs). Tracking progress on MoI requires a combined assessment of the SDG-specific means of the implementation, the elements explicitly targeted within SDG 17 and the status of implementation of the Financing for Development (FfD) Conferences, including, though not exclusively, the Addis Ababa Action Agenda (AAAA)
1
.
It is however necessary to advance three important qualifications with respect to the adequacy of the currently formulated MoI, the political context within which implementation takes place, and the overall focus of any civil society-led monitoring process.
First, civil society organizations and networks engaging with the FfD process have strongly denounced the inadequacy of the AAAA to meet the challenges it was set against and have reclaimed the FfD acronym to mean Failing to Finance Development. Indeed, the combined MoI/AAAA framework falls short of the ambition of the 2030 Agenda. Instead, the discussion is increasingly dominated by the narrative of scaling-up resources (moving “From Billions to Trillions”), which is aimed largely at catalysing and leveraging private investments. This narrative is problematic on several grounds. For one thing, it places excessive emphasis on financial resources instead of on the removal of the structural barriers that relegate many countries – particularly many African countries – to conditions of commodity-dependence and unacceptably low levels of economic diversification, because of their inequitable positioning in the global organization of production. Moreover, it ignores the unacceptable level of financialization of the global economy and the need for profound systemic reform; a good example is the fact that commodity prices are primarily driven by financial markets (derivatives in particular) rather than by the reality of production. Additionally, and probably most importantly, this narrative subjects the implementation of a global public agenda to the mechanisms and conditions of private investments and their speculative markets.
The second qualification regarding MoI concerns the political context in which implementation and monitoring take place, specifically the emerging bias in favour of the direct participation of the private (mostly corporate) sector, increasingly blurred lines between public and private interest, and lack of consideration of often blatant conflicts of interests. The continued efforts by many Member States, across the global North-South divide, to ‘seduce’ the private sector into engaging in sustainable development reveal challenging political economies and expose the covert desire to maintain current power structures, rather than try to seriously change the current socially and environmentally unsustainable business model.
It is therefore essential to locate any progressive civil society effort to monitor the implementation of the SDGs and the MoI/AAAA in this evolving, and often regressive, political context. This highlights a third important qualification, which is that progressive civil society should avoid being trapped in the implementation of elements that contradict human rights and other fundamental values. On the contrary, it should only be tracking those commitments that advance its transformative agenda, one that is far more ambitious than what exposed within the SDGs. However, the 2030 Agenda is already generating significant co-optation mechanisms that aim to domesticate civil society’s engagement by fully aligning its agenda to that of the SDGs and undermining any structures that promote dissent. This calls for a more sophisticated strategy of resistance and proactiveness, one that engages with the process without accepting its limitations and pushes for a level of ambition that is far beyond the currently framed objectives and targets.
Conceptual framework
Such a strategy highlights the need to establish a clear conceptual framework to explore progress, or lack of it, with respect to the means of implementation. This initial report proposes the following categories to track the MoI/AAAA implementation:
Provision of financial (and technical) resources;
Removal of the structural barriers to socio-economic transformation of developing countries;
Democratization of economic governance;
Reform of economic, monetary and financial systems to increase their responsiveness and coherence with sustainable development;
Rethinking of the business model and the role of the private and corporate sectors.
These categories provide a better sense of the different areas within which progress could unlock the implementation of the SDG agenda and open new areas that requires active exploration beyond the limitations of the current MoI/AAAA agendas.
While the ‘trillions’ narrative is problematic, financial resources remain critical, including international public finance, domestic resource mobilization and private finance, all of which are inadequately addressed within the current MoI/AAAA agenda.
With respect to
international public finance
, the MoI/AAAA negotiations exposed the continued attempt by developed countries to elude and downscale their historical responsibilities and previous commitment by emphasizing primarily domestic resource mobilization, South-South and triangular cooperation, migrant remittances and private flows. Not only did developing countries fail to secure new commitments regarding official development assistance (ODA), no timetable to advance progress was agreed, references to development effectiveness and untying aid commitments are unsatisfactory and the additionality of climate finance vaguely expressed. Furthermore, the initial implementation period has shown that ODA contributions are under increasing attack by conservative governments in many developed countries. The very definition of aid is evolving with the introduction of the Total Official Support for Sustainable Development (TOSSD) being developed by the Organization for Economic Cooperation and Development (OECD) to capture flows that are currently not included into the ODA definition. While this may sound good at superficial analysis, it involves significant risks in terms of undermining aid commitments by including flows that are claimed to be developmental but that in fact are not, and by providing perverse incentives to promote private investments through redirecting ODA to leverage private finance. Indeed, the concepts of blending public-private finances and redirecting development cooperation funds from poverty interventions to leverage private sector engagement and investment open the way to a renewed emphasis on new and more sophisticated forms of tied aid. Finally, the migration crises not only has again exposed the dramatic human consequences of persisting structural inequalities and development disparities, but has also resulted in the diversion of ODA by key donors to address the cost of the refugee crisis in their own countries.
With regard to
mobilizing domestic resources
, the fundamental challenge is to significantly reduce the increasing levels of outflows from Southern countries due to illicit financial flows (IFFs), debt service payments and the maintenance of foreign reserves in developed countries (see the box by Dereje Alemayehu below). However, while increased capacity to mobilize domestic resources is critical, it is not a panacea. Many developing countries, particularly Least Development Countries (LDCs), still require international public finance in the short/medium term in order to confront many of their development challenges.
Lastly, the overreliance on private finance and public-private partnerships despite little, if any, evidence of their effectiveness in public service delivery and the provision of public goods, risks compromising the state’s ability to protect, respect and fulfil human rights. Not only does this strategy involve higher costs than direct public procurement, privatizes gains while socializing risks, it changes the nature of public services and profoundly alters governance relations.
Removal of structural barriers to socio-economic transformation of developing countries. Financial resources, while important, are only a limited part of the means of implementation. The most critical dimension is related to the removal of the structural barriers that continue to trap many developing economies, especially many African countries, into heavy commodity dependence, as their role within the international organization of production is focused on providing primary agricultural produce and minerals. Many commodity-trapped economies expose small and unsophisticated local economies, with often significant disconnect between primary, secondary and tertiary sectors, and very significant import/export flows, as they export primary commodities and import virtually everything else. The openness of these economies also generates limited possibilities for industrialization and local value addition. The primary drivers of these conditions are extractive growth models that benefit rent-economies by local elites connected with international investors and the unfair trade and investment agreements (
see chapter II - 17
) It is therefore necessary to challenge the far-too-benign characterization of global value chains and expose their frequent focus on grabbing rather than adding value.
The MoI/AAAA lost an important opportunity to reaffirm the development terms that should direct trade and investment agreements. In particular, they failed to expose the increasing normative hierarchy between human rights and investors’ and other commercially framed rights that these agreements, and their Investor-State Dispute Settlements mechanisms, are fostering (
see chapter II - 17
).
The emerging emphasis on the global infrastructure agenda is another concern in this context. Rather than focusing on the much-needed infrastructural investments to strengthen local economies and promote (commodity-driven) industrialization, emphasis tends to be on large, often mega-projects driven by the ‘connecting mine-to-port’ logic that risks further ossifying the current extractive development models. Furthermore, the increased reference to infrastructure as an asset class could intensify the financialization of already weak economies and the revival of high debt stocks, with potentially grave levels of macroeconomic instability.
Another key dimension of the structural barriers to socio-economic transformation concerns technology. Despite agreement on the new Technology Facilitation Mechanism (TFM), it is important to assess the actual impact of these initiatives in addressing the technology gap (see the box by Neth Daño below).
It is also important to emphasize that technology development is not a monopoly of the formal sector, nor is it transferred and diffused only by the private sector and industrialized countries, as the TFM architecture implies. Progress cannot be measured by the uncritical acceptance of the promises of new technologies and the blind faith that these would bridge current development divides, and should rather recognize the inherent risks in establishing new, or ossifying existing, levels of inequalities.
Democratization of economic governance. The progressive effort to shift the epicentre of global economic governance from the current Bretton Woods Institution-centred system in favour of a greater role of the United Nations was seriously undermined by developed countries during the MoI/AAAA negotiations. All attempts to promote this movement that did not succeed is the proposal for a Global Tax Body to strengthen international tax cooperation, including but not limited to eliminating IFFs and tax havens. Along the same lines, the Global Infrastructure Forum (GIF) exposes another revealing anecdote. Although provided for through the AAAA, any attempt to propose even a mild reporting mechanism to the FfD Forum was stalled and so de-facto opposed by developed countries in the course of the inaugural FfD Forum (New York, April 2016).
Indeed, a bizarre ‘Out of UN implementation’ narrative characterized the initial phase of the FfD Follow-up process: the UN can propose new initiatives, but their implementation should not necessarily take place within the UN itself. Accordingly, the OECD can advance its ‘inclusive framework’ with respect to tax cooperation claiming it responds to the UN call for scaling-up action in this field, and the GIF can be operationalized with no accountability with the process that has actually established it.
However, the greatest attack against (still timid) attempts to democratize global economic governance concerns the unproblematized promotion of multi-stakeholder partnerships at all levels. These shift governance mechanisms away from legitimate rights-based and people-centred accountability, by consolidating the primacy of stakeholders against/over rights-holders with no consideration of the profoundly different nature of public and private interests.
Reform of economic, monetary and financial systems to increase their responsiveness and coherence with sustainable development. Another key dimension of MoI concerns the pressing need to reform the economic, monetary and financial systems in order to increase their responsiveness and coherence with sustainable and equitable development. The challenge is greater than simply that of alignment. The reality is that many of the drivers of economic globalization and the marginalization that it generates are deeply rooted in the current monetary and financial systems. Furthermore, these systems have created the impression, and the reality, of a distinct space where state sovereignty – and therefore peoples’ sovereignty - does not apply. An example is Argentina’s final surrender to the predatory business models of the vulture funds in April 2016, which opened a new cycle of indebtedness (for Argentina) and a new phase of uncertainty on how to handle the next generation of debt crises (for many countries). Once again, attempts to find orderly mechanisms for sovereign debt restructuring processes in the context of the United Nations met the obstinate opposition of developed countries, and with them the legitimate affirmation of the principles for responsible lending and borrowing, which have been subject to lengthy negotiations in the context of the United National Conference on Trade and Development (UNCTAD).
Beyond debt, the broader agenda of systemic reforms include the development of regulations to prevent financial crises and to limit their devastating effects, the reform of the monetary system (in terms of capital controls, financial safety nets, Special Drawing Rights, etc.), the governance reform of the International Financial Institutions (IFIs) and the increased alignment of their activities with development goals, the intractable issue of derivatives and their consequences in terms of commodity price volatility, and the management of climate risk as systemic risk with potentially devastating impact, among others. These issues are only mildly and inadequately addressed by the AAAA. Many of the SDG ambitions will therefore meet the harsh counter-realities generated by the powerful drivers of economic marginalization, unless many of these issues are seriously tackled.
To do this, it is essential to advance the development of needed regulatory frameworks to ensure business operations are fully consistent with human rights, including workers’ rights, incorporate externalities, ensure appropriate taxation of natural resources, re-establish proper relations between the real and financial economies, and promote responsible advertising and marketing, among others. Here significant tension remains between binding regulatory frameworks and voluntary guidelines, with the continued double standard of legally framing investors and other commercially framed rights without equally binding frameworks related to business conduct and responsibilities.
A separate discourse is related to the need to further regulate the increasing private delivery of public services to respect human rights, ensure that the fundamental nature of public services is not compromised, and contrast social stratifications that promote the intergenerational transmissions of inequalities. The public policy space needs to be protected from encroaching corporate capture at multiple levels, often through the continued promotion of multi-stakeholder partnerships that redirect governance away from rights-holders towards the pretence of a politically neutral understanding of stakeholders. This requires robust safeguards against conflicts of interest to ensure adequate protection of the integrity of public policy making processes and the trustworthiness of the scientific/knowledge process that generates evidence to support public policies.
Conclusions
The current MoI/AAAA will not provide the necessary instruments and resources to advance the aspirations and the extent of transformation that progressive civil society would like to foster. This fundamentally means that civil society cannot limit itself to the monitoring of the currently framed MoI targets and AAAA commitments, as these are largely inadequate, even if achieved, to support the extent of economic, social and political changes that we collectively aspire to. Hence the need to establish a far more ambitious progressive agenda that raises the bar with respect to the existing level of commitment. This report aims to provide an initial but potentially useful framework for future engagement.
Reference
United Nations (2015): Addis Ababa Action Agenda of the Third International Conference on Financing for Development. New York.
www.un.org/esa/ffd/wp-content/uploads/2015/08/AAAA_Outcome.pdf
BoxDomestic Resource Mobilization and Illicit Financial Flows By Dereje Alemayehu, Global Alliance for Tax JusticeIn terms of financing, one of the major differences between the MDGs and the SDGs is that, while the achievement of the MDGs was implicitly and explicitly made dependent on external financing, in particular on Official Development Assistance (ODA), the SDGs are mainly expected to rely on domestic resource mobilization for their implementation.While recognizing ODA as an important complementary source of development finance, in particular in Least Developed Countries (LDCs), African governments welcomed this shift of emphasis and committed themselves to enhance domestic resource mobilization to finance their own sustainable development. Over-dependence on resources supplied by external development partners is being increasingly considered as compromising African country’s commitment to pursue the development priorities they have set themselves.However, domestic resource mobilization cannot succeed without tackling illicit financial flows (IFFs) and other forms of resource leakages through tax evasion and aggressive tax avoidance. Even the OECD admits that for every US dollar which comes to developing countries as ODA, three US dollars leave these countries as illicit financial flows. The arithmetic is simple: +1 -3 = -2. It won’t be possible to raise domestic resources adequately as long as outflows exceed inflows.In their submission to the SDG consultation, called Common Africa Position,2African governments reiterated the need for “global commitment to address issues of illicit financial flows” and for this to happen they demanded “an expeditious transition to a development-friendly international financial architecture.”3African countries consider tackling illicit financial flows as a key measure to enhance domestic tax revenues. It was because of this that the African Union Commission and the UN Economic Commission for Africa were mandated to establish in 2011 a High Level Panel on Illicit Financial Flows from Africa, headed by Thabo Mbeki, former president of South Africa.After three years of case studies and continent-wide consultations the High Level Panel issued a report with findings and recommendations.4Four of the key findings are:a) IFFs from Africa are large and increasing (US$50-60 billion a year and increasing by over 20 percent annually along with the emergence of new and innovative means of generating them);b) the commercial sector is the major driver of IFFs from Africa (over 60%);c) eliminating IFFs is a political issue; andd) the global architecture for tackling IFFs is incomplete and inadequate.Emphasizing this political nature of IFFs and its solution, the report states:“The range of issues related to IFFs makes this a technically complex subject. However, we are convinced that success in addressing IFFs is ultimately a political issue. Issues involving abusive transfer pricing, trade misinvoicing, tax evasion, aggressive tax avoidance, double taxation, tax incentives, unfair contracts, financial secrecy, money laundering, smuggling, trafficking and abuse of entrusted power and their interrelationships confer a very technical character to the study of IFFs. However, the nature of actors, the cross-border character of the phenomenon, and the effect of IFFs on state and society attest to the political importance of the topic. Similarly, the solutions to IFFs that are the subject of ongoing work in various forums at the global level attest to this political significance.”5The Third International Conference on Financing for Development (FfD) held in Addis Ababa in July 2015 was expected to deliver on development finance by challenging rich countries to fulfil their ODA obligations, by proposing global policy changes, regulatory measures and institutional arrangements to curb resource leakages which drain on development finance. It failed to deliver on all fronts. Many developing countries hoped that the conference would deal with IFFs as a political problem to be tackled in an intergovernmental process in which all UN Member States participate on an equal footing. However, the paragraphs referring to IFFs in the FfD outcome document are written more in a “we take note of” style. They don’t address IFFs as a central problem to be urgently resolved to enhance domestic tax mobilization. In the end, rich countries managed to “kill” the proposal put forward by the G77 plus China for the establishment of an intergovernmental tax body based at the UN. In fact they virtually ‘boycotted’ the negotiations, until and unless the paragraph was deleted.The chances for addressing IFFs in follow-up negotiations in the FfD process, and to give a prominent place to IFFs in the means of implementation section of the 2030 Agenda and the SDG process appear to be very limited. Rich countries insist on considering domestic resource mobilization and IFFs as ‘technical’ issues that can be resolved through enhanced ‘capacity building’ of developing country revenue authorities, by multilateral and bilateral development agencies. This is merely a pretext to prevent the participation of African countries in norm setting and reforming international tax rules on an equal footing.As the African High Level Panel Report on IFFs emphasizes, “the critical ingredient in the struggle to end illicit financial flows is the political will of governments, not only technical capacity”.6But “political will of governments” does not come by itself; it needs international support and citizen mobilization to put pressure on decision- and policy-makers. The major reason for global civil society to support G77 countries in their call for the establishment of an intergovernmental UN tax body to tackle IFFs and tax dodging is because this creates an open process in which citizens can exert influence to generate this political will for measures and decisions which curb IFFs and enhance domestic resource mobilization to finance sustainable development.
BoxMulti-stakeholder STI Mechanisms at the UN: Fad or Trap? By Neth Daño, ETC GroupA string of new mechanisms dealing with science, technology and innovation (STI) and the science-policy interface have sprouted at the UN in recent years. Under the UN Framework Convention on Climate Change (UNFCCC) governments established a Technology Mechanism in 2010. The UN Environmental Programme (UNEP) spun off the Intergovernmental Platform for Biodiversity and Ecosystems Services (IPBES) in 2012 (www.ipbes.net). The UN Secretary-General created a Scientific Advisory Board (SAB) in 2013 (http://en.unesco.org/un-sab/content/scientific-advisory-board). Then, in 2015 the 2030 Agenda for Sustainable Development gave birth to the Technology Facilitation Mechanism (TFM) (https://sustainabledevelopment.un.org/TFM).These mechanisms all share one thing in common: inclusion of stakeholders beyond Member-States and government-endorsed experts.In contrast to well-established expert bodies like the Commission on Science and Technology for Development (CSTD) housed at UNCTAD and the Intergovernmental Panel on Climate Change (IPCC), the new STI mechanisms have a far less rigid attitude towards informal and non-conventional sources of knowledge and expertise. IPBES principles explicitly value the contribution of indigenous and traditional knowledge systems. The SAB and the TFM have indigenous and civil society expertise in their composition alongside eminent names in the scientific community.An inclusive approach and the recognition of diverse sources of knowledge is key to ensuring that STI contributes to achieving the 2030 Agenda for Sustainable Development. The recognition of indigenous knowledge and local innovations are already enshrined in UN treaties and it is only logical that indigenous peoples are represented in mechanisms that provide scientific and technological support to the implementation of multilateral agreements. Civil society representation in STI bodies helps ensure that the views and interests of communities shape the direction of UN priorities and programmes in STI.The inclusion of rights holders and civil society are hard-fought gains from decades of advocating to participate in decision-making on STI in global development. Since the 1990s, civil society initiatives have proactively set the pace of intergovernmental discourses in governance of new technologies at the UN. On the ground, civil society and social movements have worked with communities in the development, transfer and dissemination of environmentally sound, socially acceptable and inclusive technologies and innovations long before these became fashionable.The concept of stakeholders, however, needs to be challenged. It is based on the flawed premise that business interests have an equal stake as the holders of rights such as those held by indigenous peoples and local communities in relation to traditional knowledge systems and biological resources. This justifies that giving a seat to civil society in a multi-stakeholder mechanism entitles business and industry to a seat at the same table. The World Business Council for Sustainable Development sits alongside an indigenous peoples’ representative in the 10-Member Group that supports the TFM. The transnational oil company Shell as the representative of business NGOs in the Advisory Board of the Climate Technology Centre and Network (CTCN-AB) of the UNFCCC is entitled to an equal voice with environmental NGOs. Which stakeholders should be represented is controversial. Parties to the UNFCCC agreed to have non-governmental constituencies represented in the CTCN-AB, but only environmental, research and business NGOs – a political compromise that left out the rights holders in climate technologies - women, youth and children, farmers and indigenous peoples.Danger looms large in using stakeholder inclusion in global STI mechanisms to institutionalize a corporate sector role in the development, transfer and deployment of technologies to achieve the 2030 Agenda with no clear accountability. As civil society representatives lock horns with this sector in STI discourses around the table, UN agencies engage corporate-sector representatives in programme initiatives in between meetings. Members of the CTCN, for instance, tried to push for an engagement policy exclusively for the private sector but was blocked by the Advisory Board that transformed the policy so as to apply to civil society as a whole. While Advisory Board deliberations on the policy were underway, the CTCN went on with corporate-sector engagement funded by a bilateral donor. These non-transparent ‘back-room’ dealings indicate the creation of a stakeholder hierarchy in decision-making that casts shadows on the sincerity of the goal to “leave no one behind” in STI for the SDGs.
Notes:
1 The Addis Ababa Action Agenda is the outcome of the Third International Conference on Financing for Development, which took place in Addis Ababa, Ethiopia, in July 2015. Cf. United Nations (2015).
2Cf. African Union (2014): Common African Position (CAP) on the Post-2015 Development Agenda. Addis Ababa (www.africa-platform.org/resources/common-african-position-cap-post-2015-development-agenda).
3Ibid. p. 19.
4Cf. Report of the High Level Panel on Illicit Financial Flows from Africa 2015 (www.uneca.org/sites/default/files/PublicationFiles/iff_main_report_26feb_en.pdf).
5Ibid. p. 65.
6Ibid. p. 3.
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| https://www.socialwatch.org/fr/node/17300 |
June 2005: The Art of Sample Prep | GenomeWeb
Options for mass spec sample prep abound, but there's still no clear leader in the field of separating proteins before a proteomics experiment. Here's a look at recent developments and where they could lead.
June 2005: The Art of Sample Prep
Jun 01, 2005
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When most people think about advances in technology that have been important for proteomics experiments, the first thing that comes to mind is the mass spectrometer. After all, the mass spectrometer is one of the most advanced pieces of analytical instrumentation available to scientists, it's expensive, and furthermore, it can have really technical-sounding names like MALDI-TOF/TOF.
But behind the scenes lies another element to proteomics that in most cases is equally important to scientists' ability to extract valuable information from the experiment: the protocols and technology required to separate or otherwise prepare the protein sample prior to analysis by mass spectrometry.
Take the pilot stage of the Plasma Proteome Project as an example. Organized by the Human Proteome Organization as a group effort to catalog the proteins found in a particular sample of human plasma, the experiment, performed by 31 labs and completed in late 2004, found that variations in the approach to protein separation significantly contributed to major discrepancies in the number and type of proteins identified by the participating laboratories, according to scientists involved in administering the project.
"Once you start thinking about all these different fractionations and chromatography steps that can be used in sample prep, there are enough different alternatives so that it becomes very tricky to figure out the best combination of steps to do," says Leigh Anderson, who heads the Plasma Proteome Institute. "That means everybody is getting different sets of proteins from the sample, and that's what largely came out of that HUPO project. … We're unfortunately a long way from standardizing the platforms for discovery work."
But even if standard protein sample preparation protocols are still a long way off, it may still be instructive to take a look at recent developments in the science behind sample fractionation and separation techniques to see which types of methods seem to be most effective — or at least garnering the most attention. State-of-the-art technology in proteomics changes rapidly, but what's happening in the field now will certainly influence which direction the path toward standardization takes.
In short, there are three basic approaches to preparing a complex sample of proteins before attempting to identify or otherwise analyze the sample by mass spectrometry: one can pull out certain types of highly abundant proteins and separate the remaining components by 2D gel electrophoresis; one can string together a series of liquid chromatography steps designed to strip away abundant proteins and produce multiple fractions of time-resolved separated proteins; or one can fish out only the certain classes of proteins of particular interest to the problem under investigation. In all three categories, vendors and researchers have recently made strides in performance.
Gel electrophoresis
But some areas have seen more activity than others. In general, classical 2D gel electrophoresis, which involves separating whole proteins on the basis of isoelectric point and then by size, has reached a plateau in terms of advances in the underlying technology, says Steve Carr, a proteomics researcher who runs a lab at the Harvard/MIT Broad Institute. The technique, which first entered the proteomics scene in the mid-'70s, is still quite popular — especially in Europe, according to Anderson and Carr — but the expertise required to reproducibly perform the procedure has kept the technology concentrated in a relatively fixed number of labs.
Despite the somewhat slow rate of innovation in 2D gel technology, its ability to resolve different proteins is widely considered to be unsurpassed. In part because the technique can be so labor intensive, it can separate proteins found only in very low concentrations in a sample — at a much lower range than that of liquid chromatography approaches. In addition, 2D gels are known for their ability to separate different isoforms of the same protein — that is, proteins that vary only by their type of post-translational modification. Says Anderson: "I don't think that chromatographic separations have ever achieved the resolution that 2D gels have, [but] they can be easier to automate obviously."
Many of the recent innovations related to 2D gel electrophoresis have instead revolved around how to transfer proteins separated on gels to a platform amenable to MALDI mass spectrometry. The problem, briefly summarized, is that manually picking out spots on a gel and arraying them on a non-standard MALDI target often introduces additional variation and sources of experimental error — not to mention the process itself being quite tedious. One example of improvements in this area includes the commercially available spot-picking robots sold by companies like GE Healthcare and Genomic Solutions and specially designed MALDI targets — like Bruker Biosystems' AnchorChip — that concentrate proteins in a spot on the array while simultaneously desalting the sample.
LC/MS
In recent years liquid chromatography approaches to separating proteins have taken firm root, especially as labs have tried to increase sample throughput by installing automated systems for preparing and injecting protein samples into mass spectrometers. On the mass spectrometry side of the equation, algorithms such as SEQUEST for deconvolving complex mass spectra and identifying the constituent proteins have made it easier and faster to extract accurate protein data from proteomics experiments, further encouraging high-throughput separations protocols based on liquid chromatography technology.
Traditionally, the two basic components of any chromatographic separation scheme consist of an ion exchange column for separating proteins on the basis of charge, and a reverse phase column for separating on the basis of hydrophobicity. Recently, however, vendors have begun developing new types of columns, designed specifically for extracting the most abundant, and typically least interesting, proteins in a biological sample. Agilent Technologies, for example, has devised an immunodepletion column with polyclonal antibodies covalently bound to the packing medium designed to remove the six most abundant proteins in a sample, says Jerome Bailey, Agilent's marketing manager for bioreagents.
Carr, at the Broad Institute, is enthusiastic about Agilent's new immunodepletion column, as well as their new macroporous reverse phase HPLC column. "New phases are becoming available that seem to be useful for processing biofluids and for protein separation," he says. "More and better tools are needed, but we should be a bit cautious as to how important any one of these tools will be until carefully evaluated in labs doing lots of real experiments."
Agilent's other recent contribution to new chromatographic methods relies on microfluidics technology to perform reverse phase separations on a chip. The advantage to this approach, according to Bailey, is that it eliminates fittings between columns, reducing the potential for excess volume, which results in sharper bands that increase the detection sensitivity. "It usually takes a very skilled scientist to identify where sample losses are occurring [using standard columns at low flow rates]," he says. "With the chip, the laser ablated channels eliminate these sources of sample loss, and you substantially increase the ability to automate sample prep. It's all about ease of use."
Waters, the other major provider of chromatography columns for proteomics applications, is also working to develop systems better able to handle small protein samples, as well as miniaturized devices designed for higher sensitivity separation. "With a small column and a sensitive mass spectrometer, you can now get down to protein concentrations at the attomolar concentration range," says Tom Wheat, principal scientist and manager of the life science laboratory at Waters. The most important advances at Waters, he adds, involve automating protein separation schemes and developing software for matching chromatography and mass spectrometry data to make comparing protein expression data between two samples more automated and more accurate.
Enriching/Extracting
While many vendors and tinker-happy researchers have focused on separations schemes that strip out high-abundance proteins in order to probe the depths of potentially important proteins present only in trace quantities, other scientists have taken the opposite tack: devising methods for pulling out proteins of interest from the mass of high-abundance proteins. And while one might assume that a researcher would have to know which proteins were of interest to extract them from a sample, recent developments show that this is not necessarily the case.
One such strategy has taken shape at the American Red Cross' Holland Laboratory in Rockville, Md. David Hammond, executive director of the department of plasma derivatives, has led an effort to apply principles of combinatorial chemistry and affinity chromatography to pulling out a wide variety of proteins from samples of human plasma, whole blood, and other complex mixtures. The idea, he says, is that by attaching a vast library of small molecule capture agents (ligands) to chromatography beads, one can bind almost all of the proteins in the starting material to the column under conditions in which the abundant proteins are diluted, while the trace proteins are concentrated.
After binding to the library, the ligand-bound proteins can be assayed for a desired biological or biochemical activity using a technology Hammond has called FIoNA, for Functional Identification of Novel Activities. The proteins dissociate from the ligands during the assay: new proteins, or new activities of known proteins, can be discovered without prior knowledge of the protein or the ligand to which it bound.
Alternatively, Hammond says, all of the proteins can be eluted in one step, as a sample preparation method for proteomic analysis, in a way that allows the eluted mixture to contain a percentage of almost all of the original proteins, but at a much narrower concentration range. This strategy, which Hammond has called the Protein Equalizer, is being co-developed with Ciphergen Biosystems. Because none of the proteins is specifically depleted, and because trace proteins are enriched relative to their original concentration, this strategy can identify proteins that are undetectable using more traditional approaches to removing high-abundance proteins. A description of the Equalizer has been accepted for publication in the journal Electrophoresis
.
"But if you think about it for a minute, if the library is a million different beads, of which maybe one in a hundred thousand bind albumin, and one in a hundred thousand bind an interleukin, and you add saturating amounts of plasma serum to that library, under that circumstance you can bind 10 ng of albumin," Hammond says. "If you take the other extreme, and you've got an interleukin present at one pg/mL, you can probably bind all your interleukin, plus some more. … So what we do is to decrease the dynamic range of the source material by depleting the abundant and concentrating the trace."
Another recent addition to the strategies available for pulling out certain types of proteins from a sample has emerged from Eric Peters' lab at the Genomics Institute of the Novartis Research Foundation, and was published in the April issues of Nature Biotechnology
. In an effort to develop a new method for simplifying protein mixtures, Peters, a group leader in protein profiling and mass spectrometry, devised a scheme for tagging functional classes of peptides with perfluorinated compounds, and a fluorous-functionalized solid phase to capture these tagged molecules.
While the new method — termed "fluorous proteomics" by Peters — is functionally quite similar to the fairly widely used biotin-streptavidin interaction as a method for pulling out specific types of proteins, Peters says there are several advantages to his approach. "Biotin-avidin is the gold standard, but what's usually not talked about are the problems," he says. "You can get non-specific binding, and it is often difficult to fully elute the captured protein from the resin. We wanted to come up with a 'chemical' approach, and it's potentially an extremely cheap way to go. It has all the benefits of a solid phase extraction approach — with cheap available resins and reagents — but with some of the high level of selectivity that people associate with avidin-biotin."
The problem with these types of approaches, says Anderson of the Plasma Proteome Institute, is that when performing a proteomics discovery experiment, it's hard to know a priori
whether the proteins involved in a pathway of interest share a similar functionality that could be used to help pull them out. "The fluorous proteomics approach is a cool idea," he says, "but it may be just a technical improvement over biotin."
Putting It All Together
Perhaps it's not altogether surprising that the most thorough approaches to prefractionating protein samples involve mixing and matching various chromatographic and gel-based separations schemes. Given the lack of any silver bullet for dealing with all the issues associated with stripping away high-abundance proteins — without losing potentially valuable sample material — many researchers have turned to devising their own unique concoction of sample prep protocols.
One of the researchers particularly well-known for mixing and matching is Dave Speicher at the Wistar Institute in Philadelphia. Speicher's four-dimensional fractionation approach gained fame when it helped him identify the most proteins out of 18 labs that participated in a HUPO pilot study in 2003 and 2004 that looked at proteins in plasma. In addition, the majority of the proteins known to be present in these serum or plasma samples in the ng/ml range were detected, and a small number were even detected in the pg/ml range, according to results presented at the US HUPO meeting this March in Washington.
To achieve ng/ml protein identifications, Speicher and his research group first remove the top six most abundant proteins using Agilent's immunodepletion column, and then separate proteins according to isoelectric point using a technology called MicroSol-isoelectric focusing, which Speicher's lab developed and is now marketed as the Zoom IEF fractionator by Invitrogen. This technology uses small chambers separated by large pore acrylamide discs with immobilines at specific pH's to separate cell extracts into well resolved pools based upon isoelectric points. For the third dimension, researchers run fractions out on a one-dimensional electrophoresis gel as an additional separation mode that is orthogonal to the previous two modes. Then, for the final dimension, researchers slice up the 1D gel, digest each slice with trypsin, and run the resulting digests on a nanocapillary reverse phase column coupled directly to a high-sensitivity linear ion trap mass spectrometer.
Although Speicher's intensive fractionation scheme seems to have paid off in the HUPO plasma proteome pilot project, it's not clear that other researchers are about to adopt his approach in the name of standardization. "It'll take a long time" to standardize protein fractionation steps, says Anderson. "People will keep looking for the highest-performing methods, but in terms of pulling out particular proteins, nothing comes close to immunoassays." Carr adds that mixing and matching separation schemes works only as well as the researcher's ability to eliminate losses and contamination during the transfer steps.
For his part, Carr says that the HUPO plasma proteome pilot project has spurred researchers in the field to start taking standardizing sample prep seriously. "What's happened is that partly out of [the desire to] learn, and partly out of frustration with the way the HUPO project was actually carried out, there have been some expert consortiums formed to specifically test what are the protocols that actually work, in terms of getting us down to a reasonable level of depth of coverage in a proteome in discovery mode," says Carr.
In addition to a mouse model consortium, at least two other sets of groups with expertise in separation science, mass spectrometry, and access to high quality samples have begun working together to test and share methodologies and data, Carr adds. "Those sorts of consortium activities, where there's shared learning, will actually drive the field forward."
SIDEBAR: An Antibody for Every Important Protein?
One of the major challenges to a proteomics experiment in discovery mode is that the range of concentrations at which proteins are present varies across such a wide range — about 109 M, to be precise — that devising a system with that kind of sensitivity is a serious technical obstacle. Immunoaffinity assays, such as those that rely on antibodies or other capture agents to pick up a desired protein, are the most sensitive assays available. But in a discovery experiment, how could one develop an antibody against a protein that has yet to be discovered?
Leigh Anderson of the Plasma Proteome Institute thinks the time may not be too far off when researchers will have at their disposal capture agents for every protein in the human body — or at least capture agents designed to pick up peptides representative of every protein. The idea is that scientists would express proteins for every gene in the human genome, and devise antibodies against the peptides derived from each protein that behave well in the mass spectrometer. In this way, the theory goes, a researcher could pull out and quantify the amount of every protein of potential significance in a sample.
Anderson says, "We're getting close to the day when 22,000 genes doesn't seem like a lot. At that point, you're entitled to begin thinking about whether or not we should start from the bottom up, and just design some kind of mass spec-based assay for each protein that exists, and go look for those specifically rather than always rediscover every protein de novo."
Of course, much of this is still conceptual. But Anderson says he and his collaborators are starting to think about developing capture agents against the proteins that researchers now know to be of clinical significance. In a recent review paper in the Journal of Physiology , Anderson lists 177 candidate biomarker proteins associated with cardiovascular disease and stroke that could represent a starting point for what he refers to as "directed proteomics."
— JSM
ProteoMonitor
story: "At HUPO's Plasma Proteome Project, Standardization Takes Center Stage"
http://www.proteomonitor.com/articles/view-article.asp?Article=20041028185738
"Enrichment and analysis of peptide subsets using fluorous affinity tags and mass spectrometry" Nature Biotechnology
23, 463 - 468 (2005)
http://www.nature.com/nbt/journal/v23/n4/abs/nbt1076.html
"Microscale Solution Isoelectrofocusing: A Sample Prefractionation Method for Comprehensive Proteome Analysis"
Methods Mol Biol
. 2004;244:361-75
http://www.humanapress.com/ChapterDetail.pasp?isbn=1-59259-655-X&ccode=1-59259-655-X:361&returntoisbn
"Candidate-based proteomics in the search for biomarkers of cardiovascular disease"
J Physiol
563.1 (2005) pp 23–60
http://jp.physoc.org/cgi/content/abstract/563/1/23 | https://www.genomeweb.com/archive/art-sample-prep |
Electrochemical Gate-Controlled Conductance of Single Oligo(phenylene ethynylene)s - [scite report]
Supporting: 24, Mentioning: 256 - We have studied electron transport properties of unsubstituted oligo(phenylene ethynylene) (OPE) (1) and nitro-substituted OPE (2) covalently bound to two gold electrodes. The conductance values of single 1 and 2 are approximately 13 and approximately 6 nS, respectively. In addition to a decrease in the conductance, the presence of the nitro moiety leads to asymmetric I-V characteristics and a negative differential resistance-like (NDR-like) behavior. We have altered the nitro-substituted OPE by electrochemically reducing the nitro group and by varying the pH of the electrolyte. The conductance decreases linearly with the electron-withdrawing capability (i.e., Hammett substituent values) of the corresponding reduced species. In contrast, the conductance of 1 is independent of the pH and the electrode potential.
Electrochemical Gate-Controlled Conductance of Single Oligo(phenylene ethynylene)s
,
and Adam M. Rawlett
3
et al.
Abstract: We have studied electron transport properties of unsubstituted oligo(phenylene ethynylene) (OPE) (1) and nitro-substituted OPE (2) covalently bound to two gold electrodes. The conductance values of single 1 and 2 are approximately 13 and approximately 6 nS, respectively. In addition to a decrease in the conductance, the presence of the nitro moiety leads to asymmetric I-V characteristics and a negative differential resistance-like (NDR-like) behavior. We have altered the nitro-substituted OPE by electrochemica…Show more
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“…Extending these approaches to three-terminal devices has been extremely challenging because of geometrical and electrostatic constraints. Electrochemical gating of atomic-scale junctions and individual small molecules has also been demonstrated ͑Shu et al, 2000; Chen, Zwolak, and Di Ventra, 2005; Xiao et al, 2004 Xiao et al, , 2005 Albrecht et al, 2005; Xu et al, 2005aWe note that significant progress has been made in fabricating transistors based on carbon nanotubes. These macromolecules may be considered as onedimensional semiconductor or metallic crystals, and exhibit a number of remarkable properties, including ballistic conduction.…”
Section:A Enabling Experiments and Technologies mentioning confidence:73%
Electrostatic modification of novel materials
Ahn
1
,
Bhattacharya
2
,
Ventra
3
et al.
2006
Rev. Mod. Phys.
472 3 369 1
Application of the field-effect transistor principle to novel materials to achieve electrostatic doping is a relatively new research area. It may provide the opportunity to bring about modifications of the electronic and magnetic properties of materials through controlled and reversible changes of the carrier concentration without modifying the level of disorder, as occurs when chemical composition is altered. As well as providing a basis for new devices, electrostatic doping can in principle serve as a tool for studying quantum critical behavior, by permitting the ground state of a system to be tuned in a controlled fashion. In this paper progress in electrostatic doping of a number of materials systems is reviewed. These include structures containing complex oxides, such as cuprate superconductors and colossal magnetoresistive compounds, organic semiconductors, in the form of both single crystals and
REVIEWS OF MODERN PHYSICS, VOLUME 78, OCTOBER-DECEMBER 20060034-6861/2006/78͑4͒/1185͑28͒ ©2006 The American Physical Society 1185 thin films, inorganic layered compounds, single molecules, and magnetic semiconductors. Recent progress in the field is discussed, including enabling experiments and technologies, open scientific issues and challenges, and future research opportunities. For many of the materials considered, some of the results can be anticipated by combining knowledge of macroscopic or bulk properties and the understanding of the field-effect configuration developed during the course of the evolution of conventional microelectronics. However, because electrostatic doping is an interfacial phenomenon, which is largely an unexplored field, real progress will depend on the development of a better understanding of lattice distortion and charge transfer at interfaces in these systems.
“…Extending these approaches to three-terminal devices has been extremely challenging because of geometrical and electrostatic constraints. Electrochemical gating of atomic-scale junctions and individual small molecules has also been demonstrated ͑Shu et al, 2000; Chen, Zwolak, and Di Ventra, 2005; Xiao et al, 2004 Xiao et al, , 2005 Albrecht et al, 2005; Xu et al, 2005aWe note that significant progress has been made in fabricating transistors based on carbon nanotubes. These macromolecules may be considered as onedimensional semiconductor or metallic crystals, and exhibit a number of remarkable properties, including ballistic conduction.…”
Section:A Enabling Experiments and Technologies mentioning confidence:73%
Electrostatic modification of novel materials
Ahn
1
,
Bhattacharya
2
,
Ventra
3
et al.
2006
Rev. Mod. Phys.
472 3 369 1
Application of the field-effect transistor principle to novel materials to achieve electrostatic doping is a relatively new research area. It may provide the opportunity to bring about modifications of the electronic and magnetic properties of materials through controlled and reversible changes of the carrier concentration without modifying the level of disorder, as occurs when chemical composition is altered. As well as providing a basis for new devices, electrostatic doping can in principle serve as a tool for studying quantum critical behavior, by permitting the ground state of a system to be tuned in a controlled fashion. In this paper progress in electrostatic doping of a number of materials systems is reviewed. These include structures containing complex oxides, such as cuprate superconductors and colossal magnetoresistive compounds, organic semiconductors, in the form of both single crystals and
REVIEWS OF MODERN PHYSICS, VOLUME 78, OCTOBER-DECEMBER 20060034-6861/2006/78͑4͒/1185͑28͒ ©2006 The American Physical Society 1185 thin films, inorganic layered compounds, single molecules, and magnetic semiconductors. Recent progress in the field is discussed, including enabling experiments and technologies, open scientific issues and challenges, and future research opportunities. For many of the materials considered, some of the results can be anticipated by combining knowledge of macroscopic or bulk properties and the understanding of the field-effect configuration developed during the course of the evolution of conventional microelectronics. However, because electrostatic doping is an interfacial phenomenon, which is largely an unexplored field, real progress will depend on the development of a better understanding of lattice distortion and charge transfer at interfaces in these systems.
“…Some have argued that charging energies may be renormalized by strong coupling to the metallic source and drain [9]. Further, Coulomb charging effects can be strongly reduced in, for example, electrochemical STM experiments [33], due to the large relative dielectric constant of the surrounding solution.…”
Section:Conduction Processes and Single-electron Transistors mentioning confidence:99%
Single-molecule transistors: Electron transfer in the solid state
Natelson
1
,
Yu
2
,
Ciszek
3
et al.
2006
Chemical Physics
60 2 54 0
Single-molecule transistors (SMTs) incorporating individual small molecules are unique tools for examining the fundamental physics and chemistry of electronic transport in molecular systems at the single nanometer scale. We describe the fabrication and characterization of such devices, and the synthesis and surface attachment chemistry of novel transition metal complexes that have been incorporated into such SMTs. We present gate-modulated inelastic electron tunneling vibrational spectroscopy of single molecules, strong Kondo physics (T K $ 75 K) as evidence of excellent molecule/electrode electronic coupling, and a demonstration that covalent attachment chemistry can produce SMTs that survive repeated thermal cycling to room temperature. We conclude with a look ahead at the prospects for these nanoscale systems.
“…There are mainly two approaches for wiring molecules between electrodes. One method is to make top-contact junctions, which includes scanning probe microscopy (scanning tunneling microscopy (STM) and conducting atomic force microscopy (AFM)), [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]cross wire junctions, [23] [24] [25]mercury drop electrodes [26, 27]and thermally deposited metal films. [6]All devices manufactured by this kind of method can be categorized as 'prototype devices', which are very useful for fundamental investigations and have already provided many important results.…”
Section:Introduction mentioning confidence:99%
“… [6]All devices manufactured by this kind of method can be categorized as 'prototype devices', which are very useful for fundamental investigations and have already provided many important results. [4] [5] [6] [7] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]However, these devices are far from practical applications, as we can not imagine a nanometer device carrying a huge scanning probe microscopy (SPM) system or other systems. The other way utilizes nanogap electrodes [28] [29] [30] [31] [32]to form metal/molecule/metal devices.…”
Section:Introduction mentioning confidence:99%
Nanogap Electrodes
Li
1
,
Hu 2 ,
Zhu 3
2010
Adv. Mater.
246 1 182 1
No abstract
| https://scite.ai/reports/electrochemical-gate-controlled-conductance-of-single-zNb5wb |
What role do the youth play in effecting nonviolent social change and why? | New Tactics in Human Rights
What role do the youth play in effecting nonviolent social change and why?
What role do the youth play in effecting nonviolent social change and why?
To help start the conversation and keep the focus of this discussion thread, please consider and respond to the following questions:
Why are young people are so often the drivers of social change movements?
What drives them to stand up and make a difference?
What happens to those youth, who go out on the streets to create change; after this change has been achieved (e.g. representation in politics)?
What are the effects of the economic crisis and ongoing changing social realities, and what does this mean for youth’s involvement in social issues. For reasons of economic survival (due to a less supportive state/ social system), the younger generation might also end up having little time left as to engage in volunteer-based activism next to their paid jobs and care-taking roles.
As a start...
MENA Youth role in the Arab Spring
GhidaAnani wrote:
Young people are the future the MENA region. Young people are the Movement’s driving force here and now, and are societies’ strongest confidence for real and lasting change in their communities and beyond. They are in no doubt the key drivers of social change. Despite considering this fact, proper policies focused on engaging young people in order to build a domestic constituency for international development that will create lasting connections. Young people have grown up exposed to internet, global popular culture, and easier communications and travel, which has made the world smaller, more connected, and more accessible.
Thanks a lot Ghida for this opening comment, it would be interesting to hear your assessment of the role MENA youth have played in the Arab Spring and the popular aprisings sweeping the Middle East, especially pertaining non-violent protesting and social organizing.
Youth at the time of transformation....
The youth in the MENA region played an unprecedented role in the events referred to as the Arab Spring, especially pertaining to non-violent protesting and social organizing. These were probably best ipitimized by the actions of youth in the Libyan and Egyptian revolutions. Youth gathered in masses to peacefully protest against regimes they believed to be dictatorial and antagonistic to their values and beliefs. The united stance of these youth and their unyielding diligence in the face of violent responses from the ruling parties were, ultimately, what gave heart and strength to their successful revolutions for change. Their dedication as agents of change through peaceful means are an inspiration and a valid model to build upon for future initiatives of active non-violence and civil disobedience in the MENA region.
Why are young people often a driving force for change?
I am not sure I know the response to this question but it is true that young people are often a driving force. Certainly in Nicaragua, young people were the ones who led the sandinista Revolutuon, a violent Revolution that pushed the dicatator out of power. I guess it has to do with young people´s dreams and strong ideals about the possibility of a better society, of equality and social justice. In Nicaragua the current adull generation was the one that took down the dicatorship with guns, and we haven´t learned to make social change with non-violent tools, and the majority of the young generation are not so enthusiastic about gettting involved in politics, because many of the revolutionary leaders became corrupted and authoritarian. This is why some of us left the old Sandinista party and found it a new party, and we are now trying to encourage young people to get involved in politics again. And, yes, there are groups of young people who have been active in civil society´s human rights, some of them using non-violent tools and some others continue to use hand-made mortars and other violent tools. So we are completely certain that we need to learn more about no-violent struggle, and we will organize study groups with both young and adults in non-violence struggle.
Involving youth into politics
Hola Ruben!
Thank you for this interesting insight. I do not know Nicaragua, but from my experiences in Guatemala I am safe to say that this is no easy task. A lack of legitimacy, state violence and corruption has led a large majority of Guatemalan youth to lose all faith in their countries' official institutions; with good reason I would say. You say that you are trying to encourage young people to get involved into politics again, might I ask in what way you are trying to do this?
involving youth into politics
There are several ways we are trying to encourage young people get invoved in politics. For one thing, we join and support all the organizing efforts and demonstrations against human rights violations and state authoritarianism and violence as run by youth groups.
At Puntos de Encuentro, which is the NGO I work with, we are organizing Central American youth camps and short trainings to help youth groups to engage in dialogue and build alliances accross differences of sex, gender, sexuality, ethnicity, nationality, health an physical condition, etc, and to develop a common agenda for their organizing and activists efforts which also includes issues which are relavant to particular groups.
Also with the Sandinista Renevation Movement, which is my political party, we are conducting trainings to help young people develop their leadership within the party. In this regard, one good thing is that the MRS National President is a young woman (age 34) and there are also several young people at the maximum level of leadership.
Youth's involvement in politics and young women as leader - how?
Ruben Reyes Jiron wrote:
Hi Ruben!
Thanks for sharing, and happy to see you here! :-) . Usually , young people aren't really represented in political parties, unless it's the youth group of a specific political party. As it sounds, in your political party, young people are actively involved, and not only in a seperate group, I was wondering if 1) the youth feel their views are being seriously considered? and 2) what strategies have been used to get young people involved in this party? I'm also happy to know that the National President is a young woman! Could you please share with us if there were specific campaigns used to get her elected on this position? Thanks again and looking forward to hearing from you
Best wishes
Jose
youth involvement in politics and young women as leader?
Yes, within the MRS women have organized their own network and they are doing their own organizing and promoting their leadership within the party, and they campaigned for this young woman to become our president, and, of course, this young woman had plenty of credentials to become the president, as she was already a very outstanding leader and organizer. To get more young people involved we are organizing activities addressing young people´s particular needs such as youth camps and trainings. Also in the parties meetings, young people seem to feel at ease expressing their opinions and I´ve heard is a similar situation at the maximum level within the party. I know this situations sounds ideal,but It hasn´t always been like this. In fact, about three years ago we had started this effort of promoting young leaderships but this effort didn´t get as much support from the adult leadership back then. Nowadays, our adult leadership seem to be more convinced of the need to promote young leadership within the party and they really are supporting these new efforts.
thanks
Ruben Reyes Jiron wrote:
I know this situations sounds ideal,but It hasn´t always been like this. In fact, about three years ago we had started this effort of promoting young leaderships but this effort didn´t get as much support from the adult leadership back then. Nowadays, our adult leadership seem to be more convinced of the need to promote young leadership within the party and they really are supporting these new efforts.
That's amazing, yes it's a matter of time also before the understanding of the importance of this - thanks for sharing !
(Reply to #10)
The youth are leaders today not tomorrow
The youth are driven by a desire to see things changing for the better in their lifetime. The search for a better future couple with the desire to correct the past is what drives them. Nelson Chamisa the Minister of Information, Communication, and Technology in Zimbabwe once said "the youth are not the leaders of tommorow they are leaders today" and this is a fact. the agenda and course of history is steered by the vibrancy of the youth. One I was at a retreat camp for young boys 15-18 years old who were working with me as young activists against gender based violence. as we were struggling to come up with theme for the next campaign against gedner based violence one of the young men said "lets have our theme as reeding the past and correcting the future" and true to his suggestion the youth have the power to stir the course of the future through non-violent activism
youth and MENA
Youth should be and indeed they are involve in NV activism, but there is a majore problem with the new form of activism i believe. In ME like any other place in the wrold "powers" control the media and internet. however controling intrenet in ME by the GOV easlly can criple the movement. The majority of people are depend on internet which is controled or disconect by government. what should be the activists tactic then?
The majority of people are
Leila Zand wrote:
The majority of people are depend on internet which is controled or disconect by government. what should be the activists tactic then?
This a very important question Leila, and thanks a lot for posing it! It be differently useful to hear from folks here about their perception of it in the challenges facing youth work section of this dialogue. I found thisreportfrom theBerkman Center of Internet and SocietyatHarvard Universityon internet security in the Middle East and North Africa to be useful.
#14
Gnoam
I strongly feels like it's up
I strongly feels like it's up to the situation. I've seen, here in Israel-Palestine good and successful struggles led by both young people and by older activists. In Israel-palestine, at least in the Israeli-Jewish activists community i'm a part of, that the younger ones are the one that have more hope and energy to change what they believe to be injustice. The older activists are often more tired, hopeless in the change they can bring and seems like a lot of them stayed activists only because they felt that doing nothing is the same as doing - what they believe to be a non-working activism.
on top of that, I tend to believe that young people have more often the ability and courage to get out of the box and try to develop new, and at times more effective, tactics. While at the same time, I see(again, at least in my community) that the older activists tend to stick to the tactics they are familiar with.
Noam
Youth tactics in Israel/Palestine
Gnoam wrote:
While at the same time, I see(again, at least in my community) that the older activists tend to stick to the tactics they are familiar with.
Thanks a lot Noam for sharing this with us, it would definitely be interesting to hear from you about successful tactics that youth have used in Israel/Palestine and if you have any resources to share in both thetoolsandresourcessections of this dialogue.
Is nonviolent action multi-generational?
Dear Noam,
Thank you for your important comments and putting a spotlight on the impact how age can affect activism. My comments tend to be in the context of New Profile (www.newprofile.org/english) and how we, as a movement, also believe that we should live and practice our vision.
I agree with you that there often is a momentum of "tiredness" amongst more seasoned activists. I often think of this state of mind as despair, or a degree of despair. It is exhausting to always hold your head up high and stay true to your ideals, especially when it seems like you are walking uphill backwards as it often seems we do here in the Middle East.
That said I am not sure whether it is a matter of energy levels or that ability to focus on what is doable, what I can do as an individual and what can be done as a collective. This raises questions, in our case for example, how can Israeli-Jewish activists be the most effective in ending occupation of Palestine? Does this mean, for example, that we focus on joining weekly demonstrations in the Palestinian villlages and show our support for them and ending occupation through empathy or our numbers? Or does this mean that we should find ways to turn to Israelis, and try to change their militaristic mindset that promotes occupation, by engaging them in discussion and sharing a different perspective? It is hard to know what could be more effective because the need is so great.
As you know New Profile is a multi-generational movement of men and women between the ages 18-85. I think that one of the reasons that this works so well for me is our emphasis on equality and our ability to share the power. Every voicie carries the same weight regardless of age or seniority. This offers us opportunity to not only create safe spaces for discussion and shared learning, but also allows opportunity for input, reflection, and new ideas for actions.
A few years ago one of our members created a project called "Listening for Peace"., and he was joined by at least 12 other members of various ages. The project was based on the strong realization that most Israelis are very scared and angry with the present situation. They need an opportunity to voice their opinions and to share how they feel. They need someone to listen to them.
The “Listeners” chose Tel Aviv as their pilot city and stood in a central square with a sign that reads “How do you think we can end the conflict?” and invite passersby to stop and talk.
We believe that by creating a situation where individuals can voice their thoughts and opinions, they are also given a chance to think things out afresh. This project focuses on creating space to think about the present situation and at the same time allows for an opportunity to be listened to and show feelings, including hate, anger and despair. By using listening tools, we believe that we can build new possibilities and create new hope.
Thanks again and all the best
Ruth Hiller
Twitter @hillerruth
Listening & giving a voice to society to build new possibilities
Ruth Hiller wrote:
A few years ago one of our members created a project called "Listening for Peace"., and he was joined by at least 12 other members of various ages. The project was based on the strong realization that most Israelis are very scared and angry with the present situation. They need an opportunity to voice their opinions and to share how they feel. They need someone to listen to them.
The “Listeners” chose Tel Aviv as their pilot city and stood in a central square with a sign that reads “How do you think we can end the conflict?” and invite passersby to stop and talk.
We believe that by creating a situation where individuals can voice their thoughts and opinions, they are also given a chance to think things out afresh. This project focuses on creating space to think about the present situation and at the same time allows for an opportunity to be listened to and show feelings, including hate, anger and despair. By using listening tools, we believe that we can build new possibilities and create new hope.
What an interesting tactic, Ruth! Thanks for sharing. Listening, and being heard, is certainly a powerful act in the midst of a long, ongoing conflict. It would be great to learn more about the impact of the "Listening for Peace" project. This is a bit off-topic from engaging youth, but I wonder what the next steps could be...
New Tactics has documented a case study calledSociety as Mediator for Conflict Resolutionwhich is about how Elkarri, a group based in the Basque Region, has used a form of dialogue they call social mediation to encourage the broadest possible participation from all arenas of society to discuss solutions to the conflict. Community members were given a broad choice of ways to get involved: from signing a petition to becoming a member to participating in and organizing discussion groups. But however people chose to participate, they learned that they had a role to play in mediating the conflict that affected their lives and created pressure on the groups in conflict to make steps toward seeking peaceful resolution.
The tactic you describe above reminded me of this case study because both tactics are focused on giving a voice to the people that are stuck in the middle of conflict. Maybe this case study could spark some new ideas for tactics.
(Reply to #17)
Youth Being Heard and Outspoken in Israel-Palestine
Dear Ruth Hiller and Noam,
I was very interested by your outlook on the role of youth in activism in Israel -Palestine. As a member of a joint Israeli-Palestinian organization primarily working with youth in a triangle framework (Palestinians inside/citizens of Israel, Jewish-Israelis, Palestinians from the OpT) we indeed focus on the issues Ruth mentioned such as the importance of speaking and being heard. One of our core programmatic methodologies is to give continuous time and space to each of our Single Identity Groups while they engage in bi-national discussions.Our experience showed that there was (especially recently) a much greater need to engage youth in their own communities first, and after they have had time to first look critically at themselves and their own community do they become ready to engage in deeper and comprehensive conversations with "their enemy". In essence, our SIG framework enables youth to gain critical views which enables them to be open to new information and ideas. The process of sharing in the small group builds personal confidence and practices the important tool of active listening and respectful conversations. This becomes the foundation of how they later engage with their peers from the other groups. This provides the important need of being listened to and also provides the space for acknowledgement of other peoples feelings and emotions. Throughout their process of meeting with each other the youth begin to recognize inconsistencies in their own information, and thus become curious and motivated to learn more. This is a huge part of what we do, we find that youth will become active only when they deeply understand what it means to them, to their society and to the shared future of Israel-Palestine. Our work is founded in our belief that we must be the 'change we wish to see' so our model of a joint-team and our joint youth programs are in our view, very much a part of our activism. Our youth and team are active on the streets as well, but we believe that by merely working together in our conflict is a mode of activism and resistance to the occupation which serves to alienate and segregate Palestinains and Israelis.
I also was reminded of the importance of Role playing by your comment. I urge you to look at a recent video of one of our graduates which shows the people of sdorot role playing as Palestinians.
http://972mag.com/watch-israelis-from-sderot-play-palestinians-under-the...
(sorry for some reason hyperlink wasnt working for me)
Let me know what you think!
In peace,
Melanie
Re: Youth Being Heard and Outspoken in Israel-Palestine
Hi Melanie,
Thanks for your comments and questions. I am an admirer of Windowsand what you have achieved in the most difficult of circumstances.
I think you have raised very relevant issues with regards to where first discussions should take place. As you many know New Profile, as policy, focuses on Israeli society because that is where we feel we need to make the change. That does not mean we don't network with Palestinian organizations from Palestine. We do have collaborations over the border in specific frameworks.
Basically the outgrowth of our belief is that there is a need to question the deep-seated influence of militarism on Israeli society first; making the aim of our organization: to change the Profile(which in Israeli military slang also means army classification) of Israeli society from a militarized society of war and might, to an actively peacemaking community in which the rights of all its citizens are protected and promoted equally, and the human rights of all people residing inside and outside Israeli borders are respected. Additionally we believe that there's a broad draft resistance movement among young people in Israel today. Conscientious objection is a visible, but only a small part of that movement. We also believe that by raising awareness amongst youth we provide them with new understanding that participating in the military is a choice, and that it is also possible to choose not to participate. (I gave a broad description of our work with youth in an earlier thread that I think you will find interesting.)
Your methodology of creating active listening and respectful conversations sounds very similar to how we work. It can be a very long process, I agree, but also I believe it is the only way to gain true understanding of others and a vision of what can to be done. At the same time my question to you is how do you, as an organization, promote equality amongst so many sides, each with its particular point of view? I would argue that Israelis have the advantage of power over the Palestinians, those that live in Israel and those that live in Palestine. Do you encourage discussion regarding refusal, and if not could this be one of the discussion that we can share with your Israeli participants? I know that this might be a sensitive question. But I am asking it anyway.
Thank you for sharing the +972 clip with me. There is nothing like visuals to bring home a point. Now I would like to share something with you. This is a link to our digital exhibit Making Militarism Visible.This is one of the tools that we use to show how militarism has permeated into our everyday lives and to create discussion. We also have a roving exhibit in Hebrew. You are invited to take a look and also share this with others.
http://www.newprofile.org/english/?cat=11
Thanks again and I look forward to hearing from you, (perhaps even after this week?).
All the best,
Youth being heard and outspoken in Israel/Palestine
Dear Ruth,Thank you for your response and for sharing the New Profile material with me. In response to your question regarding how to promote equality while each group maintains its own view, meanwhile around us the imbalance of power in favor of the Israelis is apparent.This is of course a very difficult issue that we deal with. I mentioned earlier the importance of acknowledgement and recognition. Thus, part of the process of recognition is recognizing the imbalance of power, as Israelis and as Palestinians. Again like the motivation to become active, our youth discover what this imbalance of power means via their own experiences and their discussions with one another. In our preparation processes, the youth have to encounter the issues of class, race, religion, gender etc within their own group. THis provides an initial tool of analysis for understanding what imbalances of power mean and look like. When the groups then engage in bi-national discussions they are able to present their own realities and experiences and then they must analyze these experiences and create their own conflict tree map. This includes a process of sharing family histories as well. Throughout this the youth are beginning to see the hints and information that presents the imbalance of power and then they are able to analyze the conflict with an understanding of what imbalances of power means and looks like.Once there is a personal and then identity group level recognition of the imbalances of power we have to focus on overcoming feelings of guilt and victimhood and recognizing that together WE can create OUR relations based on equality and justice and respect etc. the idea is that in windows we have understood one another in a way that our societies do not, and thus while we may in windows build true equal partnerships we understand that this is not the reality around us. But the empowerment of knowing you have real partners in this struggle makes the endeavor that much more hopeful for th youth.I hope that answers your questions. In response to your question about refusal it is something we do deal with but as an apolitical organization we do not push the youth in one direction or another. Rather we encourage the youth to understand all the factors facing them and to make a critically informed decision. For example one of our recent graduates attended a new profile session during her process of decision making. I spoke with our program director who suggested that this could definitely be something of interest to incorporate new tactics into this conversation with our youth. Furthermore, I very much appreciated the information you sent and believe it is very helpful for local and international audiences.I would be happy to meet when I return to Israel as I am currently in Romania, I return dec 9, let's definitely be in touch!
Re: Youth Being Heard and Outspoken in Israel-Palestine
Dear Melanie,
Thank you for your response.
I believe that organizations, like New Profile and Windows, touch young people who are willing to question what is going on around them, and in by doing so may isolate themselves even further from friends and loved ones. That is why the safe space our orgs have created are so important. I think that we are providing a platform for a growing circle of new activists who are willing to refuse, willing to put their lives on the line in the weekly demos in the West Bank, and dare to openly oppose Israel's present day policises.
I am sure that we both would benifit from a brainstorm session together. I look forward to meeting you when you return to Israel.
(Reply to #21)
youth within New Profile
Ruth Hiller wrote:
As you know New Profile is a multi-generational movement of men and women between the ages 18-85. I think that one of the reasons that this works so well for me is our emphasis on equality and our ability to share the power. Every voicie carries the same weight regardless of age or seniority. This offers us opportunity to not only create safe spaces for discussion and shared learning, but also allows opportunity for input, reflection, and new ideas for actions.
Hi Ruth!
Thanks for sharing, I think New Profile is doing amazing and very important work. I agree that it's so extremely important to put an emphasis on equality and sharing power. From my experience in terms of partnership building between women's and men's activist groups, I have noticed that unconscious ways of thinking can be barriers to true equality and sharing of power. Quite often men's voices are taken more seriously than women's - sometimes unnoticed (e.g. the amount of time given for speaking during a meeting) and it takes a conscious effort to challenge this. I was wondering how within New Profile you ensure that every voicie carries the same weight regardless of age or seniority - have there been specific strategies for this? It would be great to hear more on this, I would love to learn more on this.
Thanks!
Peace Jose
Power sharing within New Profile
Hi Jose,
Per your query regarding how members of New Profile strive to maintain equality and power sharing, I would like to emphasize that most of our membership participates on a voluntary basis, largely without remuneration, in the non-hierarchically defined activities to which they feel they can contribute best. Paid functions or work on specific projects are taken by rotation, offering everyone a chance to earn a paycheck at some point if they so desire. Activists are encouraged to broaden their range of activity and, for that purpose, receive support and empowerment from co-members. Our model for shared work is part of our stategy. We do not have an office or employ staff. Our supposition for this is that if we did employ staff, it would lower our ability to involve volunteers.
Our monthly plenary meetings chaired by two different members each time. These work meetings, held monthly since New Profile’s foundation in 1998, serve as the movement’s main decision-making forum. Facilitation (in pairs) is rotated among members and the facilitators set the meeting agenda in dialogue with all active members. Our meetings are open to all, including potential new members.
The monthly meetings serve as an opportunity for reflection on aspects of our organizational functioning as an ongoing process. This includes issues like intergenerational working relations within the movement, or modes of non-violent, gender conscious communication, inside New Profile and in our encounters with others.Older members, with more seniority or even age, and younger and newer members have equal say, and are provided with equal time to share or express an opinion.
From time to time we will devote a plenary to a particular subject or project. This provides a wonderful opportunity for shared learning, and usually involves one of the teams preparing the discussion. We try to maintain a proportionate amount of learning in our activism so as to create a balance. Sometimes we will also hold study days and invite experts in different areas to share their work and research with us.
Most of our work is done on teams of 2, 3, or more, depending on the activity or project. Some of the projects, like our youth groups, are long term. Others such, such as preparation for a demonstration, may be short term. But each of us volunteers to contribute in what he/she feels the most comfortable with, and you can often find that many of us work on a few teams and projects at the same time.
I hope that I was able to answer your questions.
All the best,
-
thank you very much, it's very clear. It sounds like a very well thought-out structure and there's a lot to learn from it.
Thanks
Thanks a lot Ruth for sharing
Thanks a lot Ruth for sharing this "Listening for Peace" indeed seems like a fantastic tactic. I was wondering if there is any online presence for this initiative any link or anyone I can talk to to find out more?
Thanks a lot again for your active participation.
Best,
Mohammad
The decision to take a stand
Hi,
I will start from the experience of War Resisters' International and its work supporting conscientious objectors to military service. In many countries conscientious objection is an entry point to political life for young people, as they are confronted with the fact that they have to do something about their military service. If you don't want to do military service you can either try to get out but without taking a stand on why you don't want to join the military or you can make your options a political one. Usually for young people who don't want to join the military they start from a human rights perspective that it is my right to choose not to learn how to kill others, which comes more from an individual position. This is the crucial moment when if there is no way to channel this stand it can simply just end there after you managed to avoid doing military service. But if there is a way to channel this stand, being that you have other friends that are in the same position or there is an organisation working on these issues, it is possible that your decision will not end there and you will go on to start making connections realted to your decision of not joining the military, for example on the role that militarism plays in society. This can also take you to look at how your means connect with your ends, meaning that if you want to live in a society without militarism then your actions to get there have to be without the use of violence, which can take you to explore the use of nonviolent action.
So as a starting point, many young people at certain age are confronted with specific situations which is afffecting their society, at that moment you can either think that the problem is too big for you to do something. However, if this is socialised with others that also think that you can do something about it, it can mean that you start organising to try to do something to change the situation, and if this is channeled by having or forming a group working on theses issues it can mean the start of your political engagement.That's why it is important to see what are the issues young people are confronted with and how they can see that they are not alone facing these problems and that there is something possible to do - take action!
Why are young people so often the drivers of social change?
I personally believe that, while youth are quite often the drivers of social change movements, this does not happen often enough and there seems to be a sort of apathy at times, particularly in contexts where there is no immediate urgency or open, violent conflict that needs to be addressed (and here I am referring in particular too the Romanian context). And this is where I would like to hear your opinions on the possible causes of this apathy, if you've witnessed it in other contexts as well.
Now, getting back to the cases where youth do become active and involved, I believe that the main factor that drives them is the desire of having a say in the way their future will look like and believing that their actions will have an influence on how this future will look like. This, in turn, stems from youth being more and more exposed to multiple pieces of information from all over the world, including stories about nonviolent movements and strategies, and also countless articles and publications that also teach young people how to implement nonviolent actions, such as Gene Sharp's198 Methods of Nonviolent Protest and Persuasion, to mention only one.
Additionally, youth have the major advantage of being technologically savy. In other words, they have the means to mobilize their peers, they have access to countless networks and platforms, and all the social media venues like Twitter and Facebook, that makes them permanently connected with the pulse of the world and the society they live in. I'm not saying that adults are not catching up with these technological advances, but youth are getting more and more creative in using them
Apathy among youth
I am currently in Strasbourg at a conference on theEuropean Charter on Education for Democratic Citizenship and Human Rights, and among other things, we discussed the issue of what a speaker called passive citizenship or what you Iulia call apathy. Her point was that social change happens not when everything is going great in a society nor when a society is going through severe crisis, but when people feel the risk of societal crisis - that this is the best possible breeding ground for change as people are feeling threatened, but at the same time can function in a somewhat stable context. I think there is some level of truth in this, but at the same time I am convinced that active citizenship can be fostered also in a stable and well-functioning soceity, as long as young people see the possibility of influencing their context. I think apathy comes about when you see no possibilities of influencing the society around you.
I think young people's activism has a lot to do with them being less established in society, and thus with them having less to lose. If you have no mortage, kids or even job you have way more to gain from positive social change I think - and you also have more to invest - for instance time.
Greets,
Matilda Flemming
International Secretariat and Outreach Coordinator
UNOY Peacebuilders -www.unoy.org
Apathy among youth
United Network of Young Peacebuilders wrote:
Her point was that social change happens not when everything is going great in a society nor when a society is going through severe crisis, but when people feel the risk of societal crisis - that this is the best possible breeding ground for change as people are feeling threatened, but at the same time can function in a somewhat stable context. I think there is some level of truth in this, but at the same time I am convinced that active citizenship can be fostered also in a stable and well-functioning soceity, as long as young people see the possibility of influencing their context. I think apathy comes about when you see no possibilities of influencing the society around you.
Hi, Matilda!
I would just like to add that I absolutely agree with the fact that active citizenship CAN be fostered also in a stable and well-functioning society. At the same time, the concrete example of Romania where youth activism is practically missing from the social scene, made me ask myself why, however, there are cases where this doesn't happen. It might have to do, as you rightly point out, with seeing no possibility of changing the society around.
Hi Iulia,
I guess you got a
Hi Iulia,
I guess you got a good point there. I think in Europe we do see at the moment a youth which is disillusioned by politics. I am not familiar with Romania, but I see a similar developement in other Western European countries that young people often feel that they have no say in the current political system, that no space is given to them although politicians (as well as older activists sometimes) constantly state how important the youth is, while on the other hand they are ignored or not taken serious.
Additionally, the current economic crisis hits the youth harder, they are often the first to loose their jobs and will have difficulties finding a new one since they compete with a growing number of people who have more work experience. In that sense they are just busy finding a place in society, surviving, often without the feeling they can change the whole system they are caught up in. Why in some countries this situation leads to youth being passive while the same situation in other countries will trigger the youth to go onto the streets would be interesting to investigate.
(Reply to #30)
#31
Youth apathy
Merle Gosewinkel Women Peacemakers Program wrote:
Why in some countries this situation leads to youth being passive while the same situation in other countries will trigger the youth to go onto the streets would be interesting to investigate.
Thank you for your additions, Merle! I also agree that this issue deserves further discussion, and I would like to point out to the issue of education and education for active citizenship. Is this maybe not done enough to stimulate a response in young people? Could it also be that, in general, young people do not know what are the "strings they can pull", so to say, to make their voices, do not know that they can and should act for change, that there are ways they can lobby/advocate for issues that are affecting them and the society they live in? And then, there is also the question of envisioning a different kind of society, of envisioning a better future? Maybe creativity and critical thinking are not stimulated enough to encourage this kind of activism. I'm just raising some questions, because I don't have the answers either :)
Hi Merle, Iulia and
Hi Merle, Iulia and all,
Merle, you were saying that young people are not given political space. To my mind, we need to realize that we need to concur this political space ourselves - no one is going to offer us it on a silver plate.
I think the best way of learning active citizenship is through practicing it from an as early age as possible. Having my roots in the school student movement I really belive that school democracy plays a key role here. A recentreportfrom the European Commission on Citizenship Education in Europe concludes that even if student councils or other forms of democratic institutions involving students in the decision making of their schools are common in Europe today, the large majority of these student bodies only have consultative status, with very few actually having real decision making power. I think more decision making power to students could be a good way of fighting apathy among youth and of giving young people the opportunity to see that they actually can influence things.
Another thought is lowering the voting age to 16 as has been done in Austria, with quite some positive results with reagrds to active societal youth participation.
Cheers,
Matilda
UNOY Peacebuilders
LisePaaskesen
Considering young women and men
Hello all,
I am glad to read the enthusiasm and the interesting comments.
First, I would like to touch on one of Matilda's points: that youth's activism has to do with them being less established in society. I think she is right. Youth often find themselves in a little bit of awkward position. They are no longer children, nor are they adults. Similarly, they are less dependent on adults, parents or care takers; yet, they often lack the means or opportunities to act out the role of adults. Simply put, youth often find themselves in a state of limbo.
I enjoyed reading Ruth’s example of the "Listening for Peace" project. I think this example shows that youth want to be listened to and that when given the chance they will be more than happy to speak up and share their experiences and stories. Moreover, I think that if you offer youth a little, they will give back so much more. Reading the comment, however, I was wondering what happened after the pilot.
Lastly, referring to the comment posted by Ruben, I agree with your stated reasons for why youth engage in activism (young people’s dreams and strong ideals about the possibility of a better society, of equality and social justice). However, I would like to suggest these reasons for activism are not new, nor is youth non-violent activism. Youth actively push boundaries and thus become agents of change, though I think that the intensity of action has increased and the nature of activism has shifted.
One of the dangers of homogenizing a group is that much and many are left out. For example, it is important to note and to be aware of the fact that young women experience situations differently from young men and that often, as Jose noted, young women’s voices go unnoticed and that young women are left out of decision-making processes. I was wondering if anybody could share a story about young women’s vs. young men’s involvement in non-violent activism. Are young men supportive of young women participating in non-violent activism and if so, to which degree?
young men/young women
LisePaaskesen wrote:
I was wondering if anybody could share a story about young women’s vs. young men’s involvement in non-violent activism. Are young men supportive of young women participating in non-violent activism and if so, to which degree?
Dear Lise,
Living in Palestine I observe that both men and women play a very important role in nonviolent activism. In the more visible activism like demonstrations, men are often the majority, although many women take part in demonstrations and sit-ins as well. But the 'sumud' (steadfastness) of the women, the active participation in volunteerism in the community plays a very important role in the Palestinian nonviolent activism. You asked for stories so here are a couple of examples:
Palestinian women shared their personal stories of life under occupation. These stories were printed on huge posters and exhibited on the Wall (a project by the Arabic Educational Institute). Hundreds of women from villages all over the West Bank are participating in a Nonlinear Leadership Training given by Holy Land Trust. During this training they learn how to 'make the impossible possible'. The majority of our trainees participating in the MwB music&nonviolence leadership training are women. Working on the land that is occupied, continuing to pick olives although the trees are threatened by a nearby settlement, are examples of nonviolent activism in which women play a very big role.
About your question if young men are supportive:
The participants of our rap and samba leadership programs are mostly young men. But when they work with teenagers, they always make sure that at least half of them are girls. Although a girls playing samba percussion is not accepted everywhere, the young men of the samba groups have been looking for girls willing to join. In on samba group in an isolated village the two young men leading the group even made sure that their samba group was always 50/50 men and women.
(Reply to #34)
young men/young women
Dear Fabienne,
Thank you for sharing these stories! It is great to read that although young men are often in the majority, young women are not discouraged to participate. Also amazing to read that the young men of the samba groups activley look for young women to participate!
Good luck with these great projects and initiatives!
Why are young people are so often the drivers of social change m
I think its simlpy because ,youths are the future leaders of tomorrow.So if they dont get involved in social change movements, how then can they rule in a society where the decisions belong to the older generations.
The Economy, Occupation and youth activsm in Israel-Palestine
I wanted to respond particularly to the question posed at the outset focusing on how the economic crisis has impacted youth activism. IWhat I have seen recently with our youth and in society that the economy has become a very divisive factor, something that is fairly new to Israel.In Israel, class lines were blurred for many years as a result of the mainly socialist founders of Israel, at the least class issues were left unspoken. However the summer protests of last year has sparked a new discourse on the influence of classism and the role of neo-liberal capitalism in Israel. While we are fighting wars, many Israelis continue to live in painful situations both physically via poor housing and via being severely indebted because their income is not enough to support their life. Several of our youth are active in the opposition movements who are formulating their new political campaigns on the role of the economy. The concept as one recent graduate explained, is that rather than trying to focus on the Occupation, which inherently sets you aside as a 'traitor' they believe the best way to unify the Israeli society is against the tycoons and large capitalist interests running the country. This is a result also of their own experiences of being unable to progress because of the current economic situation.On the flip side in Palestine, our youth and various activist organizations focus on the fact that the lack of a well functioning economy and occupation are one in the same. In the past few months we saw youth organized demonstrations regarding the economy in the West Bank, although aimed at the PA, it became clear that neither the PA or the Occupation will stand in their way of demanding a fair economy in which they can participate in the global markets as well. What I have also seen is the lack of youth employment opportunities has resulted in greater participation of youth in activism (particularly Hebron) as it is perceived as their own hope to make a difference.In summary, I find it interesting how each side will relate the economy and the occupation. Israeli activists using the economy as a starting point to energizing Israeli society for a change from the status quo which ideally will open up a conversation down the line about the occupation. Where as, in Palestine youth are very much aware of the interconnectedness of their poor economy and the occupation and see their activism as their only solution to their economic difficulties. Rather than being driven away by the economic crisis i would argue that both Israelis and Palestinians have utilized it as a tool to expand and further their activism.
#38
Javier Garate
The economy - Chilean student movement
Dear Melaine,
Thanks for bringing the economy issue up.
I would like to shortly share the experience of thestudent movement in Chile(country where I am from). Last year the student movement was as strong as I can remember it. Students in Chile have been one of the main driving forces for social change, for example protesting against Pinochet's dictatorship, students regularly took to the streets to protests (Link to Actores Secundariosa very good film in Spanish about student protest against Pinochet). The movement then got weaker with the end of the dictatorship and without having such a clear opponent. Also there was hope that things will get better now in "democracy". It is true that things did change it terms of human rights. However the economic model implemented during the Pinochet years was continued in democracy, with destructive neo-liberal policies. So after years and years of students seeing their rights and possibilities to access good educations weaken, last year movements came stronger than for a long time to the streets, demanding good and free education. The movement first focused on the inequality in the Chilean education, and the fact that people are getting rich by running education institutions. The movement had wide support within the Chilean society as they saw it as a reflexion of what was happening at all levels of Chilean society, where there are extremely high levels of inquealities, most services are privatised and people are in huge debt to try to live to what Chilean society standards try to impose.
So people at all levels could empathise with the student movement as their struggle was everyones struggle. So even though the demands were mostly education demands, it reflected a wider demand for systemic change in Chilean society. This wouldn't have been possible without all the really inspiring actions carried by students. Some of the best examples where when the student movement organised weekend demonstrations inviting the whole family, which were extremely successful. So actions by youth can be really good as many sectors in society can empathise with them.
Javier Garate
@javitejavier
The Economy
Javier Garate wrote:
The movement had wide support within the Chilean society as they saw it as a reflexion of what was happening at all levels of Chilean society, where there are extremely high levels of inquealities, most services are privatised and people are in huge debt to try to live to what Chilean society standards try to impose.
So people at all levels could empathise with the student movement as their struggle was everyones struggle. So even though the demands were mostly education demands, it reflected a wider demand for systemic change in Chilean society. This wouldn't have been possible without all the really inspiring actions carried by students. Some of the best examples where when the student movement organised weekend demonstrations inviting the whole family, which were extremely successful. So actions by youth can be really good as many sectors in society can empathise with them.
Dear Javier,
Thanks for your informative response about the economy and the issues in Chile. I am fairly familiar with what has happened but it was interesting to learn how the student movement became the leading voice for society. I am interested to know more about whether this has continued and if the society has rallied behind the students in the face of growing government control, or have the students remained the main actors on these issues? If society has been more active, in what ways have they been active? How has the student movement tried to engage the society around them? Has it been only in street demonstrations? Or are there other actions they have done?
I am very interested to learn more about how the student movement has tried to mobilize their society and whether you feel it was successful.
Thank you!
Melanie
الجمعة, 11/30/2012 - 5:52 - صباحا
perception of failure
Dear Melanie,
Thanks for your question. This year (2012) the student movement had a lot of pressure to repeat the levels of movilisation and presence in the mainstream media. Every year the student leadership changes, which has an impact on the style how the message is communicated. Many of the 2011 student leaders, have moved to more traditional politics, some of them even running next year for congress, mostly as the political parties see them as having very strong credentials within the Chilean society.
During the summer break (January and February) the student had long evaluation sessions about what had happened during last year. One evaluation was that there were too many demonstrations and that what was needed for the upcoming year (2012) was to try to reach out to other movement and sector of Chilean society.
This was a good idea in principle, as they had already the attention of Chilean society now was the time of building stronger alliances with other movements. But in reality it meant a drop in the momentum of the movement as the presence in the street was less and in the street is where the movement showed its strength. The question is how many marches can you have in a year and try to continue gaining momentum. It is clear that other tactics need to be implemented. Still the movement is strong and very creative.
In 2011 there were different forms to engage the wider public. For example there was a self organised referendum organised by the movement asking if if you were in favour or against profiteering in education. For this referendum there were polling stations all over the country and you could also vote online. So for people who usually don't join demonstrations, this was a very easy way of showing support to the movement.
The use of art as usual was very important. Marches were very colourful and with music to try to have a positive dimenstion to counter the message coming from government and the mainstram media that the student movement was violent. A very famous action was a flash mob: "thriller for education".
In 2012 the movement had less impact but still it carried some of the momentum from 2011. And now when other sector of society want to movilise, it is crucial for them to reach out to students. The question of the movement cooptation from political parties, is an important one. Last month there were local elections and there was a wide spectrum of positions within the student movements. Some calling to boycott the elections, while other former leaders were running in the elections or actively campaigning.
The events of 2011 shaked social movements in Chile and students know they are a force that can set topics in the political agenda and can put really pressure to the powerholders. For me a very useful model to analyse a movement like the student movement in Chile is theMovement Action Plan, by Bill Moyer. In this model there are 8 stages a movement is likely to go through. I think by the end of 2012 the movement could feel in stage 7 (winning over the majority) Which means until now, the movement has focused on protest; now it is important to offer solutions. I think in 2012 is possible that the movement went back to stage 6 (perception of failure) this is enhanced by decreasing participation in movement events and negative media coverage. But this perception of failure can quickly change as the movement has done the ground work and quickly can get momentum again.
2013 is an election year in Chile, with presidential and congress elections. From many sides they will make offers to the student movement, so it will be a crucial year to see what is the strenght of the movement and use this opportunity to bring about real change.
Javier Garate
WRI
@javitejavier
Similarities in the movments in Israel and Chile
Dear JavierThis was a very interesting model you shared and I would like to continue to draw upon some of the similarities in our movements. First off negative media has certainly been an issue, while the majority may be interested in the changes in society, the media is mainly influenced by the government which obviously opposes any change in the status quo. You mentioned co-optation of the movement by political parties, while this is not totally descriptive of the situation what we have seen is that the current government using its media influence has tried to redirect the conversation back to security so that people will be too afraid to focus on the economy.On this issue I would like to ask, what kind of media tactics has the student movement been utilizing to combat the negative mainstream media? Twitter, facebook, advertising campaigns? Also, have any journalists taken on the challenge of entering into politics?(This is something increasingly common in Israeli politics)Secondly the issue of elections is also relevent for us as by February we are also facing a new Israeli election. The issues we are facing in this election are similar to what you described but not quite the same. We are seeing the young/student leaders of the movement jeapordizing their values in order to fit the model of the 'establishment of Israeli politics'. For example, newcomer and movement leader Stav Shaffir recently ranked in the top ten in the Labor party but a lot of analysis and even her friends have suggested that she had to bend on a lot of her ideals to get there. Therefore, we are fearful that although the movement leaders may reach some positions of power, they will have to make large concessions to get and stay there.Is this concession of values to reach political power something you have seen in the students who have chosen to participate in the elections? If so, how have the leaders themselves responded to this issue and also how has their constituency responded to these issues?I was very interested in the movement plan you shared as well. It was interesting to try and see where our issues fall on that map. What I felt after reading is that we too are in a place where there is perceived failure and a loss of momentum (especially now that security has become a very hard to ignore issue due to the recent war with Hamas/Gaza). I believe that move to the political realm will provide some newfound hope but the goal of creating participatory democracy has yet to be fulfilled. What I found interesting was the description of actors in the movement. As members of a joint-Israeli-Palestinian organization we are most often cast-out as 'tratiors', in the terms of the terminology you provided, we could be considered 'the rebels', the fringe, while saying the same things that others might agree with, our solidarity with Palestinians will set us aside from the mainstream. At the same time however, our youth programs aim to develop agents of change. We also utilize this term as it is our goal ,to educate youth who go on to educate their communities and societies and we aim to create a long-term network of grassroots Israeli-Palestinian activists. Thus our youth who do become active in the internal Israeli politics often have to avoid discussing their views on these other key issues, a very difficult thing for them to do.You mentioned in your post that the movement has become dvidied on how to move forward, how are they coping with this?I was very interested by the flashmob and the self-organized referendum, i plan to share these with our team and youth as interesting options for activism.Sorry for such a lengthy response!In peace,Melanie
Division or Diversity
Dear Melanie,
Thanks for your message and making the connections between the Israeli - Palestinian and the Chilean situation.
First I would like to answer to the question of division in the movement. For me the issue and this doesn't only applies to the Chilean case, but is when do we talk about division and when we talk about diversity. I think what is important is that for the outside world the movement appears as united as possible - as there is a common opponent - and in many ways this is the case in Chile, as whenever there are calls for a demonstration, students from all sectors take to the streets. The problem is when there are groups that go against the very nature of the demonstration, for example - and going back to the media presenting the demonstration as violent - the organisers call for a peaceful demonstration and groups join the demonstration and are happy to act violently. I know that many times the police are the ones that provoque the violence, but that's exactly what they want, to provoque a reaction that then can be used to delegitimise the protest. What the Chilean student movement has done is to actively engage with the violent end of the protest, making the case that it actually goes against the goals of the demonstration. This has had different levels of success, but at least the powerholders can not say that the leadership of the movement is violent.
The student movement is very diverse, for years it had a strong presence of the comunist party but recently a more independent left has had more protagonism.
So if you look at the movement from inside it can be seen as if there are strong divisions. For examples on what tactics to use or how to engage with political parties. But at the same time through coming out to the streets together they can still create a sense of unity which is very important. The important point is how to build strength from the diversity and not divisions and this relates to the isse of the different roles metioned the Movement Action Plan. That not everyone has to play the same role in a movement or that there is only one role that will bring social change. What is important is having communication channels between the different roles.
On the issue of participating or not in the election process and the impact this has. So far in Chile, it has been important that student leaders while they are leaders of the movement try to engage as little as posible in election politics, as if not they stop being seen as representing a movement but a party or other interests. The students have come out very clearly saying that their movement is ont only to change education but for a change of the whole system. Some see that to bring about this change you need to engage with electoral politics, as to change it from inside, however, other think that's impossible. At the last elections there was the lowest turn out to vote for many years, in many ways following the call of students to boycot it. So more at a movement level I think there is a majority that sees social change coming from the movement and not through election, this doesn't mean that many student also vote and some actively campaign. But as soon as student leader are seen very close to a specific political party they seem to lose their stronger movement credentials and are seen as some new and fresh faces which might bring a bit of new energy but within the same political system.
Finally on the issue of media: Of course social media has played a very important role. But also as the movement got bigger and the mainstram media could no longer ignore it, then it was important to make use as much as possible of this media. For example through interviews and debates. The debates where students debated with politicians, university directors, etc, were in many ways the most effective ones, as you could challenge the powerholders directly and the public could see the difference of ideas. For this it was very important that the student leaders were very well informed, so they could constrat all information and bring in arguments backed with research.
I think I will stop here as it is already a long answer.
Thanks
Javier
Common enemy unites
Hi Javier, thanks a lot for the elaborate picture of the situation in Chile. You write about the youth or students as if they are very much united, which could of course be the fact that they have "common enemy", the old system. I was wondering how you see this, since you talk about how they are working for social change, but often the change one group envisions is not the same as the one of the other group. I do not know the situation in Chile, but it let me think of a political experiment recently seen in Germany. The socalled Pirate party, predominantly consisting of young people, students, Internet and new media experts, won in several of the federal states of Germany, also being voted by almost exclusively young people. Hopes were high and promises made sounded wonderful: flat hierarchy, more transparency, more real democracy by using the Internet to discuss the standpoint of the party with the people on the basis. Unfortunately once they got into the governments of th different federal states, the problems began: since thy started as a party with not much content apart from demanding more transparency in politics, hey struggled to find a consens on how to relate to other political issues. The common enemy, the old political system bad bound them together, but once they had conquered that, they clear vision of hat change to bring was more difficult to ocercome. To me it shows that is is vital to already work on clear strategies long time in advance, this goes of course not just for any youth movement, but for everyone.
Building alliances
Hi Merle,
Thanks for your comment. I agree on the importance of having a long term strategy, and working on the alternatives o what in nonviolence language we calledconstructive programme. Many times the powerholders argument is: so what is the alternative you propose.
It is true that within the Chilean student movement there is a wide range of political positions when it comes to what kind of society you envision, so when looking at the big picture there are some differences. However, there was a strong unity on the diagnosis, being clear that the problems in education are a systemic problem so there needs to be a change in the system. Now when coming up with a solution there are some difference but when it came to the specific issue of education, I have to say - especially in 2011 -the movement was very good at showing that there are alternatives, and making concrete proposals. A very important moment was when the student leaders went to a session in Congress of the education commission to make their proposal, this was shown live on television and was very clear that most of the student leaders knew more about education and the different options that the politicians. The proposals were on free and quality education. So when it came to the specific issue of education there was also a broad agreement on what was the alternative.
It is not that easy when the movement started getting involved in other issues beyond education, and here there was a much wider diversity and not so clear proposals. And yes, as some of the leaders are members of political parties, as soon as it was not related to education it was seen as if they were simply representing their party's line. I already mentioned the last local elections, and one good example was some of the student leaders supporting independent candidates, some of these candidates actually got elected and the support of the student leaders was crucial on this, but again this was inside the traditional electoral politics.
So the big challenge is how a movement which becomes strong and has a lot of impact in society but is connected to one specific issue, can move to a broader discourse of social transformation. I think here you come back to the importance of alliance building, which as I mentioned earlier was one of the goals of the Chilean student movement for 2012, which I think was not really achieved. When we talk about movement building, building alliances is a key factor. How different movements can find a common ground to work together, which doesn't mean that you have to agree on everything. You need to identify what is that you have in common. For example I think the economic crisis is a big opportunity for different groups to come together under a common problem. For example WRI as an antimilitarist and nonviolence network has made theconnection between the economic crisis and military spending, andsome of WRI's members have worked closely with different occupy groups making this connection.
I'm not sure if I answered the question. But I think what is important is for movement to keep their independence as much as possible and find common grounds for alliance building, knowing that you can not agree on everything and that some compromises will need to happen, but without losing your indentity.
Thanks
Javier
WRI
Similarities in the movments in Israel and Chile
reflecting on ourselves as (young) activists
Hi everyone,
Reading through the contributions, I noticed that the issue of young activists entering mainstream power structures, trying to fit its values and jeopardizing their principles while doing so has come up several times.
I think it is an important observation, one which not concerns young people but everyone, and one we should be discussing more openly as civil society when we have our meetings or organize our trainings. Do I walk the talk all the time? Do our words match our actions as an organization? These can be uncomfortable questions, also for civil society.
Once you become a voice of influence as an activist organization, doors start to open and people will approach you - with different motives and agendas. Some genuine, some not. As nonviolent activists, it will always be important to reach out to as many people as possible (the power of numbers); to be open to joining hands with new players (even the not-so-usual suspects); but how to do this without entering a domain where you start to dilute what you stand for?
I guess something is going wrong when the collaboration/actions turns out to be more beneficial for the specific person or organization than for the cause one is supposed to be fighting.
It is important to recognize that power games are not only happening "out there" (in Politics with the big "P"), politics is also happening within civil society. I remember a discussion we had with activists recently - we were discussing the importance of networking in the MENA region - and the honest reflections that came forward from the group. People shared about the devastating competition between NGOs, the undermining effect of lack of trust between NGOs, the fact that setting up networks in the region had become a donor trend resulting in the bottom-up networks (originating from and sustained by activists' commitments) being undermined by donor-initiated/supported new flashy networks. People spoke about being torn between needing all their time and limited resources to do the work on the ground (their reason for existence) and feeling they also needed to show their face at all the network meetings/ donor events/ endless conferences in order to be "seen" and considered "still relevant" as organization.
I felt priviliged to be part of this discussion as it felt liberating to talk openly about this. It is a reality that not only exists in the MENA region but everywhere, and it is a painful one. As civil society we know we can expect power games from the establishment at one point, but the ones that come from within are the ones that hurt the most. "Divide and conquer" is affecting us all and makes many civil society organizations - whether consciously or not - get caught up in a game of survival. Which is not serving anyone in the end.
It is something we do not talk about often as activists, though perhaps by opening up and admitting that this reality exists we would be able to find better ways to deal with it. It means we need to consiously create space to reflect critically on ourselves and our work - is what we are doing still serving what we stand for? We also need to discuss what happens to ourselves when we enter arenas of power, and how to deal with the contradications that emerge from this. And we need to learn how to say "no" when the cause is no longer being served - even if this means we are the only one speaking up, and might be risking our organization/ personal position by doing so.
In our recent WPP publication on this topic, one of the interviewees mentions that often the younger activists are more daring and more confronting as they have less to loose - they usually do not have a social status or well-established organization to defend. His words reminded me of a fairytale that left a big impression on me when I was a kid: The Emperor's New Clothes. Perhaps this is the challenge for all of us as activists - to remain connected to the daring spirit inside who has nothing to loose.
Why are young people are so often the drivers of social change m
The Kenyan experience shows that young people are the most affected with the high unemployment rate and so many times they are at a point where they need to make crucial decisions in their life. The decisions dictates which directioin they will take in life. A number of things are likely to happen at this point but I will point two main ones. They may decide to be serious criminals or go to the other extreme and look at their challenges critically and become serious drivers of change.
Again the Kenyan experience, part of the reason why these young people go missing ones change has been achieved is that most of them enter the struggle with narrow visions and stand the danger of being swallowed into corrupt systems or worse still end up being compromised. The greatest risk then is that the desired change is never fully achieved.
Youths and Politics
Our young people for many years have enjoyed being foot soldiers of seasoned politicians besides not being able to marshall resources to outdo veteran politicians. To that level even the few who succeed in getting their don't find the political playing field level mainly because of finances. The veteran politicians enjoy calling the shots and the few young people are never noticed and eventually begin behaving like old politicians. The difference then becomes the same.
Why are young people are so often the drivers of social change m
Youth is the symbol of energy and deep belief in idealistic themes. This is what makes them the main drivers of social changes.They believe and they act accordingly.After few years, many family and professional responsibilities, this ideal becomes a memory of another life.One needs to believe deep enough in something to fight for it. Few years ago, in France, high school students who were not even old enough to vote were on the streets, everywhere in the country, to ask the civil society to wake up and go to vote unless they wanted the party of Le Pen (very racist) to win.It worked, these kids make it happen, they save the society.
Why are young people often the drivers of social change movts
In Uganda, it is because of the unemployment rate; this is two-fold; the twenty universities in Uganda have an average of 3000 graduates a year and none of this can find gainful employment. They look at government has being insolent about it because of the many pensioners still working. For example the average in Uganda's cabinet is 60. Then there is another group of unemployed youth because they did not go far in studies for various reasons i.e. lack of tuition, being orphaned etc. This is one of the reasons that the youth of Uganda have become actively engaged in social change movements. They feel government has let them down and that government has overstayed (27 years in power) and believe it’s time for changeAnother reason is because of access to information and social media. They can see what youth in other countries are doing e.g. Egypt, Syria etc.They therefore say-"if they can, why can’t we"
Walk to work protests
There are currently walk-to-work protests over the high standard of living. A good number of youth take part in these walks and are often teargassed and imprisoned. Some of them take advantage of this walks to riot and loot. However some of them feel used because when they are arrested, the organisers of the protests are not there to help them out e.g. bail
walk to work protests
one of the links on the walk to work protests
http://www.aljazeera.com/indepth/features/2011/04/201142831330647345.html
| https://www.newtactics.org/ar/comment/5643 |
Grand Loop dreaming
Grand Loop dreaming
Topic Name: Grand Loop dreaming Reply #60 on: March 10, 2018, 09:29:59 AM
Gimmearaise Location: Crested Butte, CO Posts: 313 Re: Grand Loop dreaming « Reply #60 on: March 10, 2018, 09:29:59 AM » Based on the Columbine Pass SNOTEL, the route this year might be passable sooner than most years, we are currently looking at a total snowpack of 21 inches and it looks to be melting pretty quickly. That being said, who knows what spring will offer and I have a hunch that it might be a wet one considering how dry this winter has been. Thats how it works, right? https://wcc.sc.egov.usda.gov/nwcc/site?sitenum=409 So...... if we want to bring this race back, we should brainstorm a group start. Personally, I'm busy most of May with a trip to Peru, but I don't necessarily need to partake in the group start, I just think we should set a date and keep it rather consistent from year to year. It seems in the past, early June was the best time to start, and to avoid some heat, maybe we start on a Friday evening, say 5pm? What do people think about June 1st or June 8th start with the thought of going counter-clockwise starting at the Lunch Loops TH. Also, it sounds like they are going to finish the path from Fruita to Loma here soon, this will be a nice addition to the route and a great alternative to I70. I was pretty scared going through this section during my ITT attempt this past fall. I had a number of 18 wheelers honk at me showing there displeasure of me riding the HWY. Does any GL locals have an update on this path? It also sounds like Paul Koski is working on improving some trails into Nucla, which would be much appreciate, but you will still have to endure the Koski Traverse, something that basically broke me to my core this past fall. There is an optional resupply in Nucla, and this happens to be the only resupply along the route outside of services near GJ/Fruita. It is my understanding this is a much more difficult route than what was initially drawn up, and breaking 3 days, seems next to imposable, but who knows. Anyways, I just wanted to get the ground work started. I'm happy to organize this, but at the same time, I have yet to complete the whole route. I'm going to perhaps give it a go if weather allows in early May but a new job and a busy schedule may not allow. I might just try to run Nucla to GJ, we shall see. Thanks, Neil Logged WWW.BikepackingSummit.com
Topic Name: Grand Loop dreaming Reply #61 on: March 12, 2018, 07:59:16 AM wolfmansbro Posts: 41 Re: Grand Loop dreaming « Reply #61 on: March 12, 2018, 07:59:16 AM » If the snow melts early, I'm game for a April 27th or May 4th Depart. Rest of May and June are booked for me. Logged BikepackUtah.com | Insta
Topic Name: Grand Loop dreaming Reply #62 on: March 12, 2018, 08:44:20 AM
DaveH Moderator Posts: 973 Re: Grand Loop dreaming « Reply #62 on: March 12, 2018, 08:44:20 AM » I've never seen the Tab clear out early May but these aren't ordinary conditions. It just might go. The long range forecast http://www.cpc.ncep.noaa.gov/products/predictions/long_range/seasonal.php?lead=2 is warm and dry. You'd want to see the Columbine snowtel bottom out early to mid April and a following 2-3 weeks of well above normal temps to have viable conditions. One alternative - since the route is going through some metamorphosis, you could remove that small bit of singletrack at the top of the Tab. The route would be passable at least 2 weeks earlier without that section, it is the spring crux. Snow in the trees makes for slow melt and a hidden trail. Without that section the route would stick to the Divide road up top then drop down to Roubidoux by jeep road. That might be a messy wet slog late april/early may but you could follow it. Whatever route you decide on will almost certainly become the new race route, so choose wisely Logged
Topic Name: Grand Loop dreaming Reply #63 on: March 12, 2018, 08:54:29 AM
DaveH Moderator Posts: 973 Re: Grand Loop dreaming « Reply #63 on: March 12, 2018, 08:54:29 AM » Quote from: the.hamtron on November 02, 2017, 09:47:03 PM Got out for a counter-clockwise tour of the Grand Loop starting this past Sunday morning, departing around 8:45am from Dewey. I decided to ride the same route as Neil, thinking that it seemed more reasonable to detour into Nucla for resupply, and I also wanted to get through the high points of the route before moisture/snow moved into the area late Monday/early Tues. I had a blast, mostly(!), fully invested in the experience, enjoying ticking off miles through sweeping and ever-changing landscapes, from the desert to the high desert, to the sub alpine and back, it was wild to ride through the beautifully diverse Colorado Plateau. I'm still being haunted by the specter of my experience on the Grand Loop, but god damn, it felt good to rip and romp around on the bike through such beautiful country. What a blessing to call Colorado home! I packed way too much water (120 oz) and food (2 days worth) from the start, my bike weighing more than I care to remember. Definitely felt the burden by the end of the 100 mile day, succumbing to sleep fairly early, around 10:30. Wasn't motivated to begin riding in the cold and dark morning, so I woke with the sun after laying down for 8 hours. I was less than 2 hours out from Nucla, so I rallied into town for resupply, and was on my way to tackle the Plateau. A long, grind of a climb took me up to Columbine Pass, and then what seemed like endless riding across the plateau, with short shots descending into watersheds and then the steep, chunky climb out. Rode hard on the gravel service road through a snow squall in the middle of the night, snowflakes blazing by in the glow of my K-Lite, loving every second. Got in 140 miles before I laid down to sleep around 2. Woke at 7 having slept poorly, and thought it would be a fairly quick ride into GJ. After descending down a ways and crossing HY141, I didn't realize the extent of the rough and tough stretch of the Tabaguache, before FINALLY dropping into GJ. A quick resupply and lunch and I was off, heading to Loma and then south, as it looked like the route had me riding the Interstate(?). Started on the Kokopelli around 2pm, and was LOVING the views of the Colorado river and canyons from the cliff shelves, and I guess the single track was ok too after mostly 300 miles of double-track and gravel roads. Rode hard this final stretch, mashing away, as I still had a 3.5 hour drive home and work waiting for me at 10am the next morning. In my haste and discomfort, I bailed off the route proper when I hit CR128, opting to ride 5-6 miles of pavement back to where I started. Finished around 11pm, and was super psyched to be done, but not so psyched to drive home. This route is rad, thanks to everyone who established it! - Paul H Fantastic! I didn't see your post until now...it's always exciting to see someone complete this loop. It doesn't happen very often, but when it does it leaves impressions that last forever. 120 oz water doesn't sound like much for a GL ride to me but then again I have only done it late may/early june. Snow...yea I've had frost but no snow! That yellow jacket section of the koko is one tough way to setup a finish, you chose wisely Sounds like a great adventure, thanks for sharing! Logged
Topic Name: Grand Loop dreaming Reply #64 on: March 12, 2018, 05:57:43 PM
MikeC Posts: 314 Re: Grand Loop dreaming « Reply #64 on: March 12, 2018, 05:57:43 PM » Quote from: Gimmearaise on March 10, 2018, 09:29:59 AM It seems in the past, early June was the best time to start, and to avoid some heat, maybe we start on a Friday evening, say 5pm? What do people think about June 1st or June 8th start with the thought of going counter-clockwise starting at the Lunch Loops TH. Also, it sounds like they are going to finish the path from Fruita to Loma here soon Lots of heavy equipment working on the trail near the Loma exit right now. Trail is done within ~2 miles of there, and it looks like the last bridge might even be in place. Won't be done in weeks -- they tend to drag things out finishing benches, signage, etc... -- but early June seems totally safe to bet on. Historically we left on a Friday night for exactly the reason you mentioned -- heat avoidance. It was also chosen so that if you were gunning for a fast time it'd put you into Bedrock in time to catch the store before closing on the second night. For now, I'm just going to ignore DH posting encouragement to make this a road race... Logged www.lacemine29.com
Topic Name: Grand Loop dreaming Reply #65 on: March 14, 2018, 05:52:58 PM snowblind Posts: 5 Re: Grand Loop dreaming « Reply #65 on: March 14, 2018, 05:52:58 PM » I’m thinking of giving it a go on Memorial Day weekend to take advantage of the paid day off. I’m betting that unless it starts snowing, the trail will be clear given the low snow year. I could be wrong but I’m betting I’m not. Friday afternoon start. Anyone want to commit to a start date? Plus I’m most likely traveling for work the traditional starting weekend. Jim Logged
Topic Name: Grand Loop dreaming Reply #66 on: March 15, 2018, 08:57:53 AM wolfmansbro Posts: 41 Re: Grand Loop dreaming « Reply #66 on: March 15, 2018, 08:57:53 AM » How about we set an unconventional date for the start? We could use Dave's formula of Columbine Snowtel SWE at zero, and we depart the first Friday after it is at zero for 2 weeks? That would theoretically give everyone a two weeks notice to ask for time off work. Logged BikepackUtah.com | Insta
Topic Name: Grand Loop dreaming Reply #67 on: March 15, 2018, 09:11:50 AM Cedar Wing Location: Bend, OR Posts: 18 Re: Grand Loop dreaming « Reply #67 on: March 15, 2018, 09:11:50 AM » Pumped this is getting picked up with a potential group start. I would be in and dates can be flexible for me, just wanted to let the group know of another racer. Would be traveling in from Dillon, CO too if folks want to try and coordinate travel or other bikepack pursuits before CTR. Logged
Topic Name: Grand Loop dreaming Reply #68 on: March 15, 2018, 12:23:54 PM the.hamtron Location: Marble, CO Posts: 8 Re: Grand Loop dreaming « Reply #68 on: March 15, 2018, 12:23:54 PM » I'm interested, date depending. Logged
Topic Name: Grand Loop dreaming Reply #69 on: March 15, 2018, 08:12:41 PM peteshoe Location: Littleton CO Posts: 64 Re: Grand Loop dreaming « Reply #69 on: March 15, 2018, 08:12:41 PM » I think I could make June 1st or 8th work. If we're picking a consistent date, the first Friday of June has a ring to it. This would also remove the snow risk of which Dave speaks. This has been on my bucket list for a while, I'd love to give it a go - Logged
Topic Name: Grand Loop dreaming Reply #70 on: March 15, 2018, 09:49:34 PM
Gimmearaise Location: Crested Butte, CO Posts: 313 Re: Grand Loop dreaming « Reply #70 on: March 15, 2018, 09:49:34 PM » Alright, this is great, people are interested. For future years sake I do like the idea of the first Friday in June, but I also like Jason's start idea, but then you can't really plan very far in advance if people need to put in time off months in advance. Maybe Memorial Day weekend could work? Mike, If we do end up removing the singletrack at the top of the Tab, you know the Koski travers is a extremely difficult, and we add all the singletrack into Nucla, this and adding the Western Rim could even things out perhaps. This would be far more rugged than the Bedrock detour and still allow a resupply in Nucla. I like the idea of rolling this event a bit earlier as it gets so damn hot out in the desert sections. A Memorial Day start every year could be nice for vacation time. Let me know what you think. I'll try and recon the TAB before this years GD but it might not happen if I can't find time in Early May. Thanks, Neil Logged WWW.BikepackingSummit.com
Topic Name: Grand Loop dreaming Reply #71 on: March 15, 2018, 11:10:58 PM
MikeC Posts: 314 Re: Grand Loop dreaming « Reply #71 on: March 15, 2018, 11:10:58 PM » Quote from: Gimmearaise on March 15, 2018, 09:49:34 PM Mike, If we do end up removing the singletrack at the top of the Tab, you know the Koski travers is a extremely difficult, and we add all the singletrack into Nucla, this and adding the Western Rim could even things out perhaps. This would be far more rugged than the Bedrock detour and still allow a resupply in Nucla. I like the idea of rolling this event a bit earlier as it gets so damn hot out in the desert sections. This route/race is a crowd-sourced thing now, not one person's event. As such, the group gets to determine what level of rationalization makes sense. Removing the Tab singletrack does make sense in that it allows for an earlier common start. I can't necessarily fault anyone for wanting that. But it's also sort of a cornerstone of the route. Not because it's big or epic or sweet or stunning, but *because* it makes planning more challenging. We take our local loops for granted because they're *right there* and we can ride them anytime. Anyone that's been out there will argue that the Grand Loop will never be taken for granted, no matter how many tiny course changes are made. And I think that should be the goal -- to keep it big, and bad, and unpredictable, and hard on every level. Even before we get there. Death by a thousand cuts is what I fear. It's supposed to leave a mark that never, ever goes away. It wouldn't be nearly as profound to the finisher if it didn't. Logged www.lacemine29.com
Topic Name: Grand Loop dreaming Reply #72 on: March 16, 2018, 04:33:24 PM Biggs23 Posts: 39 Re: Grand Loop dreaming « Reply #72 on: March 16, 2018, 04:33:24 PM » Well,whatever route/date is chosen I'm down to give it a go.I've played around out there over the years and yes the GL is an ass kicker,but what the heck sounds like a great way to kick off the Summer. Logged
Topic Name: Grand Loop dreaming Reply #73 on: April 05, 2018, 07:42:21 PM snowblind Posts: 5 Re: Grand Loop dreaming « Reply #73 on: April 05, 2018, 07:42:21 PM » Looks like the snow is melting nicely. I’m still thinking Memorial Day weekend. If it’s just me, I’d roll out from Fruita around noon on Friday. If a group is forming I’d be fine with starting in GJ although I like the idea of doorstep to doorstep better. I’ll probably do a little recon the end of April and check out the southern side of the loop a bit. Logged
Topic Name: Grand Loop dreaming Reply #74 on: April 06, 2018, 10:12:40 AM Biggs23 Posts: 39 Re: Grand Loop dreaming « Reply #74 on: April 06, 2018, 10:12:40 AM » Quote from: snowblind on April 05, 2018, 07:42:21 PM Looks like the snow is melting nicely. I’m still thinking Memorial Day weekend. If it’s just me, I’d roll out from Fruita around noon on Friday. If a group is forming I’d be fine with starting in GJ although I like the idea of doorstep to doorstep better. I’ll probably do a little recon the end of April and check out the southern side of the loop a bit. I like the start time.I can make this happen.GJ/Fruita start I'm good either way. Logged
Topic Name: Grand Loop dreaming Reply #75 on: April 06, 2018, 10:20:04 AM MikeC Posts: 314 Re: Grand Loop dreaming « Reply #75 on: April 06, 2018, 10:20:04 AM » FYI, the bike path from Fruita to Loma is definitely progressing every day. But I heard that DOT doesn't anticipate it being done all the way/open until July. IMO, no biggie to just ride the 10' wide shoulder of I-70 for ~4 miles from Fruita. That's what I've always done. Logged www.lacemine29.com
Topic Name: Grand Loop dreaming Reply #76 on: April 06, 2018, 01:48:39 PM Biggs23 Posts: 39 Re: Grand Loop dreaming « Reply #76 on: April 06, 2018, 01:48:39 PM » Quote from: MikeC on April 06, 2018, 10:20:04 AM FYI, the bike path from Fruita to Loma is definitely progressing every day. But I heard that DOT doesn't anticipate it being done all the way/open until July. IMO, no biggie to just ride the 10' wide shoulder of I-70 for ~4 miles from Fruita. That's what I've always done. Thanks for the info Mike.Bike path from Fruita to Loma,pretty sweet. Logged
Topic Name: Grand Loop dreaming Reply #77 on: April 12, 2018, 09:11:03 AM wolfmansbro Posts: 41 Re: Grand Loop dreaming « Reply #77 on: April 12, 2018, 09:11:03 AM » down to 2" of snow. Seems like we might only be a few weeks out.... Logged BikepackUtah.com | Insta
Topic Name: Grand Loop dreaming Reply #78 on: April 15, 2018, 07:46:30 AM snowblind Posts: 5 Re: Grand Loop dreaming « Reply #78 on: April 15, 2018, 07:46:30 AM » It's now bottomed out, going to be a dangerous fire year. I won't be able to swing any earlier then Memorial Day weekend. Post up a report if you go earlier. Logged
Topic Name: Grand Loop dreaming Reply #79 on: April 16, 2018, 08:16:56 AM peteshoe Location: Littleton CO Posts: 64 Re: Grand Loop dreaming « Reply #79 on: April 16, 2018, 08:16:56 AM » I can't do the holiday weekend, that's kids/family time for me. I'm still looking for an ITT window the 1st or 2nd week of June if anyone wants to join me - Logged
| http://www.bikepacking.net/forum/ultra-racing/grand-loop-dreaming/msg93189/ |
Study of Citrate Adsorbed on the Au(111) Surface by Scanning Probe Microscopy - [scite report]
Supporting: 10, Contrasting: 2, Mentioning: 62 - A combined scanning probe microscopy study of citrate adsorbed on Au(111) has been conducted. The adlayer structure of citrate on Au(111) is imaged using in situ scanning tunneling microscopy for the first time. Citrate anions are found to form stable and well-ordered adlayers with (4 × 2 3) symmetry. The effect of the citrate adlayer on the interaction between the gold surface and fibrinogen, the protein that has a major role in blood coagulation, has been investigated by atomic force microscopy. The results indicate that citrate modification may change the biocompatibility of gold.
Study of Citrate Adsorbed on the Au(111) Surface by Scanning Probe Microscopy
3
et al.
Abstract: A combined scanning probe microscopy study of citrate adsorbed on Au(111) has been conducted. The adlayer structure of citrate on Au(111) is imaged using in situ scanning tunneling microscopy for the first time. Citrate anions are found to form stable and well-ordered adlayers with (4 × 2 3) symmetry. The effect of the citrate adlayer on the interaction between the gold surface and fibrinogen, the protein that has a major role in blood coagulation, has been investigated by atomic force microscopy. The results …Show more
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“…A model was proposed in which the three, g-2 coordinating carboxylate groups were tilted from the electrode surface. Independently, Lin et al [3]demonstrated that citrate anions form an ordered superlattice structure as determined by in situ STM.…”
Section:Introduction mentioning confidence:98%
“…Despite its importance in gold colloid chemistry, the molecular level details of the surface coordination and bonding of citrate to gold surfaces was until relatively recently largely ignored. Citrate adsorption on gold colloids has been studied with surface enhanced Raman spectroscopy (SERS) and on gold electrodes with the aid of in situ infrared spectroscopy [1, 2]and in situ STM [3, 4]. The SERS spectra of citrate monolayers adsorbed on gold sols show bands at 1535, 1380 and 800 cm À1 .…”
Section:Introduction mentioning confidence:99%
Electrochemical evaluation of citrate adsorption on Au(111) and the stability of citrate-reduced gold colloids
Kunze
1
,
Burgess
2
,
Nichols
3
et al.
2007
Journal of Electroanalytical Chemistry
69 13 67 2
No abstract
“…A model was proposed in which the three, g-2 coordinating carboxylate groups were tilted from the electrode surface. Independently, Lin et al [3]demonstrated that citrate anions form an ordered superlattice structure as determined by in situ STM.…”
Section:Introduction mentioning confidence:98%
“…Despite its importance in gold colloid chemistry, the molecular level details of the surface coordination and bonding of citrate to gold surfaces was until relatively recently largely ignored. Citrate adsorption on gold colloids has been studied with surface enhanced Raman spectroscopy (SERS) and on gold electrodes with the aid of in situ infrared spectroscopy [1, 2]and in situ STM [3, 4]. The SERS spectra of citrate monolayers adsorbed on gold sols show bands at 1535, 1380 and 800 cm À1 .…”
Section:Introduction mentioning confidence:99%
Electrochemical evaluation of citrate adsorption on Au(111) and the stability of citrate-reduced gold colloids
Kunze
1
,
Burgess
2
,
Nichols
3
et al.
2007
Journal of Electroanalytical Chemistry
69 13 67 2
No abstract
“…Therefore, electrostatic stabilization is preferred to polymer stabilizers for electrocatalyst preparation. Citrate ions have been used in aqueous colloidal solutions of Ag, Pd, Au, and Pt [17] [18] [19] [20]. The acetate anion was also found to permit the formation of nonagglomerated Ru particles in polyols [23].…”
Section:Results mentioning confidence:99%
“…The synthesis strategy presented here is simple and effective and provides a promising method for preparing carbon supported size-selected noble metal catalysts. In addition, since it has been reported that acetate can be used as stabilizer to synthesize other noble metal nanoparticles in polyol [17] [18] [19] [20] [21] [22] [23], the method presented in this work will be expected to prepare other supported noble metal and Pt-based alloy catalysts such as PtRu/C, which are more suitable for methanol electrooxidation due to their good tolerance for carbon monoxide poisoning. …”
Section:Results mentioning confidence:99%
“…The citrate anion has been used as stabilizer to prepare noble metal nanoparticles such as gold [17], palladium [18], silver [19]and platinum [20]. Recently, sodium acetate was also found to be a good stabilizer for preparing Pt and Ru nanoparticles in the liquid polyol process [21, 22].…”
Section:Introduction mentioning confidence:99%
Yu
1
,
Chen
2
,
Zhao
3
et al.
2006
J Appl Electrochem
Pt/C electrocatalysts were prepared from a solution of H 2 PtCl 6 in ethylene glycol in the presence of XC-72 carbon by adding a small amount of sodium acetate as stabilizer. Repeated TEM images showed that the platinum nanoparticles were small and uniform in size and highly dispersed on XC-72 carbon supports when a small amount of sodium acetate solution was added to the synthesis solution. The Pt/C electrocatalysts exhibited very high electrocatalytic activity for liquid methanol oxidation. The effects of adding acetate on Pt particle size and size distribution are discussed. It is demonstrated that acetate can be used as a good stabilizer for preparing Pt/C catalyst with fine and uniform Pt particles.
| https://scite.ai/reports/study-of-citrate-adsorbed-on-Mv166p |
Total reserves as a percentage of the total external debt in Costa Rica 2021 | Statista
The total reserves as a percentage of the total external debt in Costa Rica decreased to 20.48 percent since the previous year.
Economy & Politics›
Politics & Government
Total reserves as a percentage of the total external debt in Costa Rica 1999-2021
Published byStatista Research Department,Jun 26, 2023
The total reserves as a percentage of the total external debt in Costa Rica decreased to 20.48 percent since the previous year. As a result, the reserves as share of external debt in Costa Rica saw its lowest number in 2021 with 20.48 percent.
For more insights about the total reserves as a percentage of the total external debt consider different countries: In 2021, in comparison to Costa Rica, the reserves as share of external debt inColombiaas well as inGuatemalawas considerably higher.
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Total reserves as a percentage of the total external debt in Costa Rica from 1999 to 2021
tablecolumn chart
CharacteristicIn percent
202120.48
202023.13
201929.99
201826.44
201727.91
201629.63
201533.21
201436.57
201342.78
201247.91
201146.3
201056.75
200952.4
200843
200748.93
200644.57
200535.68
200433.67
200332.56
200229.63
200127.23
200028.09
199934.66
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World Bank. (May 10, 2023). Total reserves as a percentage of the total external debt in Costa Rica from 1999 to 2021 [Graph]. InStatista. Retrieved July 05, 2023, from https://www.statista.com/statistics/1390839/total-reserves-as-a-percentage-of-the-total-external-debt-costa-rica/
World Bank. "Total reserves as a percentage of the total external debt in Costa Rica from 1999 to 2021." Chart. May 10, 2023. Statista. Accessed July 05, 2023. https://www.statista.com/statistics/1390839/total-reserves-as-a-percentage-of-the-total-external-debt-costa-rica/
World Bank. (2023).Total reserves as a percentage of the total external debt in Costa Rica from 1999 to 2021.Statista. Statista Inc.. Accessed: July 05, 2023. https://www.statista.com/statistics/1390839/total-reserves-as-a-percentage-of-the-total-external-debt-costa-rica/
World Bank. "Total Reserves as a Percentage of The Total External Debt in Costa Rica from 1999 to 2021."Statista, Statista Inc., 10 May 2023, https://www.statista.com/statistics/1390839/total-reserves-as-a-percentage-of-the-total-external-debt-costa-rica/
World Bank, Total reserves as a percentage of the total external debt in Costa Rica from 1999 to 2021 Statista, https://www.statista.com/statistics/1390839/total-reserves-as-a-percentage-of-the-total-external-debt-costa-rica/ (last visited July 05, 2023)
Total reserves as a percentage of the total external debt in Costa Rica from 1999 to 2021 [Graph], World Bank, May 10, 2023. [Online]. Available: https://www.statista.com/statistics/1390839/total-reserves-as-a-percentage-of-the-total-external-debt-costa-rica/
| https://www.statista.com/statistics/1390839/total-reserves-as-a-percentage-of-the-total-external-debt-costa-rica/ |
Norman Rogers Airport Breathes New Life into Kingston | Airport Improvement Magazine
Norman Rogers Airport Breathes New Life into Kingston
Just as home rennovations turn life upside down for families, infrastructure projects complicate life for airport operators. Kingston’s Norman Rogers Airport (YGK) in eastern Ontario, Canada, worked dilligently to keep operations running smoothly for customers while completing $16 million of improvements spanning landside and airside areas alike.
Ultimately, the work scope included a 6,000-square-foot terminal expansion with renovations and extensions that added 1,000 feet to one of the airport’s two asphalt runways. Construction started in April 2018, and the expanded runway was operational in December 2018. The grand reopening of the terminal building occurred in July 2019.
Aron Winterstein, acting manager at YGK, explains that the overriding goal was to create a beautiful gateway to the picturesque place on the shores of Lake Ontario known as Limestone City.
facts&figuresProject:Expansion & RenovationLocation:Norman Rogers Airport – Kingston, ONOwner:City of Kingston2018 Passenger Volume:80,000Primary Projects:Extending runway; expanding & renovating terminalTotal Cost:$16.1 millionTimeline:Construction began April 2018; runway operational Dec. 2018; terminal grand reopening July 2019Key Runway Components:1,000-foot extension; new LED lighting; designed to meet Transport Canada TP312-5th editionKey Terminal Components:6,000 sq. ft. of new space; limestone wall art installation; elevator to 2nd floor; new departures loungeDesign/Builder:H.R. Doornekamp Construction Ltd.Architect:HDR Architecture Associates Inc.Civil, Structural, Mechanical & Electrical Engineer:EXP EngineersAirfield Lighting:Approach Navigation Systems Inc.Paving:Coco PavingRequired Fill for Runway Extensions:200,000 metric tonnes
“For this project, we had a significant focus on customer experience,” says Winterstein. “We’re making sure we have an efficient, modern facility that we can continue to use long into the future.”
Taking Off
The project focused on three main objectives: extending the primary runway, expanding the terminal building and enhancing the customer experience at YGK.
First, Runway 01-19 was extended from 5,000 to 6,000 feet. Project designers added 300 feet to the south end, and another 700 feet to the north. This work required approximately 200,000 metric tonnes of new granular material.
Winterstein explains that airport and city officials considered the extra runway length an essential component to help YGK stay connected to the world now and in the future. With a 6,000-foot runway, the airport is not only safer for small aircraft, it now has the capacity to bring in larger aircraft such as the Dash 8, Q400 and Boeing 737.
The construction team was tasked with building the runway extensions to meet Transport Canada’s new TP312-5th edition Aerodrome Standards and Recommended Practices. According to Jeff Simpson, project manager/estimator for design/builder H.R. Doornekamp Construction, several changes were incorporated between the fourth and fifth editions of the standard. Some of those changes include the types of paint markings required for short lines such as taxiway lines and new standards for runway signs. But the integrated design/build team, the city’s team and agencies including Transport Canada and NAV Canada worked together to make sure that the airfield project at YGK achieved compliance.
In addition to building the runway extensions, crews upgraded the instrument landing system with new technology and installed LED lighting.
Material Matters
Handling the massive amount of fill that was required for the north side of the runway extension proved to be a key challenge for the project team. Trucking in 200,000 metric tonnes of fill would have presented logistical and envrionmental challenges. So the team devised another way.
Instead of relying on trucks, H.R. Doornekamp transported the fill on barges that run along the shores of Lake Ontario. The fill came from the company’s quarry in Picton, which is about 37 miles west of the airport. Winterstein notes that this strategy was not only more efficient, but it also reduced the project’s greenhouse gas emissions by keeping a parade of trucks off the road.
Construction of the runway extensions was extended for about one year when the poor condition of existing power cabling for lighting and communications was detected early in the design and construction phases.
The city elected to incorporate additional upgrades to the primary electrical cabling for runway lighting, which involved the complete replacement of existing aging infrastructure that was previously identified to remain. In addition, a wireless system replaced some of the former communications lines.
Improving Facilities & Service
The terminal building, which was previously about 11,000 square feet, now stands at 17,000 square feet—an increase of approximately 54%.
Beyond expanding the physical size of the building, the city and airport focused on giving passengers a better overall experience at YGK. Jason-Emery Groen, vice president and design director of HDR Architecture Associates Inc., notes that the terminal expansion was designed not just for functionality, but also to give arriving passengers a sense of place.
“This is not just a building designed to get as many passengers to move through it as possible,” Groen explains. “We were thinking about how people will arrive in the city and what their first impression will be.”
Typically, when architects design such features, they leave it to the masons to install them according to drawings. However, in this case, Groen and his team arrived onsite daily to help lay the stones with the mason to ensure it would be assembled properly.
Planning Ahead
After the city issued the original concept design to design-builders potentially competing for the job, HDR and and H.R. Doornekamp determined that the construction sequencing could put work crews in the way of tarmac operations, which would prove complicated and expensive. That inspired a plan to expand the terminal laterally—extending west to east—and thus avoid protruding onto the tarmac. This way, Groen explains, if the city of Kingston wants to expand the terminal again, it can avoid dismantling the tarmac, which provides value well into the future.
“The city told us this is one of the reasons we won the project,” he notes.
As the acting airport manager, Winterstein acknowledges this was an important part of HDR’s bid. However, there is some dispute in his mind over who the real winner is at the end of the day. “This beautiful facility is a resource for our residents, and our region,” he remarks. “With the renovations behind us and new infrastructure in place, we are looking forward. YGK Airport is ready for takeoff.”
Subcategory:
Terminals
| https://airportimprovement.com/article/norman-rogers-airport-breathes-new-life-kingston?page=755 |
Fully gapped superconductivity and topological aspects of the noncentrosymmetric superconductor TaReSi | Request PDF
Request PDF | Fully gapped superconductivity and topological aspects of the noncentrosymmetric superconductor TaReSi | We report a study of the noncentrosymmetric TaReSi superconductor by means of the muon-spin rotation and relaxation (μSR) technique, complemented... | Find, read and cite all the research you need on ResearchGate
Fully gapped superconductivity and topological aspects of the noncentrosymmetric superconductor TaReSi
June 2023
DOI: 10.1103/PhysRevB.107.224504
Authors:
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Tian Shang
East China Normal University
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Jianzhou Zhao
Southwest University of Science and Technology
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Lunhui Hu
University of California, San Diego
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Dariusz Jakub Gawryluk
Paul Scherrer Institut
Abstract
We report a study of the noncentrosymmetric TaReSi superconductor by means of the muon-spin rotation and relaxation (μSR) technique, complemented by electronic band-structure calculations. Its superconductivity, with Tc=5.5K and upper critical field μ0Hc2(0)∼3.4T, was characterized via electrical-resistivity and magnetic-susceptibility measurements. The temperature-dependent superfluid density, obtained from transverse-field μSR, suggests a fully gapped superconducting state in TaReSi, with an energy gap Δ0=0.79meV and a magnetic penetration depth λ0=562nm. The absence of a spontaneous magnetization below Tc, as confirmed by zero-field μSR, indicates a preserved time-reversal symmetry in the superconducting state. The density of states near the Fermi level is dominated by the Ta- and Re-5d orbitals, which account for the relatively large band splitting due to the antisymmetric spin-orbit coupling. In its normal state, TaReSi behaves as a three-dimensional Kramers nodal-line semimetal, characterized by an hourglass-shaped dispersion protected by glide reflection. By combining nontrivial electronic bands with intrinsic superconductivity, TaReSi is a promising material for investigating the topological aspects of noncentrosymmetric superconductors.
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... Outstanding differences between absolute B c2 (T) values defined by different criteria were recently demonstrated in isotropic superconductor TaReSi by Shang et al.
[96]
, and for anisotropic superconductor LaFeAsO by Zhigadlo et al. [97], while the vanishing of the diamagnetic response [96][97][98][99] remains the most accurate criterion to determine the upper critical field. In regard to the B c2 (T) anisotropy, which is the topic of the study, different criteria of the B c2 (T) definition lead to not only different γ ξ (T) values, but also to the change in the function trend, i.e., decrease/increase type [97]. ...
... Outstanding differences between absolute B c2 (T) values defined by different criteria were recently demonstrated in isotropic superconductor TaReSi by Shang et al. [96], and for anisotropic superconductor LaFeAsO by Zhigadlo et al. [97], while the vanishing of the diamagnetic response
[96]
[97][98][99] remains the most accurate criterion to determine the upper critical field. In regard to the B c2 (T) anisotropy, which is the topic of the study, different criteria of the B c2 (T) definition lead to not only different γ ξ (T) values, but also to the change in the function trend, i.e., decrease/increase type [97]. ...
Intrinsic Coherence Length Anisotropy in Nickelates and Some Iron-Based Superconductors
Full-text available
Jun 2023
Evgeny F. Talantsev
Nickelate superconductors, R1−xAxNiO2 (where R is a rare earth metal and A = Sr, Ca), experimentally discovered in 2019, exhibit many unexplained mysteries, such as the existence of a superconducting state with Tc (up to 18 K) in thin films and yet absent in bulk materials. Another unexplained mystery of nickelates is their temperature-dependent upper critical field, Bc2(T), which can be nicely fitted to two-dimensional (2D) models; however, the deduced film thickness, dsc,GL, exceeds the physical film thickness, dsc, by a manifold. To address the latter, it should be noted that 2D models assume that dsc is less than the in-plane and out-of-plane ground-state coherence lengths, dsc<ξab(0) and dsc<ξc(0), respectively, and, in addition, that the inequality ξc(0)<ξab(0) satisfies. Analysis of the reported experimental Bc2(T) data showed that at least one of these conditions does not satisfy for R1-xAxNiO2 films. This implies that nickelate films are not 2D superconductors, despite the superconducting state being observed only in thin films. Based on this, here we propose an analytical three-dimensional (3D) model for a global data fit of in-plane and out-of-plane Bc2(T) in nickelates. The model is based on a heuristic expression for temperature-dependent coherence length anisotropy: γξ(T)=γξ(0)1−1a×TTc, where a>1 is a unitless free-fitting parameter. The proposed expression for γξ(T), perhaps, has a much broader application because it has been successfully applied to bulk pnictide and chalcogenide superconductors.
Unconventional superconductivity in topological Kramers nodal-line semimetals
Crystalline symmetry is a defining factor of the electronic band topology in solids, where many-body interactions often induce a spontaneous breaking of symmetry. Superconductors lacking an inversion center are among the best systems to study such effects or even to achieve topological superconductivity. Here, we demonstrate that TRuSi materials (with T a transition metal) belong to this class. Their bulk normal states behave as three-dimensional Kramers nodal-line semimetals, characterized by large antisymmetric spin-orbit couplings and by hourglass-like dispersions. Our muon-spin spectroscopy measurements show that certain TRuSi compounds spontaneously break the time-reversal symmetry at the superconducting transition, while unexpectedly showing a fully gapped superconductivity. Their unconventional behavior is consistent with a unitary (s + ip) pairing, reflecting a mixture of spin singlets and spin triplets. By combining an intrinsic time-reversal symmetry-breaking superconductivity with nontrivial electronic bands, TRuSi compounds provide an ideal platform for investigating the rich interplay between unconventional superconductivity and the exotic properties of Kramers nodal-line/hourglass fermions.
Time-Reversal Symmetry Breaking in Re-Based Superconductors: Recent Developments
Article
Full-text available
In the recent search for unconventional- and topological superconductivity, noncentrosymmetric superconductors (NCSCs) rank among the most promising candidate materials. Surprisingly, some of them—especially those containing rhenium—seem to exhibit also time-reversal symmetry (TRS) breaking in their superconducting state, while TRS is preserved in many other isostructural NCSCs. To date, a satisfactory explanation for such discrepant behavior, albeit crucial for understanding the unconventional superconductivity of these materials, is still missing. Here we review the most recent developments regarding the Re-based class, where the muon-spin relaxation (μSR) technique plays a key role due to its high sensitivity to the weak internal fields associated with the TRS breaking phenomenon. We discuss different cases of Re-containing superconductors, comprising both centrosymmetric- and noncentrosymmetric crystal structures, ranging from pure rhenium, to ReT (T = 3d-5d early transition metals), to the dilute-Re case of ReBe22. μSR results suggest that the rhenium presence and its amount are two key factors for the appearance and the extent of TRS breaking in Re-based superconductors. Besides summarizing the existing findings, we also put forward future research ideas regarding the exciting field of materials showing TRS breaking.
Kramers nodal line metals
Article
Full-text available
Recently, it was pointed out that all chiral crystals with spin-orbit coupling (SOC) can be Kramers Weyl semimetals (KWSs) which possess Weyl points pinned at time-reversal invariant momenta. In this work, we show that all achiral non-centrosymmetric materials with SOC can be a new class of topological materials, which we term Kramers nodal line metals (KNLMs). In KNLMs, there are doubly degenerate lines, which we call Kramers nodal lines (KNLs), connecting time-reversal invariant momenta. The KNLs create two types of Fermi surfaces, namely, the spindle torus type and the octdong type. Interestingly, all the electrons on octdong Fermi surfaces are described by two-dimensional massless Dirac Hamiltonians. These materials support quantized optical conductance in thin films. We further show that KNLMs can be regarded as parent states of KWSs. Therefore, we conclude that all non-centrosymmetric metals with SOC are topological, as they can be either KWSs or KNLMs. Chiral crystals with spin-orbit coupling (SOC) termed Kramers Weyl semimetals possess Weyl points at time-reversal invariant momenta. Here, the authors propose a new class of topological materials with doubly degenerate lines connecting time-reversal invariant momenta in achiral noncentrosymmetric materials with SOC.
Re1−xMox as an ideal test case of time-reversal symmetry breaking in unconventional superconductors
| https://www.researchgate.net/publication/371440201_Fully_gapped_superconductivity_and_topological_aspects_of_the_noncentrosymmetric_superconductor_TaReSi |
Arkansas Power & Light Co. v. Jennings, 258 Ark. 908, 529. S.W.2d 866 (1975) | Caselaw Access Project
Full text of Arkansas Power & Light Co. v. Jennings, 258 Ark. 908, 529. S.W.2d 866 (1975) from the Caselaw Access Project.
Arkansas Power & Light Co. v. Jennings, 258 Ark. 908, 529. S.W.2d 866 (1975)
Dec. 1, 1975 · Arkansas Supreme Court · 75-141
258 Ark. 908, 529. S.W.2d 866
Case outline
majority — john a. fogleman, justice.
Arkansas Power & Light Co. v. Jennings, 258 Ark. 908, 529. S.W.2d 866 (1975)
Dec. 1, 1975 · Arkansas Supreme Court · 75-141
258 Ark. 908, 529. S.W.2d 866
ARKANSAS POWER & LIGHT COMPANY v. Jennie D. JENNINGS
ARKANSAS POWER & LIGHT COMPANY v. Jennie D. JENNINGS
75-141
529. S.W. 2d 866
Opinion delivered December 1, 1975
*909 House, Holmes & Jewell,for appellant.
James M. McHaney, John C. Calhoun Jr.and Owens, McHaney & McHaney,for appellee.
John A. Fogleman, Justice.
Arkansas Power & Light Company took an 8.4791-acre strip of land for right-of-way through a 315-acre tract owned by Mrs.Jennie D. Jennings. The jury awarded the landowner $22,350 as just compensation. We find no reversible error on any of the four points relied upon by appellant. We will discuss them in the order they are presented by appellant.
THE TRIAL COURT ERRED IN PERMITTING APPELLEE TO INTRODUCE PROOF AS TO SPECIAL DAMAGES SUFFERED BY THE JENNINGS PROPERTY OUTSIDE THE RIGHT-OF-WAY WHEN THEY WERE NOT SPECIFICALLY PLED.
William B. Putnam testified for the landowner as an expert witness. One item of testimony which appellant found objectionable was to the effect that Putnam, upon measuring the right-of-way, found it to be 191 feet wide at one point, but meandering back into the 180-foot width described in the complaint. Appellant’s attorney objected upon the ground that appellee had not pleaded the taking of a wider right-of-way and that he did not know that this question was in issue. This objection was overruled and no other objection was made to this testimony. A second item to which appellant objected was testimony of K. E. Sorrels about the effect of the use of the right-of-way on the waters of Fletcher Creek which*910flowed through the Jennings tract. Appellant’s attorney again objected that this type of damage had not been specifically pleaded. When this objection was overruled, no further objection was made.
In neither instance did appellant plead surprise or move for a continuance to enable it to prepare to controvert the evidence after the objections made were overruled. Appellant’s principal reliance is placed upon Arkansas Louisiana Gas Co.v. Verser,251 Ark. 764,475 S.W. 2d 148. But there the condemnor not only objected, it moved for a mistrial and in the alternative for a continuance in order to prepare appropriate defenses. Even if we should say that these items were matters of special damage, the important consideration here is whether the appellant was taken by surprise and made a specific objection on that account. Fosterv. Arkansas State Highway Commission,258 Ark. 176,527 S.W. 2d 601(1975). In holding that there is no prejudicial error in admitting similar evidence in Arkansas Louisiana Gas Co.v. McGaughey Bros.,250 Ark. 1083,468 S.W. 2d 754, we said:
(omitting citations)
*** When the trial court permits the introduction of evidence in the face of an objection that the point at issue was not raised by the pleadings, the effect of the ruling is to treat the pleadings as amended to conform to the proof. *** So the trial court’s ruling here was equivalent to treating the issue as if it had been asserted by a pleading amended at that stage of the proceeding. The purpose of requiring special damages to be pleaded is to prevent surprise. *** If appellant had pleaded surprise, when its objection was overruled, it might have been entitled to a continuance, if an issue of special damages not pleaded had arisen, in order to prepare to meet it. *** But where no surprise is pleaded and no time requested to prepare to meet the issue, there is no error. ***
This language is peculiarly applicable here. In addition, Putnam did not attribute any particular amount of damage to any of these elements. He stated that the value of the Jen*911nings tract before the taking was $597,208 and after the taking $540,343, leaving a difference of $56,865. He assigned a value of $16,101 to the right-of-way taken by applying a value of $1,900 per acre to the acreage the power company claimed to have been taken, not some larger area. He considered the remaining lands to be diminished $40,754 in value due to the taking. He was never afforded an opportunity to specify the amount of damage he attributed to these elements appellant considers impermissible.1See Arkansas State Highway Commissionv. Woody,248 Ark. 657,453 S.W. 2d 45.
THE TRIAL COURT ERRED IN PERMITTING APPELLEE’S VALUE WITNESS TO COMPARE LOT SALES TO THE LANDOWNER’S 315 ACRE TRACT FOR THE PURPOSE OF ESTABLISHING VALUE.
The witness Putnam testified that the highest and best use of the Jennings property was as suburban subdivision development and stated that he had studied the “so-called” comparative sales in the vicinity of the Jennings property in using the market data approach to property evaluation. He felt there were sufficient sales in the vicinity to give a reasonable degree of comparison to the Jennings property. One of nine that he specifically mentioned was the sale of 90 acres by Douglas to Colbert. The testimony giving rise to this objection arose in this manner:
Q. I believe you have testified that this last piece of property that Mr. Robinson referred to here and here were being used now as suburban type dubdivision?
A. That is correct, two tracts have sold for Twenty Five Hundred Dollars an acre.
When objection was made because of the non-comparability of “two acres” to the 315-acre Jennings tract, Putnam testified on further examination that the Jennings*912property was in a higher state of development than the property involved in the Douglas-Colbert transaction, that there were no sewer or water lines serving the Colbert property and no development there which was not in existence on the Jennings property on the date of taking. Putnam expressed the opinion that on the date of the taking, the Jennings property had a value of $1,900 per acre.
Appellant argues that by overruling its objection, the court permitted the witness to compare lot sales to the entire Jennings tract in arriving at his opinion as to value. This testimony was not given as a basis of Putnam’s opinion as to value. It was brought out only in support of his testimony as to the highest and best use of the Jennings property — a matter which was in issue. The sale that he considered as a part of his market data was the sale of the entire 90-acre tract rather than the ¿wo five-acre lots. The 90-acre tract itself was only one of nine sales Putnam found to be sufficiently similar to the Jennings tract to warrant his consideration. These two transactions were not offered as independent evidence of the value of the Jennings property (which included some rugged terrain as well as a creek bed) or its value if sold in five-acre lots. Strangely enough, no objection was interposed when Putnam, in earlier testimony and in response to requests that he describe these sales that he considered to afford a basis for his opinion, had stated that five-acre tracts from the Colbert land had sold at $2,500 per acre and that lots of the same size had been sold at the same price by the purchaser in another sale he considered as a part of his market data. Furthermore, appellant did not, at any time, ask that the jury be admonished that this testimony could not be considered as evidence of value of the Jennings property or that any limiting instruction be given. This point affords no basis for a finding of prejudicial error. See Arkansas State Highway Commissionv. Sargent,241 Ark. 783,410 S.W. 2d 381; Arkansas Louisiana Gas Co.v. Verser,251 Ark. 764,475 S.W. 2d 148; Arkansas State Highway Commissionv. Person,258 Ark. 379,525 S.W. 2d 77(1975).
THE TRIAL COURT ERRED IN REFUSING TO ADMIT INTO EVIDENCE ALL THE FACTS SURROUNDING THE APPRAISAL MADE OF*913THE SUBJECT PROPERTY AT THE REQUEST OF THE EXECUTOR OF THE ZACK O. JENNINGS ESTATE.
The trial court refused to admit into evidence the Federal Estate Tax return of Zade O. Jennings, the late husband of appellee. Mr. Jennings died in 1972, and an estate tax was paid by his estate. Worthen Bank was the executor of his will. Louis East, who was called as a witness by appellant, made an appraisal as of July 31, 1972 for estate tax purposes. Appellant argues that, in addition to permitting the witness to state the values he assigned to the propeety when he made the appraisal, the court should have admitted the estate tax return and permitted East to state for whom he made the appraisal and for what purpose.
Cases cited by appellant holding that a valuation of property made by the owner for the purpose of taxation are inapposite, as are cases in which the evidence has been made admissible by statute. There is no evidence that Mrs. Jennings had anything to do with the valuation of the land or the selection of the appraiser, who was a former employee of the Worthen Bank.
The assessment or valuation of land for tax purposes by someone other than the owner is not admissible in evidence in Arkansas, in the absence of a statute. It was not error to exclude the return for estate taxes, because the determination of value by someone other than the owner for different purposes is not a fair criterion of its market value. Texas & St. Louis Railway Co.v. Eddy,42 Ark. 527; Springfield & Memphis Railway Co.v. Rhea,44 Ark. 258; St. Louis, I. M. & S. Ry. Co.v. Magness,93 Ark. 46,123 S.W. 786. These particular holdings relate to assessments for general taxation, and the rule on which they are based is well nigh universal as to valuations made by others than the owner, particularly in eminent domain cases. 5 Nichols on Eminent Domain 22-1, §22.1, and cases cited; Annot.39 ALR 2d 209, 214 (1955); 1 Orgel on Valuation under Eminent Domain 633, § 151. See e.g., Metteev. Urban Renewal Agency213 Kan. 787,518 P. 2d 555(1974); Murdockv. United States,160 F. 2d 358(8 Cir., 1947); Johnson and Wimsattv. Reichelderfer,60 U.S. App. D.C.*914186,50 F. 2d 336(Ct. Ap., D.C., 1931); Liennemanv. City of Omaha,191 Neb. 442,215 N.W. 2d 893(1974); Connecticut Printers, Inc.v. Redevelopment Agency,159 Conn. 407,270 A. 2d 549(1970); Statev. Griffith,292 Ala. 123, 290 S. 2d 162 (1974).
The rationale is frequently founded upon the basis that the valuation is res inter alios acta. 5 Nichols on Eminent Domain, 22-6, § 22.1; 1 Orgel on Valuation under Eminent Domain 634, §151 (1953); Metteev. Urban Renewal Agency,supra; Annot.39 ALR 2d 209, 228 (1955); Kansas City & G.R. Co.v. Haake,331 Mo. 429,53 S.W. 2d 891,84 ALR 1477(1932); Suffolk & Carolina Railway Co.v. Westend Land & Improvement Co.,137 N.C. 330,49 S.E.350,68 LRA 333,107 Am. St. Rep. 490(1904). It is sometimes based upon unreliability because of non-participation by the owner; Annot.39 ALR 2d 209, 225; See also, on unreliability, 1 Orgel on Valuation under Eminent Domain 629, §150; Statev. 45,621 Sq. Ft.,475 P. 2d 553(Alaska, 1970); sometimes as hearsay, Annot39 ALR 2d 209, 226.
Of course, the same rationale would require the application of the rule of exclusion to estate tax returns and probate valuations in eminent domain proceedings. Wherever the question has arisen it has been applied, sometimes in total reliance upon cases holding tax assessments inadmissible. See, Holmesv. State,109 N.H. 319,251 A. 2d 320(1969); City of LaMesav. Tweed & Gambrell Planing Mill,146 C.A. 2d 762,304 P. 2d 803(1956); Jonesv. Iowa State Highway Commission,259 Ia. 616,144 N.W. 2d 277(1966); United Statesv. 243.22 Acres,48 F.S. 177 ED, NY, (1942). We are not concerned with the situation that might prevail if questions had been asked value witnesses on cross-examination. The circuit judge certainly was not too restrictive in his ruling in this case.
THE TRIAL COURT ERRED IN GIVING DEFENDANT’S REQUESTED INSTRUCTION NO. 10.
This actually was a request by appellant for the submission of forms of verdict to the jury. The court instructed the jury to determine the amount of compensation to be paid for*915the lands taken and then to fix separately the amount of damages, if any, to appellee’s remaining lands. The objection made to the court’s submission of the issue was that this method was misleading and focused attention on damages to the remainder. No objection was offered by appellant to an instruction stating that the first question for the jury’s decision was the amount of just compensation due for the strip of land taken and the second was whether there was any resulting diminution in value of the remaining lands, and if so, the amount of money that would compensate the landowner for that damage.
Appellant now makes the additional argument that the instruction permitted the jury to compensate Mrs. Jennings twice for the same land, and relies upon Arkansas Power & Light Co.v. Mayo,244 Ark. 435,425 S.W. 2d 531. Frankly, we do not see how the jury could possibly have been misled. We find the case relied upon by appellant totally different from this one. There the court found (4-3) that a combination of two separate instructions could have been confusing to the jury. One of them was taken to mean that the condemnor was liable for the full value of the tract taken and the other told the jury that it should determine the fair market value of the property before the taking and then the fair market value after the taking and award the landowner the difference. Whatever inconsistencies existed there are absent here.
We do not see how this instruction unduly focused attention on damages to the remaining lands. The jury was told by the instruction that it should “decide whether there are damages to the remainder” and, ifit found that there were, to find the amount. The jury was further told that, if it found no damages to the remainder, it should write the word “None” in the blank provided for stating the amount of damages. We have previously held that similar instructions were not erroneous, where, as here, benefits are not to be offset against damages. Arkansas Louisiana Gas Co.v. Howell,244 Ark. 86,423 S.W. 2d 867. See St. Louis, I.M. & S. Ry. Co.v. Theodore Maxfield Co.,94 Ark. 135,126 S.W. 83; 26 LRA (n.s.) 1111; Pine Bluff & W. Ry. Co.v. Kelly,78 Ark. 83,93 S.W. 562. See also Youngv. Arkansas State Highway Commission,242 Ark. 812,*916415 S.W. 2d 575; Arkansas State Highway Commissionv. Morris,244 Ark. 1152,429 S.W. 2d 114.
The judgment is affirmed.
1
We do not pass on the question whether either or both of these elements were special damages. See, however. Arkansas State Highway Commissionv. Dixon,247 Ark. 130,444 S.W. 2d 571; Arkansas Louisiana Gas Co.v. McGaughey,supra; Fosterv. Arkansas State HighwayCommission, supra.
| https://cite.case.law/ark/258/908/ |
| A sample pipeline, that is, a "cheat sheet" of sorts for approaching... | Download Scientific Diagram
Download scientific diagram | | A sample pipeline, that is, a " cheat sheet" of sorts for approaching explainability. from publication: Principles and Practice of Explainable Machine Learning | Artificial intelligence (AI) provides many opportunities to improve private and public life. Discovering patterns and structures in large troves of data in an automated manner is a core component of data science, and currently drives applications in diverse areas such as... | Machine Learning, Artificial Intelligence and Data Science | ResearchGate, the professional network for scientists.
| A sample pipeline, that is, a "cheat sheet" of sorts for approaching explainability.
Source publication
Principles and Practice of Explainable Machine Learning
Article
Full-text available
Ioannis Papantonis
Artificial intelligence (AI) provides many opportunities to improve private and public life. Discovering patterns and structures in large troves of data in an automated manner is a core component of data science, and currently drives applications in diverse areas such as computational biology, law and finance. However, such a highly positive impact...
Citations
... The people who create AI systems, the decision-makers who use them, and those who are ultimately affected by the results of those decisions should all be considered (Arrieta et al. 2020). To effectively communicate with a wide range of audiences, precise and relevant explanations must be created
(Belle and Papantonis 2021)
. Future AI must include qualities like transparency, trustworthiness, and comprehensibility to be widely used. ...
... More knowledge or intuition is required to fully understand AI systems' inputs, operations, and outputs. Building stronger model-specific techniques is one area that could get more attention in the future
(Belle and Papantonis 2021)
. Exploring this avenue can produce ways to use a model's unique properties to provide explanations, perhaps boosting fidelity and enabling greater examination of the model's internal workings instead of only explaining its conclusion. ...
Human-centric and semantics-based explainable event detection: a survey
Full-text available
In recent years, there has been a surge of interest in Artificial Intelligence (AI) systems that can provide human-centric explanations for decisions or predictions. No matter how good and efficient an AI model is, users or practitioners find it difficult to trust it if they cannot understand the AI model or its behaviours. Incorporating explainability that is human-centric in event detection systems is significant for building a decision-making process that is more trustworthy and sustainable. Human-centric and semantics-based explainable event detection will achieve trustworthiness, explainability, and reliability, which are currently lacking in AI systems. This paper provides a survey on human-centric explainable AI, explainable event detection, and semantics-based explainable event detection by answering some research questions that bother on the characteristics of human-centric explanations, the state of explainable AI, methods for human-centric explanations, the essence of human-centricity in explainable event detection, research efforts in explainable event solutions, and the benefits of integrating semantics into explainable event detection. The findings from the survey show the current state of human-centric explainability, the potential of integrating semantics into explainable AI, the open problems, and the future directions which can guide researchers in the explainable AI domain.
... What is the trade-off between the explainability and performance of the AI model?
[16,
18,20,25,28,29] AI Use case Role and impact of AI What is the purpose of AI in the use case? [17,22,25,29,30,31] XAI system Use case Goal and approach of XAI system ...
... What is the purpose of XAI in the use case? [17,18,25 [10,
16,
17,18,19,20,24,26,27,29,36] Methods and techniques to evaluate XAI ...
A Conceptual Model for Implementing Explainable AI by Design: Results of an Empirical Study
Chapter
Full-text available
Artificial Intelligence (AI) offers organizations unprecedented opportunities. However, one of the risks of using AI is that its outcomes and inner workings are not intelligible. In industries where trust is critical, such as healthcare and finance, explainable AI (XAI) is a necessity. However, the implementation of XAI is not straightforward, as it requires addressing both technical and social aspects. Previous studies on XAI primarily focused on either technical or social aspects and lacked a practical perspective. This study aims to empirically examine the XAI related aspects faced by developers, users, and managers of AI systems during the development process of the AI system. To this end, a multiple case study was conducted in two Dutch financial services companies using four use cases. Our findings reveal a wide range of aspects that must be considered during XAI implementation, which we grouped and integrated into a conceptual model. This model helps practitioners to make informed decisions when developing XAI. We argue that the diversity of aspects to consider necessitates an XAI “by design” approach, especially in high-risk use cases in industries where the stakes are high such as finance, public services, and healthcare. As such, the conceptual model offers a taxonomy for method engineering of XAI related methods, techniques, and tools.
... The study reported the lowest user satisfaction with causal explanations and the highest levels of trust with intentional explanations, while mixed explanations led to the best functional understanding of the system. Related evaluation of understandability, usefulness, trustworthiness, informativeness, and satisfaction with explanations, generated with popular XAI methods (LIME [38], SHAP [39], and Partial Dependence Plots or PDP
[40]
) was conducted by [41], reporting higher satisfaction with global explanations with novice users compared to local feature explanations. Comparing the popular methods, PDP performed best on all evaluated criteria. ...
Assessing Perceived Trust and Satisfaction with Multiple Explanation Techniques in XAI-Enhanced Learning Analytics
Article
Full-text available
Vili Podgorelec
This study aimed to observe the impact of eight explainable AI (XAI) explanation techniques on user trust and satisfaction in the context of XAI-enhanced learning analytics while comparing two groups of STEM college students based on their Bologna study level, using various established feature relevance techniques, certainty, and comparison explanations. Overall, the students reported the highest trust in local feature explanation in the form of a bar graph. Additionally, master’s students presented with global feature explanations also reported high trust in this form of explanation. The highest measured explanation satisfaction was observed with the local feature explanation technique in the group of bachelor’s and master’s students, with master’s students additionally expressing high satisfaction with the global feature importance explanation. A detailed overview shows that the two observed groups of students displayed consensus in favored explanation techniques when evaluating trust and explanation satisfaction. Certainty explanation techniques were perceived with lower trust and satisfaction than were local feature relevance explanation techniques. The correlation between itemized results was documented and measured with the Trust in Automation questionnaire and Explanation Satisfaction Scale questionnaire. Master’s-level students self-reported an overall higher understanding of the explanations and higher overall satisfaction with explanations and perceived the explanations as less harmful.
... In addition to SHAP, we used the Local Interpretable Model-Agnostic Explanations (LIME). LIME is a model-agnostic technique that can explain the predictions of any black-box machine learning model, providing insights into the model's decision-making process at the individual prediction level, rather than offering only a global explanation of how the model works
(48)
. In this study, we applied the LIME framework to generate explanations for the CPM efficacy in a single patient under two different scenarios (preserved and impaired CPM). ...
... Third, it is worth mentioning that other protocols to measure CPM efficacy may yield different results. Fourth, although explanation provided by LIME is clinically relevant (58), LIME explanations are only local and may not generalize to other features or populations
(48)
. Finally, it is worth noting that the models developed in this study exhibit a high level of complexity, primarily due to the inclusion of a large number of features. ...
Exploratory analysis of 5 supervised machine learning models for predicting the efficacy of the endogenous pain inhibitory pathway in patients with musculoskeletal pain
Objectives:
The identification of factors that influence the efficacy of endogenous pain inhibitory pathways remains challenging due to different protocols and populations. We explored five machine learning (ML) models to estimate the Conditioned Pain Modulation (CPM) efficacy.
Design:
Exploratory, cross-sectional design.
Setting and participants:
This study was conducted in an outpatient setting and included 311 patients with musculoskeletal pain.
Methods:
Data collection included sociodemographic, lifestyle, and clinical characteristics. CPM efficacy was calculated by comparing the pressure pain thresholds before and after patients submerged their non-dominant hand in a bucket of cold water (cold-pressure test) (1-4 °C). We developed five ML models: decision tree, random forest, gradient-boosted trees, logistic regression, and support vector machine.
Main outcome measures:
Model performance were assessed using receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, precision, recall, F1-score, and the Matthews Correlation Coefficient (MCC). To interpret and explain the predictions, we used SHapley Additive explanation values and Local Interpretable Model-Agnostic Explanations.
Results:
The XGBoost model presented the highest performance with an accuracy of 0.81 (95% CI = 0.73 to 0.89), F1 score of 0.80 (95% CI = 0.74 to 0.87), AUC of 0.81 (95% CI: 0.74 to 0.88), MCC of 0.61, and Kappa of 0.61. The model was influenced by duration of pain, fatigue, physical activity, and the number of painful areas.
Conclusions:
XGBoost showed potential in predicting the CPM efficacy in patients with musculoskeletal pain on our dataset. Further research is needed to ensure the external validity and clinical utility of this model.
... Explainable AI (XAI) is the leading current approach within the AI community investigating how the decisions and actions of machines can be made explicable to human users (Gunning 2017;
Belle & Papantonis 2021)
. Core to this is the notion that transparency not only requires that the operation of the system be visible, but that it can provide comprehensible explanations as well. ...
... The vast majority of advances in XAI focus on the technical operation of AI (Arrieta et al. 2019, Belle and
Papantonis 2021)
(Belle and Papantonis, 2021)
6]
[23]
Belle and Papantonis, 2021)
(Belle and Papantonis, 2021;
Holzinger, 2018;Márquez-Chamorro et al., 2017). ...
(Belle and Papantonis, 2021;
Ribeiro et al., 2016). However, in many real-world scenarios, e.g., healthcare and finance, explanations of why a model gives certain predictions are sorely needed, while in other domains they would be at least useful (Holzinger, 2018). ...
... A criterion used to classify interpretability methods refers to the way in which the predictive model outcome is obtained. According to this criterion, the interpretability method can be local, if it explains the behavior of the predictive model for a given instance, or global, if it seeks to do it for the model as a whole
(Belle and Papantonis, 2021)
. A local interpretation method explains individual predictions (Ribeiro et al., 2016). ...
| https://www.researchgate.net/figure/A-sample-pipeline-that-is-a-cheat-sheet-of-sorts-for-approaching-explainability_fig8_352905892 |
Interventions to Increase Rescreening for Repeat Chlamydial Infection | Request PDF
Request PDF | Interventions to Increase Rescreening for Repeat Chlamydial Infection | Repeat infection with Chlamydia trachomatis following treatment is common and increases the risk of sequelae. Despite clinical guidelines... | Find, read and cite all the research you need on ResearchGate
Interventions to Increase Rescreening for Repeat Chlamydial Infection
Sexually Transmitted Diseases 39(2):136-46
DOI: 10.1097/OLQ.0b013e31823ed4ec
Abstract
Repeat infection with Chlamydia trachomatis following treatment is common and increases the risk of sequelae. Despite clinical guidelines recommending rescreening within 3 months of treatment, rescreening rates remain low. We undertook a systematic review to identify studies that compared rates of rescreening for repeat chlamydial infection between patients receiving and not receiving an intervention.
We searched Medline, EMBASE, and conference Web sites from 2000 to September 2010 using variations of the terms "chlamydia" and "rescreening" and "intervention." We used meta-analysis to calculate the overall relative risk (RR) effect on rescreening rates by study design and strategy type.
We identified 8 randomized controlled trials (RCTs) and 4 controlled observational studies, all conducted in the United States. Four RCTs assessed mailed screening kits ± reminders, with an average effect estimate of 1.30 (95% confidence interval [CI]: 1.01-1.50); 2 RCTs assessed motivational interviewing ± reminders with a summary effect of 2.15 (95% CI: 0.92-3.37); one RCT evaluated the effect of reminders with a RR of 9.67 (95% CI: 1.31-71.31), and another RCT assessed the effect of a $20 patient incentive with a RR of 1.16 (95% CI: 0.62-2.17). Three controlled observational studies assessed reminder strategies with RRs of 1.97 (95% CI: 1.76-2.21), 1.01 (95% CI: 0.66-1.55), and 1.88 (95% CI: 1.58-2.24)-a summary effect was not calculated due to significant heterogeneity; and one controlled observational study assessed the promotion of clinical guidelines with a RR of 1.35 (95% CI: 0.96-1.90).
The review suggests that the use of mailed screening kits is an important strategy to increase rescreening, reminder systems are promising, and motivational interviewing is worth investigation.
2.3+ billion citations
... There is evidence for the effectiveness of patient reminders in increasing screening and rescreening for priority STIs in STI clinic settings. 3,
12
Mailed screening kits were effective in increasing rescreening in two of the three studies assessing this intervention in STI clinics in a recent review. 12 Phone reminders showed inconclusive evidence for effectiveness. ...
... 3,12 Mailed screening kits were effective in increasing rescreening in two of the three studies assessing this intervention in STI clinics in a recent review.
12
Phone reminders showed inconclusive evidence for effectiveness. 12 The addition of mail screening kits to routine SMS reminders resulted in substantial improvements in chlamydia retesting rates and detection of more repeat positive tests, compared with SMS alone in a recent trial. ...
... 12 Phone reminders showed inconclusive evidence for effectiveness.
12
The addition of mail screening kits to routine SMS reminders resulted in substantial improvements in chlamydia retesting rates and detection of more repeat positive tests, compared with SMS alone in a recent trial. 13 A review assessing interventions to promote screening for bacterial STIs among MSM men 3 included one study in a sexual health clinic that assessed SMS reminders for repeat STI screening after an STI consultation among MSM. ...
.Evidence review for NSW Sexually Transmissible Infections (STI) Strategy: an Evidence Check rapid review brokered by the Sax Institute (www.saxinstitute.org.au) for the Centre for Population Health, NSW Ministry of Health,
Technical Report
Full-text available
Oct 2015
Gill Schierhout
Basil Donovan
Rebecca Guy
John Kaldor
This rapid review was commissioned by the Centre for Population Health, New South Wales (NSW) Ministry
of Health and the Sax Institute to inform the development of the NSW Sexually Transmissible Infections
Strategy 2016–2020. The focus of this review is on the effectiveness of interventions aiming to reduce the
transmission of Sexually Transmissible Infections (STIs) in different settings. Consistent with the developing
NSW STI strategy, this review focuses on interventions in relation to testing, treatment, partner notification
and prevention of re-infection of three priority STIs (chlamydia, gonorrhoea and syphilis), in five priority
settings (primary health care; sexual health services; Aboriginal Community Controlled Health Services;
antenatal services; and services for young people) for five priority populations (gay and other men who have
sex with men (MSM); gay men living with HIV; young people aged 16–29 years; Aboriginal and Torres Strait
Islander people and people involved in sex work). The review was also tasked with identifyin g evidence for
the effectiveness of interventions in additional settings (including but not limited to drug and alcohol
services, emergency departments, mental health services and correctional services).
... In the present study, we attempt to analyze which determinants are related to the low uptake of Chlamydia trachomatis (Ct) testing in a group of [16]
[17]
[18][19][20][21][22][23][24][25][26][27][28][29][30] year-old individuals drawn from the general population. It is hard to convince people to participate in Ct screening programs outside the clinical setting [1,2]. ...
... The current study is the third in a series of studies assessing Ct testing in [16]
[17]
[18][19][20][21][22][23][24][25][26][27][28][29] year olds in Limburg, the Netherlands. In our first study, we identified determinants of Ct screening behavior and reasons for nonparticipation [1]. ...
... Online interventions [15] and screening in primary care [16] may go some way towards increasing the number of people participating in screening programs. Focusing on rescreening positives
[17]
and clinicbased interventions [18] would fit well with our finding regarding the relevance of susceptibility. Making testing easier and reducing barriers [19,20] would be consistent with our findings on self-efficacy; while using social and sexual networks, for example to contact peers who have shown evidence of risky behavior, testing behavior, and Ct positivity [21], would be consistent with our findings on the relevance of both susceptibility and perceived norms. ...
Predictors of Chlamydia Trachomatis testing: Perceived norms, susceptibility, changes in partner status, and underestimation of own risk
Article
Full-text available
Jan 2016
BMC PUBLIC HEALTH
Gill Ten Hoor
Robert A C Ruiter
Jan Van bergen
Gerjo Kok
Background:
It is hard to convince people to participate in chlamydia screening programs outside the clinical setting. In two earlier studies (BMC Public Health. 2013;13:1091; J Med Internet Res. 2014;16(1):e24), we identified explicit and implicit determinants of chlamydia screening behavior and attempted, unsuccessfully, to improve participation rates by optimizing the recruitment letter. In the present study, we examined the links between a number of social-cognitive determinants (e.g., stereotypical beliefs about a person with chlamydia, intentions, changes in partner status), and self-reported chlamydia testing behavior six months after the initial study.
Methods:
The present study is a follow-up to our first study (T0). We assessed self-reported testing behavior 6 months after the first measure by means of an online questionnaire (T1; N = 269). Furthermore, at T1, we measured the social-cognitive determinants in more detail, and explored the influence of stereotypical beliefs and any changes in partner status during this six month period.
Results:
In total, 25 (9.1 %) of the participants tested for chlamydia at some point during the six months between baseline (T0) and follow up (T1). Testing behavior was influenced by testing intentions in combination with changes in risk behavior. The higher the participants' own numbers of partners ever, the higher they estimated the number of partners of the stereotypical person with chlamydia. Testing intentions were most strongly predicted by perceived norms and susceptibility, and having had multiple partners in the last 6 months (R(2) = .41).
Conclusion:
The most relevant determinants for testing intentions and behavior were susceptibility, subjective norms and changes in partner status. We found a systematic tendency for individuals to underestimate their own risk, especially the risk of inconsistent condom use. Future research should focus on more promising alternatives to population-based interventions, such as online interventions, screening in primary care, the rescreening of positives, and clinic-based interventions. This future research should also focus on making testing easier and reducing barriers to testing, as well as using social and sexual networks in order to reach more people.
... Mailed home collection kits have been demonstrated in a meta-analysis of controlled studies by Guy and colleagues, to increase retesting rates by an average of 30% (pooled effect estimate = 1.30; 95% CI: 1.10-1.50)
[48]
. The same meta-analysis showed reminder strategies including phone calls (+/-letters) and postcard reminders also resulted in a modest increase in rescreening. ...
... SMS reminders have the advantage of automation, convenience, confidentiality and immediacy [52] and have been found to be acceptable in the sexual health context [53,54]. Subsequent to the review by Guy et al.
[48]
, three Australian before-after studies have demonstrated that SMS reminders increase STI retesting rates in sexual health clinic patients [35,52,55]. ...
... One of the major problems in interpreting the findings from studies to date is suboptimal study designs. Many of the studies included in the review by Guy et al.
[48]
were evaluated using a before-after design and it is Figure 2 Algorithm to differentiate between chlamydia reinfection, treatment failure and persistent infection (adapted from Batteiger et al. [18] and Walker et al. [13]). N/A = Genotype result not available. ...
Rationale and design of REACT: A randomised controlled trial assessing the effectiveness of home-collection to increase chlamydia retesting and detect repeat positive tests
Article
Full-text available
BMC INFECT DIS
Kirsty S Smith
Marcus Y Chen
Jane Hocking
Rebecca Guy
Background:
Repeat infection with Chlamydia trachomatis is common and increases the risk of sequelae in women and HIV seroconversion in men who have sex with men (MSM). Despite guidelines recommending chlamydia retesting three months after treatment, retesting rates are low. We are conducting the first randomised controlled trial to assess the effectiveness of home collection combined with short message service (SMS) reminders on chlamydia retesting and reinfection rates in three risk groups.
Methods/design:
The REACT (retest after Chlamydia trachomatis) trial involves 600 patients diagnosed with chlamydia: 200 MSM, 200 women and 200 heterosexual men recruited from two Australian sexual health clinics where SMS reminders for retesting are routine practice. Participants will be randomised to the home group (3-month SMS reminder and home-collection) or the clinic group (3-month SMS reminder to return to the clinic). Participants in the home group will be given the choice of attending the clinic if they prefer. The mailed home-collection kit includes a self-collected vaginal swab (women), UriSWAB (Copan) for urine collection (heterosexual men), and UriSWAB plus rectal swab (MSM). The primary outcome is the retest rate at 1-4 months after a chlamydia diagnosis, and the secondary outcomes are: the repeat positive test rate; the reinfection rate; the acceptability of home testing with SMS reminders; and the cost effectiveness of home testing. Sexual behaviour data collected via an online survey at 4-5 months, and genotyping of repeat infections, will be used to discriminate reinfections from treatment failures. The trial will be conducted over two years. An intention to treat analysis will be conducted.
Discussion:
This study will provide evidence about the effectiveness of home-collection combined with SMS reminders on chlamydia retesting, repeat infection and reinfection rates in three risk groups. The trial will determine client acceptability and cost effectiveness of this strategy.
Trial registration:
Australian and New Zealand Clinical Trials Registry ACTRN12611000968976.
... However, uptake of repeat testing is generally low and the most effective way to increase the uptake is unknown. Guy et al. performed a systematic review and identified posting testkits as an important strategy to increase repeat testing uptake
[10]
. ...
... In a meta-analysis, it was found that mailing testkits is an effective strategy to increase rescreening, but also that telephone reminders are promising. Text messaging (SMS) has been found to have similar effects as letters and phone calls, but is much cheaper and easier to implement
[10]
. ...
... Automated SMS reminders should preferably be built-in to electronic patient registration systems. It has been demonstrated in various interventions that patients may choose different strategies depending on their personal circumstances
[10]
, hence personal preferences should be taken into account. However, providing good and accessible retest services is not the only way to reach a higher retest rate. ...
Retesting for genital Chlamydia trachomatis among visitors of a sexually transmitted infections clinic: Randomized intervention trial of home- versus clinic-based recall
Article
Full-text available
BMC INFECT DIS
Hannelore M Götz
Mireille E Wolfers
Ad Luijendijk
Ingrid V F van den Broek
Background
Reinfections of Chlamydia trachomatis (Ct) are common. In a two-armed intervention study at an urban STI clinic in the Netherlands, heterosexual Ct-positive visitors received an invitation for retesting after 4–5 months. Interventions were either home-based sampling by mailed test-kit, or clinic-based testing without appointment.
Methods
Data collection included socio-demographic and sexual behavioural variables at first (T0) and repeat test (T1). Participation in retesting, prevalence and determinants of repeat infection among study participants are described and compared with findings from non-participants.
Results
Of the 216 visitors enrolled in the study, 75 accepted retesting (35%). The retest participation was 46% (50/109) in the home group versus 23% (25/107) in the clinic group (p = 0.001). Men were less often retested than women (15% versus 43%, p < 0.001). The overall chlamydia positivity rate at retest was 17.3% (13/75) compared to 12.4% seen at all visits at the STI clinic in 2011. Repeated infections were more frequent among non-Dutch than Dutch participants (27.0% versus 7.9%; p = 0.04) and in persons reporting symptoms (31.0% versus 7.0%; p = 0.01). Both untreated infections of current partners as well as unprotected sex with new partners contribute to repeated infections.
Conclusion
The high rate of repeated infections indicates the need for interventions to increase retesting; improvement of partner-management and risk reduction counselling remain necessary. Home- based testing was more effective than clinic-based testing. However other strategies, including self-triage of patients, may also increase repeat testing rates and personal preferences should be taken into account.
... Overall, the test rate can be considered moderate when compared with other studies that have used active recall or home-collection testing, with testing rates in these studies ranging from 3-48%
[11]
. It should be noted that direct comparisons are difficult to make, as retest rates differ by sex, age and the approach taken. ...
... It is unknown to what extent retesting rates were underestimated in the current study, as a proportion of patients may have undergone screening of their own volition, either at our clinic or at other health services. Previous studies have demonstrated a lower positivity rate in those who retest following active recall as compared to retesting without active recall, and it has been suggested that interventions to encourage rescreening may (also) reach patients at lower risk of re-infection
[11]
. ...
Acceptance of Home-Based Chlamydia Genital and Anorectal Testing Using Short Message Service (SMS) in Previously Tested Young People and Their Social and Sexual Networks
Article
Full-text available
PLOS ONE
Kevin Theunissen
Petra F G Wolffs
Christian Hoebe
Background:
Control strategies for Chlamydia trachomatis (CT) are most effective when targeting people at highest risk. We assessed test acceptance of home-collection test kits offered by short messaging services (SMS) texts, in high-risk young people, i.e. those who had previously tested CT positive (positive indices), or negative reporting more than 3 sex partners (negative indices), and their sexual and social networks.
Methods:
Young (16 to 25 years old) heterosexuals who previously tested positive (n=536) or negative (n=536) in our STI clinic received, 3 to 20 months after their initial screening, an SMS inviting them to re-test. They were offered a free home-collection test kit including a genital (men and women) and anorectal (women only) test, and a test kit to pass on to a friend or sex partner (peer). SMS reminders were sent in case of non-response. We assessed proportions of tests requested and returned, peers tested, and positivity. Associations with the individual's initial screening result and other factors were explored using logistic regression.
Results:
Of 1072 people invited to retest, 34.4% (n=369) requested a test. Of these, 55.8% (n=206) retested. Overall, retest participation was higher in positive (22%) than in negative indices (16%) (p<0.001); it was also higher in women and in those aged >22 years. Positivity was 13% and 7% in positive and negative indices, respectively. One in 3 retesters also had a peer tested. Of tested peers (n=87), 84% were friends, 31% were first-time testers, and 7% tested positive.
Conclusion:
Acceptance of a relatively low-cost strategy for genital and anorectal testing, i.e. using SMS and home-collection test kits, was highest in individuals who previously tested CT positive suggesting that implementation for this group may be considered. By further including a peer-led testing component, undetected CT positives can be identified in the social networks surrounding a high-risk individual.
... The five that were not peerreviewed were a national public health report [13], a letter to an editor [14], a PhD thesis [15], a conference paper [16] and a poster [17]. Two of the articles that cited the guidance were part of the wider ECDC chlamydia control project [4,18], and a further three were self-citations by authors of the guidance [19][20]
[21]
. All but three of the articles reported studies conducted in a high-income setting, the others being Sudan [22], Russia [23] and Nigeria [24]. ...
... All other studies cited the guidance as a secondary reference to background information about chlamydia epidemiology and natural history. [13,14,16,
[21]
[22][23][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] 'Chlamydia is the commonest curable sexually transmitted infection (STI) in Europe and the United States.' (Booth, 2014) Chlamydia as a public health concern (n=3) [14,17,44] 'Left untreated infection can have serious consequences, such as ectopic pregnancy and infertility in women and epididymitis and reactive arthritis in men.' (Jennison, 2011) Cost of chlamydia or cost effectiveness of screening (n=3) [22,45,46] 'Estimates of the probability of late sequelae of chlamydial infection, including TFI, impact upon the cost effectiveness of chlamydial screening programmes.' (Kavanagh, 2013) Screening as a method of reducing transmission or morbidity (n=8) [20,24,34,[46][47][48][49][50] 'In many developed countries, screening programmes for Chlamydia have been set up to reduce transmission and reproductive tract morbidity.' (Mawak, 2011) Type of information References Examples Criteria for screening (n=2) [40,46] 'In England the recommendation [for annual screening] applies to women aged 24 or less.' (Oakeshott, 2011) Study informed/used same methods/linked to launch of guidance (n=4) [4,18,19,51] The approach to control (n=5) [15,26,32,33,36] 'The current levels of chlamydia control in the Republic of Ireland correspond most closely with Level A and Level B, as outlined in the ECDC Guidance on Chlamydia control in Europe.' (Balfe, 2012) Control activities in specific countries (n=6) [6,40,42,[52][53][54] 'Clinical guidelines in many countries recommend annual CT screening for all sexually active young women and extend to young men in some countries.' ...
Chlamydia control in Europe - Qualitative evaluation of the impact of the 2009 ECDC guidance document Chlamydia control in Europe
Technical Report
Full-text available
Jan 2015
ECDC
Helen Ward
Bethan Davies
Minttu M Rönn
... A recent systematic review demonstrated phone reminders, and home-based selfcollection kits are effective at increasing retesting, while further evaluation of motivational interviewing and SMS reminders is warranted.
31
Our analysis also demonstrated opportunities where retesting rates could be easily increased at GP clinics. First, in 1.5e4 and 1.5e12 months after a positive test, an additional 32% and 40% of individuals, respectively, re-attended the same clinic but were not retested. ...
... Men attending the GP clinics had lower retesting rates than women, which is consistent with previous studies and probably reflective of lower healthcare-seeking behaviour among men in general.
31
As demonstrated in our analysis, men were less likely to re-attend after a positive test by 4 and 12 months, and among those that did re-attend, men attended fewer times than women. These data suggest that different strategies for men and women may be needed to optimise retesting rates. ...
Missed opportunities - Low levels of chlamydia retesting at Australian general practices, 2008-2009
Article
Full-text available
Mar 2012
SEX TRANSM INFECT
Anna Bowring
Maelenn Gouillou
Rebecca Guy
Margaret Hellard
Chlamydia reinfection is common and increases the risk of reproductive complications. Guidelines for Australian general practitioners recommend retesting 3-12 months after a positive result but not before 6 weeks. The authors describe retesting rates among 16-29-year-old patients diagnosed as having chlamydia at 25 general practice clinics participating in the Australian Collaboration for Chlamydia Enhanced Sentinel Surveillance system.
The authors calculated annual testing and positivity rates for 16-29-year-olds attending in 2008-2009, re-attendance and retesting rates within <6 weeks, 1.5-4 months and 1.5-12 months of a positive test in 2008-2009 and positivity at retest (where results were available). Results There were 50,408 individuals (60.4% women) who attended in 2008-2009. Annually, 7.4% and 7.3% were tested for chlamydia, of whom 9.1% and 8.0% tested positive, respectively. Within 1.5-4 months of a positive test, 24.6% re-attended and were retested (19% tested positive), 31.6% re-attended and were not retested and 43.9% did not re-attend. Within 1.5-12 months, 40% re-attended and were retested (16% tested positive), 40% re-attended and were not retested and 20% did not re-attend. Of individuals re-attending in 1.5-12 months but not retested, 50% had re-attended three or more times in the period. Within 6 weeks of a positive test, 25% were retested.
A high proportion of 16-29-year-olds re-attended general practices in the recommended retest periods, but retesting rates were low and multiple missed opportunities were common. The findings highlight the need for strategies such as electronic clinician prompts, patient recall systems and promotion of retesting guidelines.
... Besides, the review identified two RCT assessing the effect of motivational interview with or without reminders, one RCT assessing the effect of patient incentive ($20) and one observational study assessing the effect of the promotion of clinical guideline. However, the effectiveness of these strategies could not be supported by these included studies
23
was high (9.1-9.5%) 33,34 . ...
A Systematic Literature Review of Reviews on the Effectiveness of Chlamydia Testing
Article
Jan 2019
WCW Wong
STH Lau
EPH Choi
JM Saunders
Chlamydia trachomatis is the most common bacterial sexually transmitted infection, causing significant morbidity and economic burden. Strategies like national screening programs or home-testing kits were introduced in some developed countries, yet their effectiveness remains controversial. In this systematic review, we examined reviews of chlamydia screening interventions to assess their effectiveness and the elements that contribute to their success to guide public policy and future research. We assessed English material published after 2000 in PubMed, the Cochrane Library, the British Nursing Index, Medical Database, and Sociological Abstracts, in addition to World Health Organization Global Health Sector Strategies, the European Center for Disease Prevention and Control guidelines, and the Prospective Register of Systematic Reviews. Systematic reviews that focused on chlamydia screening interventions were included. Using the socioecological model, we examined the levels of interventions that may affect the uptake of chlamydia screening. A total of 19 systematic reviews were included. Self-collection in home-testing kits significantly increased screening among girls and women 14-50 years of age. At the organizational level, using electronic health records and not creating additional costs facilitated testing. At the community level, outreach interventions in community and parent centers and homeless shelters achieved high screening rates. At the policy level, interventions with educational and advisory elements could result in significant improvements in screening rates.
... These findings are consistent with reports from other jurisdictions. 15-21 Notwithstanding pilot projects demonstrating potential interventions to increase repeat chlamydia testing, [22]
[23]
[24][25][26] substantial work still needs to be done to translate guideline recommendations into routine practice. ...
Temporal Patterns in Chlamydia Repeat Testing in Massachusetts
Article
Mar 2019
AM J PREV MED
Elizabeth C. Dee
Katherine Hsu
Benjamin A Kruskal
Michael Klompas
Introduction:
National guidelines recommend test-of-cure for pregnant women and test-of-reinfection for all patients with chlamydia infections in order to interrupt transmission and prevent adverse sequelae for patients, partners, and newborns. Little is known about retesting and positivity rates, and whether they are changing over time, particularly in private sector practices.
Methods:
Electronic health record data on patients with chlamydia tests were extracted from three independent clinical practice groups serving ≅20% of the Massachusetts population. Records were extracted using the Electronic medical record Support for Public Health platform (esphealth.org). These data were analyzed for temporal trends in annual repeat testing rates by using generalized estimating equations after index positive chlamydia tests between 2010 and 2015 and for differences in intervals to first repeat tests among pregnant females, non-pregnant females, and males. Data extraction and analysis were performed during calendar years 2017 and 2018.
Results:
An index positive C. trachomatis result was identified for 972 pregnant female cases, 10,309 non-pregnant female cases, and 4,973 male cases. Test-of-cure 3-5 weeks after an index positive test occurred in 37% of pregnant females. Test-of-reinfection 8-16 weeks after an index positive test occurred in 39% of pregnant females, 18% of non-pregnant females, and 9% of males. There were no significant increases in test-of-cure or test-of-reinfection rates from 2010 to 2015. Among cases with repeat tests, 16% of pregnant females, 15% of non-pregnant females, and 16% of males had positive results.
Conclusions:
Chlamydia test-of-cure and test-of-reinfection rates are low, with no evidence of improvement over time. There are substantial opportunities to improve adherence to chlamydia repeat testing recommendations.
... 7,9,34 Strategies to improve adherence to repeat testing could include standing orders, phone reminders, and mailed screening test kits. [35]
[36]
[37] Low condom use among young women at risk for STIs highlights the importance for health promotion and program activities to emphasize dual prevention of STI and unintended pregnancy. 38 A flexible and comprehensive approach to STI prevention is needed to address high rates of repeat infections among women. ...
High Rates of Repeat Chlamydial Infections Among Young Women-Louisiana, 2000-2015
Article
Full-text available
Aug 2018
SEX TRANSM DIS
Susan Cha
Dan Newman
Mohammad Rahman
Thomas A Peterman
Background:
Chlamydial infections are common among young women and can lead to serious reproductive health complications. We assessed the risk of reported repeat chlamydial infection among young women in Louisiana and time interval between infections by age and race/ethnicity.
Methods:
We analyzed surveillance data on chlamydial infections reported among women in Louisiana from January 1, 2000 to December 31, 2015. Multiple reports for the same person were matched using unique codes. Chlamydial infections reported more than 30 days after a previous positive test were considered new infections. Women aged 15-34 years at first infection during 2000-2012 were censored after three years or after they had a repeat infection. Cumulative incidence and incidence rate of repeat chlamydial infection among women were determined by year of first infection. Race- and age-specific results were obtained using stratified analyses.
Results:
One in four women diagnosed with a chlamydial infection at 15-34 years of age in Louisiana had a reported repeat infection in three years or less. Risk of repeat infection increased for younger women, racial/ethnic minorities, and women in more recent cohorts. Young black women aged 15-19 years in 2012 had the highest risk (44%). Black women also had shorter intervals between infections than white women.
Conclusions:
Repeat chlamydial infections were common, especially among young black women. The true number is likely higher because surveillance data only count infections that were detected and reported. Comprehensive prevention strategies are needed to address high rates of repeat chlamydial infections among women.
... In-home self-collected specimens may increase the utilization of anatomic site-specific testing for CT and NG infections. As public health professionals promote patients' self-collection of specimens as part of STI testing, in-home self-collected specimens that can be mailed to the laboratory by the patient represents a critical step forward in ensuring high-risk patients have access to regular STI testing [6][7][8]
[9]
. ...
Comparing mail-in self-collected specimens sent via United States Postal Service versus clinic-collected specimens for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae in extra-genital sites
Article
Full-text available
Dec 2017
PLOS ONE
Katheryn R. Salow
Adam Carl Cohen
Claire C Bristow
Jeffrey Klausner
Objectives
To evaluate the concordance between clinic-collected extra-genital specimens and self-collected mailed-in extra-genital specimens among participants seeking sexually transmitted infection testing at a free clinic in Hollywood, CA.
Methods
A convenience sample of 210 men who have sex with men were enrolled between February 29, 2016 and December 21, 2016 and received mail-in testing kits for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG). All testing was performed using the GeneXpert® CT/NG (Cepheid, Sunnyvale, CA).
Results
From the 210 mail-in kits distributed, 149 mail-in kits (71.0%) were returned to the laboratory, resulting in 145 pairs (clinic-collected and mail-in) of rectal test results and 148 pairs of pharyngeal test results for both CT and NG detection. The concordance was 95.0% for all CT rectal tests, 99.3% for all CT pharyngeal tests, 95.7% for all NG rectal tests, and 97.2% for all NG pharyngeal tests.
Conclusion
Roughly two-thirds of mail-in test kits were returned and concordance was generally high, however more than one-third of positive results were missed in mail-in samples. The prevalence of potential false-negative results among mail-in samples warrants caution when implementing mail-in STI testing strategies.
... 10 A systematic review found that reminders and postal screening kits could increase retesting rates by 80% and 25%, respectively.
11
Recently Desai et al 6 also found that home sampling and SMS reminders appeared to increase retesting, but the range was wide and the evidence limited by study heterogeneity. Studies in Australia indicated that SMS reminders increased retesting rates and that an additional financial incentive did not increase rates further. ...
An observational study to evaluate three pilot programmes of retesting chlamydia-positive individuals within 6 months in the South West of England
Article
Full-text available
Oct 2015
Georgina Nicole Angel
Patrick J Horner
Norah O'Brien
Katherine Mary Elizabeth Turner
Objectives
To evaluate 3 pilot chlamydia retesting programmes in South West England which were initiated prior to the release of new National Chlamydia Screening Programme (NCSP) guidelines recommending retesting in 2014.
Methods
Individuals testing positive between August 2012 and July 2013 in Bristol (n=346), Cornwall (n=252) and Dorset (n=180) programmes were eligible for inclusion in the retesting pilots. The primary outcomes were retest within 6 months (yes/no) and repeat diagnosis at retest (yes/no), adjusted for area, age and gender.
Results
Overall 303/778 (39.0%) of participants were retested within 6 months and 31/299 (10.4%) were positive at retest. Females were more likely to retest than males and Dorset had higher retesting rates than the other areas.
Conclusions
More than a third of those eligible were retested within the time frame of the study. Chlamydia retesting programmes appear feasible within the context of current programmes to identify individuals at continued risk of infection with relatively low resource and time input.
... Review articles summarizing interventions to improve STD screening were used to obtain additional studies for inclusion. [18]
[19]
[20][21] Additional inclusion criteria were publication in the English language and analysis using a control group or a before-and-after comparison. Analyses published as meeting proceedings or in conference abstracts were excluded. ...
Interventions to Improve Sexually Transmitted Disease Screening in Clinic-Based Settings
Article
Full-text available
Jun 2015
SEX TRANSM DIS
Melanie Taylor
Jessica Frasure-Williams
Phyllis Burnett
Ina U Park
Background:
The asymptomatic nature and suboptimal screening rates of sexually transmitted diseases (STD) call for implementation of successful interventions to improve screening in community-based clinic settings with attention to cost and resources.
Methods:
We used MEDLINE to systematically review comparative analyses of interventions to improve STD (chlamydia, gonorrhea, or syphilis) screening or rescreening in clinic-based settings that were published between January 2000 and January 2014. Absolute differences in the percent of the target population screened between comparison groups or relative percent increase in the number of tests or patients tested were used to score the interventions as highly effective (>20% increase) or moderately effective (5%-19% increase) in improving screening. Published cost of the interventions was described where available and, when not available, was estimated.
Results:
Of the 4566 citations reviewed, 38 articles describing 42 interventions met the inclusion criteria. Of the 42 interventions, 16 (38.1%) were categorized as highly effective and 14 (33.3%) as moderately effective. Effective low-cost interventions (<$1000) included the strategic placement of specimen collection materials or automatic collection of STD specimens as part of a routine visit (7 highly effective and 1 moderately effective) and the use of electronic health records (EHRs; 3 highly effective and 4 moderately effective). Patient reminders for screening or rescreening (via text, telephone, and postcards) were highly effective (3) or moderately effective (2) and low or moderate cost (<$1001-10,000). Interventions with dedicated clinic staff to improve STD screening were highly effective (2) or moderately effective in improving STD screening (1) but high-cost ($10,001-$100,000).
Conclusions:
Successful interventions include changing clinic flow to routinely collect specimens for testing, using EHR screening reminders, and reminding patients to get screened or rescreened. These strategies can be tailored to different clinic settings to improve screening at a low cost.
... A recent meta-analysis
29
demonstrated that phone calls, letters, postcard reminders, and home collection kits resulted in modest increases in chlamydia retesting. As the majority of Australians have a mobile phone 30 and messages are inexpensive, immediate, and can be automated, 31 using short message service (SMS) to remind people to return for retesting is a potentially effective strategy. ...
Dual Intervention to Increase Chlamydia Retesting
Article
Jul 2015
AM J PREV MED
Kirsty S Smith
Jane Hocking
Marcus Y Chen
Rebecca Guy
Introduction Chlamydia retesting 3 months after treatment is recommended to detect reinfections, but retesting rates are typically low. The purpose of this study is to determine if the addition of a postal home collection kit to a short message service (SMS) reminder at 3 months increases the percentage of patients retested for chlamydia at 1–4 months, compared to SMS alone. Design In this unblinded randomized controlled trial, participants were randomized 1:1 to intervention (home arm) or control (clinic arm) status. Setting/participants Participants included 200 each of women, heterosexual men, and men who have sex with men diagnosed and treated for chlamydia at sexual health services. Intervention Three months after chlamydia diagnosis, home arm participants received an SMS reminder and postal home collection kit (women, vaginal swab; heterosexual men, Copan UriSwab; men who have sex with men, UriSwab and rectal swab). Main outcome measures The main outcome measures were the percentage of participants retested at 1–4 months after chlamydia diagnosis and the percentage in each arm with repeat positive tests, by risk group and overall, analyzed by intention to treat. Data were collected from 2011 to 2013 and analyzed in 2014. Results The percentage retested within 1–4 months of chlamydia diagnosis was significantly higher in home versus clinic arm participants among women (64% [66/103] vs 39% [38/97], p p =0.002); men who have sex with men (62% [61/98] vs 44% [45/102], p =0.010); and overall (61% [184/302] vs 39% [117/298], p p =0.021) and overall (10% [31/302] vs 4% [12/298], p =0.006). Conclusions The addition of a postal home collection kit to routine SMS reminders resulted in substantial improvements in chlamydia retesting rates in all three risk groups and detection of more repeat positive tests, compared with SMS alone. Extending the intervention to other primary care settings with low retesting rates should be considered.
... Prospective longitudinal studies of the same individuals 5 can almost never be incorporated into routine national surveillance due to cost, and retrospective cohorts are currently not feasible as levels of repeat testing are low in the general population.
6
An alternative approach to direct measurement is to infer prevalence and incidence by using all relevant and available data coupled with a quantitative framework which links these data to the epidemiological indicators. This epidemiological modelling approach is appealing because it does not require additional primary data collection, is not costly and can produce estimates that can be applied repeatedly every year. ...
A new approach to estimating trends in chlamydia incidence
Article
Full-text available
Jan 2015
Hammad Ali
E. Cameron
Christopher C. Drovandi
David P Wilson
Directly measuring disease incidence in a population is difficult and not feasible to do routinely. We describe the development and application of a new method for estimating at a population level the number of incident genital chlamydia infections, and the corresponding incidence rates, by age and sex using routine surveillance data.
A Bayesian statistical approach was developed to calibrate the parameters of a decision-pathway tree against national data on numbers of notifications and tests conducted (2001-2013). Independent beta probability density functions were adopted for priors on the time-independent parameters; the shapes of these beta parameters were chosen to match prior estimates sourced from peer-reviewed literature or expert opinion. To best facilitate the calibration, multivariate Gaussian priors on (the logistic transforms of) the time-dependent parameters were adopted, using the Matérn covariance function to favour small changes over consecutive years and across adjacent age cohorts. The model outcomes were validated by comparing them with other independent empirical epidemiological measures, that is, prevalence and incidence as reported by other studies.
Model-based estimates suggest that the total number of people acquiring chlamydia per year in Australia has increased by ∼120% over 12 years. Nationally, an estimated 356 000 people acquired chlamydia in 2013, which is 4.3 times the number of reported diagnoses. This corresponded to a chlamydia annual incidence estimate of 1.54% in 2013, increased from 0.81% in 2001 (∼90% increase).
We developed a statistical method which uses routine surveillance (notifications and testing) data to produce estimates of the extent and trends in chlamydia incidence.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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... In the consultation phase we emphasized to health services the importance of the cross-over design to ensure long term policy change and funding. Finally, repeat positivity rates are calculated from those who re-tested and these need to be similar in both POC and non-POC arms to minimize biaseslower re-testing rates are often associated with higher repeat positivity due to re-testing in those with symptoms
[53]
. To mimimise any imbalance in retesting rates, a quality improvement program and incentives associated with re-testing have been provided in both arms. ...
A randomised trial of point-of-care tests for chlamydia and gonorrhoea infections in remote Aboriginal communities: Test, Treat ANd GO- the “TTANGO” trial protocol
Article
Full-text available
Oct 2013
BMC INFECT DIS
Lisa Natoli
James Ward
John Kaldor
Rebecca Guy
Background:
High prevalence rates of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) have been reported in Aboriginal people in remote and regional areas of Australia for well over two decades, and repeat positivity rates are high. To interrupt disease transmission and reduce the risk of complications, early diagnosis and treatment is important. However in many remote and regional areas there are long delays between testing for these curable sexually transmissible infections and providing treatment, due to both physical distance from laboratories and difficulties when recalling patients for subsequent management once results are available. Point-of-care (POC) tests have the potential to provide more timely diagnosis, to increase treatment and contact tracing, and in turn reduce CT and NG infection rates.
Methods/design:
TTANGO (Test, Treat, ANd GO) is a cross-over cluster randomised controlled trial in 12 regional or remote Australian health services, which predominantly provide clinical services to Aboriginal people. The overall aim of TTANGO is to measure the clinical effectiveness, cost-effectiveness and cultural and operational acceptability of molecular POC testing for CT and NG infection. The primary outcome is repeat positivity at three months after treatment of an initial CT or NG infection. Participating health services will undertake the clinical management of CT and NG under two different modalities for one year each. In the first year, six health services will be randomly assigned to manage these infections under current diagnostic guidelines. The other six will supplement current diagnostic guidelines with POC testing, whereby diagnosis is made and subsequent treatment for those with positive POC tests is offered at the initial consultation. In the second year, the health services will cross over to the opposite management modality. TTANGO will be conducted over four years; 1.5 years of trial initiation and community consultation, 2 years of trial conditions and evaluation, and 6 months of data analysis and feedback.
Discussion:
TTANGO is the first cluster randomised trial of POC testing for CT and NG internationally. The results of this trial will provide crucial information to guide sexual health clinical practice in remote Aboriginal communities and other high prevalence settings.
Trial registration:
Australian and New Zealand Clinical Trials Registry ACTRN12613000808741.
... A recent systematic review found that mailed selfcollected specimen test kits increased retesting rates by an average of 30% (pooled effect estimate = 1.30; 95% CI: 1.01-1.50)
[176]
. ...
Advances in sampling and screening for chlamydia
Article
Mar 2013
FUTURE MICROBIOL
Jane Hocking
Rebecca Guy
Jennifer McIntosh
Sepehr Tabrizi
Chlamydia is the most commonly diagnosed bacterial sexually transmitted infection in the developed world, with diagnosis rates continuing to increase each year. As chlamydia is largely asymptomatic, screening and treatment is the main way to detect cases and reduce transmission. Recent advances in self-collected specimens and laboratory tests has made chlamydia screening easier to implement as well as possible in nonclinical settings. This review will discuss new approaches to specimen collection and how these have expanded opportunities for reaching target populations for chlamydia screening. Furthermore, it will discuss how advanced molecular microbiological methods can be used with self-collected specimens to further our knowledge of the epidemiology of chlamydia and the dynamics of transmission.
... Chlamydia control policy must include a focus on reducing re-infection through both increased re-testing at 3 months and improved partner notification. A recent systematic review found that mailed screening kits and reminder systems can be effective at increasing re-testing
[32]
both of which would be feasible in general practice with appropriate training and support. The higher organism load in prevalent compared with incident infections including re-infections, is difficult to interpret because infections diagnosed at recruitment would have included both recently acquired and infections of over 12 months duration. ...
Chlamydia trachomatis Incidence and Re-Infection among Young Women – Behavioural and Microbiological Characteristics
Article
Full-text available
May 2012
PLOS ONE
Jennifer McIntosh
Sepehr Tabrizi
Christopher Fairley
Jane Hocking
This study aimed to estimate rates of chlamydia incidence and re-infection and to investigate the dynamics of chlamydia organism load in prevalent, incident and re-infections among young Australian women.
1,116 women aged 16 to 25 years were recruited from primary care clinics in Australia. Vaginal swabs were collected at 3 to 6 month intervals for chlamydia testing. Chlamydia organism load was measured by quantitative PCR.
There were 47 incident cases of chlamydia diagnosed and 1,056.34 person years of follow up with a rate of 4.4 per 100 person years (95% CI: 3.3, 5.9). Incident infection was associated with being aged 16 to 20 years [RR = 3.7 (95%CI: 1.9, 7.1)], being employed [RR = 2.4 (95%CI: 1.1, 4.9)] and having two or more new sex partners [RR = 5.5 (95%CI: 2.6, 11.7)]. Recent antibiotic use was associated with a reduced incidence [RR:0.1 (95%CI: 0.0, 0.5)]. There were 14 re-infections with a rate of 22.3 per 100 person years (95%CI: 13.2, 37.6). The median time to re-infection was 4.6 months. Organism load was higher for prevalent than incident infections (p<0.01) and for prevalent than re-infections (p<0.01).
Chlamydia is common among young women and a high proportion of women are re-infected within a short period of time, highlighting the need for effective partner treatment and repeat testing. The difference in organism load between prevalent and incident infections suggests prevalent infection may be more important for ongoing transmission of chlamydia.
Intensified partner notification and repeat testing can improve the effectiveness of screening in reducing Chlamydia trachomatis prevalence: a mathematical modelling study
Article
Nov 2021
B.B.C. Hui
Sabine Braat
David G Regan
Jane Hocking
Background
The Australian Chlamydia Control Effectiveness Pilot (ACCEPt) was a cluster randomised controlled trial designed to assess the effectiveness of annual chlamydia testing through general practice in Australia. The trial showed that testing rates increased among sexually active men and women aged 16–29 years, but after 3 years the estimated chlamydia prevalence did not differ between intervention and control communities. We developed a mathematical model to estimate the potential longer-term impact of chlamydia testing on prevalence in the general population.
Methods
We developed an individual-based model to simulate the transmission of Chlamydia trachomatis in a heterosexual population, calibrated to ACCEPt data. A proportion of the modelled population were tested for chlamydia and treated annually at coverage achieved in the control and intervention arms of ACCEPt. We estimated the reduction in chlamydia prevalence achieved by increasing retesting and by treating the partners of infected individuals up to 9 years after introduction of the intervention.
Results
Increasing the testing coverage in the general Australian heterosexual population to the level achieved in the ACCEPt intervention arm resulted in reduction in the population-level prevalence of chlamydia from 4.6% to 2.7% in those aged 16–29 years old after 10 years (a relative reduction of 41%). The prevalence reduces to 2.2% if the proportion retested within 4 months of treatment is doubled from the rate achieved in the ACCEPt intervention arm (a relative reduction of 52%), and to 1.9% if the partner treatment rate is increased from 30%, as assumed in the base case, to 50% (a relative reduction of 59%).
Conclusion
A reduction in C. trachomatis prevalence could be achieved if the level of testing as observed in the ACCEPt intervention arm can be maintained at a population level. More substantial reductions can be achieved with intensified case management comprising retesting of those treated and treatment of partners of infected individuals.
Quality improvement interventions for improving the detection and management of curable sexually transmitted infections in primary care: Reviews
Chapter
Oct 2016
Barbara Nattabi
Sajni Gudka
Alice Rumbold
James Ward
Chlamydia trachomatis (Trachoma, Genital Infections, Perinatal Infections, and Lymphogranuloma Venereum)
Article
Jan 2014
B.E. Batteiger
Ming Tan
View
Chlamydia trachomatis
Chapter
Dec 2013
Charlotte Gaydos
Chlamydia trachomatis is the most common bacterial sexually transmitted disease (STD) in the United States. In 2010 there were 1.3 million cases reported to the Centers for Disease Control and Prevention (CDC). Chlamydial infections in humans are associated with many clinical syndromes ranging from cervicitis, salpingitis, acute urethral syndrome, endometritis, ectopic pregnancy, infertility, and pelvic inflammatory disease (PID) in females; conjunctivitis and pneumonia in infants; and urethritis, proctitis, and epididymitis in males. Infections in women are usually asymptomatic, requiring that infections be identified by screening both symptomatic and asymptomatic women. Professional organizations recommend screening all sexually active women≤25 years of age for chlamydia. Nucleic acid amplification tests (NAATs) are highly sensitive and are the only test type recommended by the CDC. NAATs can be used on samples from urine and vaginal swabs, making outreach screening possible. Chlamydia-associated morbidity in women, highly sensitive tests, and noninvasive sample types have resulted in aggressive public health approaches to preventing the sequelae of chlamydial infections.
Die deutsche Übersetzung des Motivational Interviewing Sequential Code for Observing Process Exchanges (MI-SCOPE;D)
Article
Aug 2012
W Hannöver
Carola Blaut
Christina Kniehase
Hans Joachim Hannich
To investigate the effectiveness of MI, reliable instruments are necessary. The MI-SCOPE enables coding of transcripted MI-interactions. The interrater-reliability is estimated with =0.67. Aim of this study is to check the reliability of the German translation of the MI-SCOPE. In a first step, transcripts are parsed into separate semantic utterances. Parses are then assigned to one of 49 MI-relevant categories. Databasis is a random sample of 20% each from 78 sessions with post partum mothers who smoked prior to or in pregnancy. 3 coders independently rated the transcripts. Agreements for parsing lay between =0.813 and =0.951 and did not differ between the 3 combinations of coders (Kruskal-Wallis χ 2=0.704, df=2, p=0.703). Agreements for coding ranged between =0.590 and =0.788 and did not differ between the 3 combinations of coders (Kruskal-Wallis χ 2=3.594, df=2, p=0.166). With the MI-SCOPE;D a reliable coding system to investigate MI-interventions is available.
Detecting re-infection in patients after an initial diagnosis of gonorrhoea: is routine recall for re-screening useful?
Article
Aug 2014
INT J STD AIDS
K. Fernando
Tom Fowler
Jan Harding
Jdc Ross
To assess the outcome of routine sexually transmitted infection re-screening after a three-month interval in unselected patients diagnosed with gonorrhoea, we sought to assess whether this active approach would result in an increase in the number of people attending clinic and subsequently diagnosed with gonorrhoea re-infection, compared with normal re-presentation rates. A recall group of patients were invited for re-screening three months after their initial diagnosis of gonorrhoea. Permission was sought to send a reminder two weeks prior to their scheduled recall appointment. Comparisons were made with a historical control group of patients with gonorrhoea in the absence of any formal recall. Of the 242 patients in the intervention arm, 96 (40%) re-attended within six months, and 15 (6%) tested gonorrhoea positive. Two hundred and two patients were assessed in the control group, of whom 45 (22%) re-attended within six months, and 13 (6%) tested gonorrhoea positive. Women were more likely than men to re-attend following active recall, but they were not at higher risk of re-attending while re-infected with gonorrhoea. Active recall following a gonorrhoea diagnosis significantly increases re-attendance rates for repeat screening but did not result in an increased number of subsequent gonorrhoea diagnoses.
Is out-of-pocket cost a barrier to receiving repeat tests for chlamydia and gonorrhoea?
Article
Apr 2013
INT J STD AIDS
Luona Shi
Yiyun Xie
Jinan Liu
M. Mahmud Khan
We aimed to examine whether out-of-pocket (OOP) costs associated with chlamydia (CT) and gonorrhoea (GC) screening tests is a barrier to receiving CT/GC re-screening and follow-up annual screening. A major health insurance claims database 2006-2010 was used for analysis. The date of first CT/GC diagnosis was used as the index date, and OOP costs at index date for screening tests were retrieved. A re-screening test and an annual screening were defined as tests that occurred within 90-180 days and 181-395 days of the index date, respectively. Re-screening rates were 11.7% and 10.9% and annual screening rates were 24.7% and 23.7% for CT and GC cases, respectively. Compared with the CT patients without OOP expenses, those with OOP expenses of $30 or higher had significantly reduced likelihood of receiving re-screening and annual screening. Similar results were found for GC patients. We concluded that OOP costs serve as a significant barrier to re-screening and annual screening.
Characteristics and predictors of women who obtain rescreening for sexually transmitted infections using the www.iwantthekit.org screening program
Article
Full-text available
Jul 2013
INT J STD AIDS
Charlotte Gaydos
Mathilda Barnes
Mary Jett-Goheen
Yu-Hsiang Hsieh
Professional organizations recommend rescreening chlamydia-infected women. The iwantthekit Internet-screening program offered rescreening opportunities by using iwantthekit. Mailed, home-collected vaginal swabs were tested for chlamydia, gonorrhea, and trichomonas by nucleic acid amplification tests. Demographics and risk behaviors of repeat users were determined from questionnaires. Predictors of repeat users were measured in a matched case-control study. Of 1747 women, 304 (17%), who used iwantthekit, indicated they had used the kit previously. Mean age was 24.7 ± 5.7 year and 69% were African American. Repeat iwantthekit users were more likely to be ≥20 years (OR = 2.10); were more likely to have been treated for a sexually transmitted infection (OR = 2.32); less likely to drink alcohol before sex (OR = 0.63); and to never use condoms (OR = 0.43). Of repeaters, 84.2% had a negative prior test and 15.8% had a positive. At current test, 13.2% were infected. Previous trichomonas was associated with current trichomonas (p < 0.05). The iwantthekit may offer rescreening opportunities for previously infected women.
Chlamydia and Gonorrhea
Article
Feb 2013
ANN INTERN MED
Kimberly Workowski
Opportunities for Chlamydia Control in the Era of Healthcare Reform: Lessons from Two Decades of Innovative Family Planning Care
Article
Jan 2013
Catherine Satterwhite
Joan M Chow
Kyle T Bernstein
Heidi Marie Bauer
In the USA, family planning clinics are primary providers of reproductive healthcare to young women and their male partners and have long provided quality sexually transmitted infection (STI) care and prevention. Chlamydia, an easily treatable STI that can lead to serious adverse outcomes if untreated, is the most common bacterial STI in the USA, and annual chlamydia screening is recommended for sexually active women aged ≤25 years. As early adopters of routine screening, family planning clinics screen >50% of all care-seeking eligible women for chlamydia, performing better than private sector healthcare plans. To achieve high levels of quality care, family planning clinics have been leaders in implementing evidence-based care delivery and developing prevention innovations. As national healthcare reform is implemented in the USA and categorical STI clinics close, public-sector demand on family planning clinics will increase.
Insights into the timing of repeated testing after treatment for Chlamydia trachomatis: data and modelling study
Article
Jun 2012
SEX TRANSM INFECT
Janneke C. M. Heijne
Sereina Annik Herzog
Christian L. Althaus
Nicola Low
Objectives:
The objective of this study was to determine the optimal time interval for a repeated Chlamydia trachomatis (chlamydia) test.
Methods:
The authors used claims data for US women aged 15-25 years who were enrolled in commercial health insurance plans in the MarketScan database between 2002 and 2006. The authors determined the numbers of initial positive and negative tests that were followed by a repeated test and the positivity of repeated tests. The authors used a dynamic transmission pair model that reflects the partnership formation and separation processes in 15-25 year olds to determine the time course of repeated infections in women under different levels of notifying the current partner. The authors then explored the additional impact of repeated testing uptake on reducing chlamydia prevalence.
Results:
40% (4949/12 413) of positive tests were followed by a repeated test compared with 22% (89 119/402 659) of negative tests at any time. Positivity of repeated tests followed by an initial positive test was high: 15% (736) after a positive test versus 3% (2886) after a negative test. The transmission model showed a peak in repeated infections between 2 and 5 months after treatment. For a chlamydia testing uptake of 10% per year, the additional impact of repeated testing on reducing chlamydia population prevalence was modest.
Conclusions:
The mathematical model predictions support the recommended interval for repeat chlamydia testing. This study provides information that can be used to design randomised controlled trials to determine more effective interventions to prevent chlamydial reinfection.
SMS reminders improve re-screening in women and heterosexual men with chlamydia infection at Sydney Sexual Health Centre: a before-and-after study
Article
Apr 2012
SEX TRANSM INFECT
Handan Wand
Vickie Knight
Anna McNulty
Rebecca Guy
Background In 2009, Sydney Sexual Health Centre implemented a short message service (SMS) reminder system to improve re-screening after chlamydia infection. SMS reminders were sent at 3 months recommending the patient make an appointment for a re-screen.
Methods Using a before-and-after study, the authors compared the proportion re-screened within 1–4 months of chlamydia infection in women and heterosexual men who were sent an SMS in January to December 2009 (intervention period) with a 18-month period before the SMS was introduced (before period). The authors used a χ2 test and multivariate regression. Visitors and sex workers were excluded.
Results In the intervention period, 141 of 343 (41%) patients were diagnosed with chlamydia and sent the SMS reminder. In the before period, 338 patients were diagnosed as having chlamydia and none received a reminder. The following baseline characteristics were significantly different between those sent the SMS in the intervention period and the before period: new patients (82% vs 72%, p=0.02), aged <25 years (51% vs 33% p<0.01), three or more sexual partners in the last 3 months (31% vs 27%, p<0.01) and anogenital symptoms (52% vs 38%, p<0.01). The proportion re-screened 1–4 months after chlamydia infection was significantly higher in people sent the SMS (30%) than the before period (21%), p=0.04, and after adjusting for baseline differences, the OR was 1.57 (95% CI 1.01 to 2.46).
Conclusions SMS reminders increased re-screening in patients diagnosed as having chlamydia at a sexual health clinic. The clinic now plans to introduce electronic prompts to maximise the uptake of the initiative and consider strategies to further increase re-screening.
Re-testing for chlamydia at sexual health services in Australia, 2004-08
Article
Full-text available
| https://www.researchgate.net/publication/221751445_Interventions_to_Increase_Rescreening_for_Repeat_Chlamydial_Infection |
BCM-HGSC | Eric Boerwinkle, Ph.D. | page 14
Associate Director, Baylor College of Medicine Human Genome Sequencing Center Contact information eboerwin@bcm.edu Other positions Dean, UTHealth School of Public Health M. David Low Chair in Public Health Kozmetsky Family Chair in Human Genetics Professor, Human Genetics Center and Dept. of Epidemiology Research interests The research interests of Dr. Boerwinkle encompass the
Eric Boerwinkle, Ph.D.
Associate Director, Baylor College of Medicine Human Genome Sequencing Center
Contact information
eboerwin@bcm.edu (link sends e-mail)
Other positions
Dean, UTHealth School of Public HealthM. David Low Chair in Public HealthKozmetsky Family Chair in Human GeneticsProfessor, Human Genetics Center and Dept. of Epidemiology
Research interests
The research interests of Dr. Boerwinkle encompass the genetic analysis of the common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes.
Dr. Boerwinkle received his B.S. in Biology from the University of Cincinnati in 1980, an M.A. in Statistics (1984), and M.S. and Ph.D. in Human Genetics (1985) from the University of Michigan, Ann Arbor where he served as Senior Research Associate in the Department of Human Genetics from 1985-1986. He joined the University of Texas-Houston Center for Demographic/ Population Genetics in 1986 as a Research Assistant and became Assistant Professor in the same year. In 1991 he joined the Department of Human Genetics at the School of Public Health, University of Texas-Houston Health Science Center as Associate Professor, in 1996 was promoted to Professor, and in 1997, Director of the Human Genetics Center. He became a faculty member of the Institute of Molecular Medicine in 1996 and became Professor and Director of the Research Center for Human Genetics.
Dr. Boerwinkle is a member of the American Diabetes Association and the American Society of Human Genetics. The research interests of Dr. Boerwinkle encompass the genetic analysis of common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes. This work includes localizing genes which contribute to disease risk, identification of potentially functional mutations within these genes, testing these candidate functional mutations in experimental systems, defining the impact of gene variation on the epidemiology of disease, and determining the extent to which these genes interact with environmental factors to contribute to disease risk. Activities include both statistical analysis and laboratory work. A large part of Dr. Boerwinkle's current research effort consist of localizing genes contributing to disease risk using modern genome-wide mapping methods. Success depends on keeping up with the latest genomic technical advances. The laboratory is set-up and operating as a high through-put sequencing and genotyping facility in which speed, accuracy and efficiency are monitored continuously. However, we are constantly seeking out more efficient methods to collect and manage genetic information.
Dr. Boerwinkle and colleagues have completed the world's first genome-wide analyses for a variety of CAD risk factors, including diabetes and hypertension. These investigations have lead to the identification of novel susceptibility genes in both cases. Dr. Boerwinkle is particularly interested in methods for identifying potentially functional mutations within a gene region. This seemingly simple objective is made difficult because the functional mutations are expected to have small effects and are imbedded in a sea of silent genetic variation. Once nearly all of the variation is catalogued directly by DNA sequencing, individuals are genotyped for each variable site. Both novel and traditional statistical methods are applied to relate the array of genetic information to a wealth of phenotypic data. This algorithm generates "candidate functional mutations" that are then tested in an in vitro or mouse model system. Once a functional mutation has been identified, Dr. Boerwinkle's group evaluates the ability of the variable site to predict the onset of disease (e.g. myocardial infarction or stroke) above and beyond traditional risk factors. This work is carried out as part of multiple prospective studies of cardiovascular disease and its risk factors in tens of thousands of individuals representing the major American ethnic groups.
Finally, he is working on experimental designs for studying genotype by environment interaction in humans. In particular, we are working on the extent to which interindividual variation in lipid lowering and anti-hypertensive medications are influenced by genetic factors. The practical objective of the research is to use genetic information to identify individuals at increase risk of disease and to design more efficacious interventions. Genetic studies are defining, at the molecular level, novel mechanisms of disease risk, onset and progression. Dr. Boerwinkle and collaborators address the localization of genes which contribute to disease risk in cardiovascular diseases, hypertension and diabetes. The methodology used involves screening of families having the disease and linking the presence of disease with known markers of the human genome. In this manner, the genomic region in which relevant mutations are located can be mapped and the relevant DNA sequenced. By assessing the structural change the mutation may have caused in the gene product (protein), it is possible to infer how it may affect biological function. In order to determine experimentally whether a mutation is functional, it is necessary to introduce the mutated gene into an animal, usually a mouse, and assess its biological effects on the animal's phenotype.
Dr. Boerwinkle has participated in multiple notable discoveries since joining the Institute. Only two will be highlighted here. First, Dr. Boerwinkle's group has completed the first ever genome-wide search for genes contributing to inter-individual blood pressure levels. This initial effort has lead to the identification of an important gene (an adrenergic receptor) which influences blood pressure levels and the risk to hypertension. This is the first time that such a genome-wide approach has led to the identification of a susceptibility gene to a major cardiovascular disease risk factor. Second, Dr. Boerwinkle has participated in similar efforts to identify genes contributing to the risk of developing non-insulin dependent (type II) diabetes. In this case, however, there were no genes in the region that were suspects for the disease. A team of collaborating investigators have painstakingly characterized the genetic region and identified the mutated gene (in this case a protease). This is the first time that anyone has ever positionally cloned a gene contributing to any common chronic disease. This work is of obvious potential clinical importance. It may lead to improved prediction of those at increased risk of disease and the design of more efficacious intervention strategies. The technologies and information from the human genome project provide new tools for lessening the burden of ill-health. Dr. Boerwinkle's accomplishments in developing an internationally recognized team of investigators targeting the genetics of cardiovascular disease and its risk factors ensures a productive future and further discoveries.
Publications
2015
Yuan B , Pehlivan D , Karaca E , Patel N , Charng W-L , Gambin T , et al. . Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes. J Clin Invest. 2015;125(2):636-51. PubMed DOI Google Scholar Tagged
Davies G , Armstrong N , Bis JC , Bressler J , Chouraki V , Giddaluru S , et al. . Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). Mol Psychiatry. 2015;20(2):183-92. PubMed DOI Google Scholar Tagged
Riveiro-Álvarez R , Xie YAngela , López-Martínez M-Á , Gambin T , Pérez-Carro R , Ávila-Fernández A , et al. . New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy. JAMA Ophthalmol. 2015;133(2):133-9. PubMed DOI Google Scholar Tagged
Shetty PB , Tang H , Feng T , Tayo B , Morrison AC , Kardia SLR , et al. . Variants for HDL-C, LDL-C, and triglycerides identified from admixture mapping and fine-mapping analysis in African American families. Circ Cardiovasc Genet. 2015;8(1):106-13. PubMed DOI Google Scholar Tagged
Yazdani A , Yazdani A , Boerwinkle E . Rare variants analysis using penalization methods for whole genome sequence data. BMC Bioinformatics. 2015;16:405. PubMed DOI Google Scholar Tagged
Gaulton KJ , Ferreira T , Lee Y , Raimondo A , Mägi R , Reschen ME , et al. . Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nat Genet. 2015;47(12):1415-25. PubMed DOI Google Scholar Tagged
Chong JX , Buckingham KJ , Jhangiani SN , Boehm C , Sobreira N , Smith JD , et al. . The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities. Am J Hum Genet. 2015;97(2):199-215. PubMed DOI Google Scholar Tagged
Gonzaga-Jauregui C , Harel T , Gambin T , Kousi M , Griffin LB , Francescatto L , et al. . Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Rep. 2015;12(7):1169-83. PubMed DOI Google Scholar Tagged
Demerath EW , Guan W , Grove ML , Aslibekyan S , Mendelson M , Zhou Y-H , et al. . Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci. Hum Mol Genet. 2015;24(15):4464-79. PubMed DOI Google Scholar Tagged
Bainbridge MN , Davis EE , Choi W-Y , Dickson A , Martinez HR , Wang M , et al. . Loss of Function Mutations in NNT Are Associated With Left Ventricular Noncompaction. Circ Cardiovasc Genet. 2015;8(4):544-52. PubMed DOI Google Scholar Tagged
Pokharel Y , Sun W , Polfus LM , Folsom AR , Heiss G , A Sharrett R , et al. . Lipoprotein associated phospholipase A2 activity, apolipoprotein C3 loss-of-function variants and cardiovascular disease: The Atherosclerosis Risk In Communities Study. Atherosclerosis. 2015;241(2):641-8. PubMed DOI Google Scholar Tagged
van der Lee SJ , Holstege H , Wong THang , Jakobsdottir J , Bis JC , Chouraki V , et al. . PLD3 variants in population studies. Nature. 2015;520(7545):E2-3. PubMed DOI Google Scholar Tagged
Weng L-C , Cushman M , Pankow JS , Basu S , Boerwinkle E , Folsom AR , et al. . A genetic association study of activated partial thromboplastin time in European Americans and African Americans: the ARIC Study. Hum Mol Genet. 2015;24(8):2401-8. PubMed DOI Google Scholar Tagged
Dong C , Wei P , Jian X , Gibbs RA , Boerwinkle E , Wang K , et al. . Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet. 2015;24(8):2125-37. PubMed DOI Google Scholar Tagged
English AC , Salerno WJ , Hampton OA , Gonzaga-Jauregui C , Ambreth S , Ritter DI , et al. . Assessing structural variation in a personal genome-towards a human reference diploid genome. BMC Genomics. 2015;16:286. PubMed DOI Google Scholar Tagged
Rahbar MH , Samms-Vaughan M , Ma J , Bressler J , Loveland KA , Hessabi M , et al. . Interaction between GSTT1 and GSTP1 allele variants as a risk modulating-factor for autism spectrum disorders. Res Autism Spectr Disord. 2015;12:1-9. PubMed DOI Google Scholar Tagged
Del-Aguila JL , Cooper-Dehoff RM , Chapman AB , Gums JG , Beitelshees AL , Bailey K , et al. . Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide. Pharmacogenomics J. 2015;15(2):153-7. PubMed DOI Google Scholar Tagged
Beck TF , Campeau PM , Jhangiani SN , Gambin T , Li AH , Abo-Zahrah R , et al. . FBN1 contributing to familial congenital diaphragmatic hernia. Am J Med Genet A. 2015;167A(4):831-6. PubMed DOI Google Scholar Tagged
Yu B , Li AH , Muzny DM , Veeraraghavan N , de Vries PS , Bis JC , et al. . Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease. Circ Cardiovasc Genet. 2015;8(2):351-5. PubMed DOI Google Scholar Tagged
Verhaaren BFJ , Debette S , Bis JC , Smith JA , M Ikram K , Adams HH , et al. . Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. Circ Cardiovasc Genet. 2015;8(2):398-409. PubMed DOI Google Scholar Tagged
| https://www.hgsc.bcm.edu/people/boerwinkle-e?f%5Bauthor%5D=7853&f%5Btg%5D=R&o=asc&page=13&s=type |
When ?Semper Fi? Takes on a New Meaning - The Patriot Files Forums
When ?Semper Fi? Takes on a New Meaning Marines
When ?Semper Fi? Takes on a New Meaning
When ?Semper Fi? Takes on a New Meaning
As a career Marine officer, I have a gnawing feeling in my gut constantly reminding me that there are Marines fighting, dying and doing what Marines do best in Iraq and Afghanistan, while I am relatively safe and sound back in the Pentagon.
Not being there with the Marines who are risking all they have for the freedom of the Iraqi and Afghani people is a humbling experience, especially in those times when I feel justified in complaining about the Pentagon bureaucracy or getting stuck in rush-hour Beltway traffic. Knowing Marines are deployed to active combat zones has a special way of putting life in perspective for me.
Part of that gnawing feeling in my gut is knowing I cannot do anything directly to help or support all the deployed Marines. When you are part of a team, it is important to contribute to your team's success to the best of your abilities. Some relatively recent experiences and unexpected opportunities have proven to me that the Navy-Marine Corps team is stronger than ever. I also have received updated information on a number of great ways for people to indirectly support their winning team efforts.
The bad news, as expected, is that a good number of Marines and sailors are coming back to the United States from the Iraq and Afghanistan theaters less than whole. Many soldiers are also returning in the same condition. The great news is that these warriors are receiving the best military medical care possible.
Practically all returning soldiers and airmen receive their primary medical care from the Walter Reed Army Medical Center in Washington, D.C., while practically all returning Marines and sailors receive their primary medical care at the National Naval Medical Center in Bethesda, Md. In some cases, these warriors are directly benefiting from the most advanced state-of-the-art technological advances available anywhere in the world.
According to hospital sources, the majority of the injuries they are treating are the result of shrapnel and traumatic amputations from mortars, hand grenades, rocket-propelled grenades, and improvised explosive devices (IEDs). The injuries in some cases are unprecedented and a true testament to the battlefield triage skills of our deployed medical personnel, the responsiveness of our medical evacuation systems, and the strength and courage of our injured warriors.
Injured Marines and sailors are usually flown into Andrews Air Force Base, just outside of Washington, D.C. These medical evacuation flights can sometimes arrive up to three times a week and they usually contain about 20-40 patients. On the ground to meet and greet them are representatives from Bethesda?s Marine Liaison Office. The dedicated Liaison Office Marines make sure the injured Marines are safely transported to and efficiently established in their hospital rooms.
The Liaison Office Marines? close, personal relationships with the injured Marines, the injured Marines? families and the hospital staff are comforting and inspiring to all involved. These unsung Marines have a very stressful and sensitive job, and they handle it with grace, dignity, and true professionalism.
The Marine Liaison Office provides great intangible support to the injured Marines and their families, but they are largely dependent on donations of material items for many of the injured Marines? physical needs.
Items such as books, blankets, umbrellas, medicated hand/foot lotions, electric razors, CDs/DVDs/VHS tapes, gym/travel bags, and padded weight-lifting gloves (sizes M, L, XL) will help with their comfort during their recovery and physical therapy sessions.
Due to concerns about spreading germs and infections, only brand new clothing and materials are being accepted. Since these donations are provided to the Marines and their families and taken with them when they leave, these items need constant replenishment. Those interested in contributing materials can send them to:
Marine Corps Liaison Office
National Naval Medical Center (NNMC)
8901 Wisconsin Avenue
Bethesda, MD 20889
The Marine Liaison Office is not alone in this vital mission of supporting and comforting the injured Marines and their families. Their Navy-Marine Corps team ?supporting network? includes outstanding support from and visibility within the offices of the Commandant and Assistant Commandant of the Marine Corps, many other offices within Headquarters Marine Corps, and all the corpsmen, chaplains, surgeons, medical technicians, and senior enlisted and officer leadership at Bethesda. Being surrounded by such incredible support is a true force-multiplier for the liaison office.
Besides the immediate, short-term support provided by Bethesda?s Marine Liaison Office and their supporting network, on May 18, 2004, the Injured Marine Semper Fi Fund (which has Internal Revenue Service (IRS) 501(c)(3) publicly supported charitable organization status) was established to provide both short- and long-term support to injured Marines and their families. According to the information letter:
?At this time, the Department of Defense (DoD) will pay lodging and travel expenses for two next of kin to visit those Marines considered seriously injured. DoD pays for these two individuals to stay for the duration of up to one week. After the term of one week, if the family members choose to stay at their Marine?s bedside, it is the sole responsibility of the family to arrange and pay for lodging and transportation. Additionally, next of kin are defined as the two family members a Marine lists in his record. In the case of a married Marine who has listed his spouse as his primary next of kin and his father as the secondary next of kin, DoD does not accommodate the mother, children, siblings, or grandparents with payment of travel expenses. DoD does not reimburse families under any circumstances for rental cars, long-term childcare, or lost income. In the case of Marines requiring long-term rehabilitative care, these financial burdens remain with families for a period of years.?
?The Injured Marine Semper Fi Fund has a close working relationship with the United States Marine Corps and is assessing the needs of injured Marines and their families on a regular basis. In the short-term crisis time, lodging, transportation, and assistance with daily financial burdens for the families of these injured Marines is the most challenging area of concern and where the Fund will assist the most. When families arrive, they do so under extraordinary stress and limited financial resources to help them survive in the D.C. area for any period of time. They arrive ? from cities and towns all over the country, and in most cases are entirely unfamiliar with their surroundings. They spend time round the clock at the bedside of their Marine, and do so for weeks at a time. They need assistance with airline tickets for additional family members to provide relief for the primary and secondary next of kin, as well as hotel accommodations, rental cars, food, and other essentials. As you know, this can be expensive for any family, especially those with very limited resources. In the long-term, the Injured Marine Semper Fi Fund will track and monitor the needs of families as they move from the crisis stage to rehabilitative stage with financial assistance for items including but not limited to, handicap accessible and orthopedic equipment, respite care, and childcare needs.?
For anyone interested, donations to the Injured Marine Semper Fi Fund can be sent to the following address:
Injured Marine Semper Fi Fund
825 College Blvd Suite 102
PMB 609
Oceanside, CA 92057
I just realized an odd thing happened to me by the time I finished writing this article: that gnawing feeling in my gut is gone. Not everyone can directly support our deployed warriors, but everyone now has opportunities to support those warriors and their families who have given so much for our country.
Lt. Col. Matthew Dodd USMC is a Senior Editor of DefenseWatch. He can be reached at
mattdodd1775@hotmail.com
. Please send Feedback responses to
dwfeedback@yahoo.com
.
Ellie
__________________
IN LOVING MEMORY OF MY HUSBAND
SSgt. Roger A.
One Proud Marine
1961-1977
68/69
Once A Marine............Always A Marine............. http://www.geocities.com/thedrifter001/
| http://www.patriotfiles.com/forum/showthread.php?p=71477 |
RTPI | Implementing 20 Minute Neighbourhoods in Planning Policy and Practice
This briefing identifies the potential for embedding the concept of 20 minute neighbourhoods in Scottish planning policy and practice
20 Minute Neighbourhoods
Implementing 20 Minute Neighbourhoods in Planning Policy and Practice
This policy briefing paper looks at the 20 minute neighbourhood concept and how it can be embedded in Scottish planning policy and practice.
You can download this paper in PDF formathereor read in full below.
Contents
Introduction
Embedding in planning policy
Development Management
Place-based partnerships
Executive summary
The Covid-19 pandemic has had an immediate, and likely a lasting effect, on how we use towns and cities to live, work and play in. 20 minute neighbourhoods are a concept of urban development that has ascended rapidly in the minds of policymakers, politicians and the general public across the world. The basic premise is a model of urban development that creates neighbourhoods where daily services can be accessed within a 20 minute walk. This briefing paper focuses on the role planning policy and practice and place-based partnerships can have in delivering the concept in Scotland. This report recommends a range of areas of planning policy, development management and public service delivery which could be adjusted to include interventions to support 20 minute neighbourhoods. The on-going planning reform in Scotland, including the implementation of the Planning (Scotland) Act 2019 through drafting of the National Planning Framework 4 (NPF4), secondary legislation and guidance, provides an excellent opportunity to do so.
Policy and guidance opportunity areas identified:
NPF4 and LDP policies including transport, density, services and green infrastructure
Designing Streets policy statement
Creating Places policy statement
Open Space Strategies
Woodland and Forestry Strategies.
Play sufficiency assessments
Digital Planning Strategy
Development management procedures identified:
Pre-application process
Planning obligations
Outcome focused performance measures
The briefing concludes with a discussion on the role of placed-based partnerships, focusing in particular on the role for the Place Principle and Local Place Plans in supporting delivery of 20 minute neighbourhoods.
1. Introduction
The Covid-19 pandemic has had a profound and lasting impact across the world. Responding to this unprecedented shock to the social and economic system, the Royal Town Planning Institute sets out in its ‘Plan The World We Need’ campaign, the vital contribution that planning can make toward to a sustainable, resilient and inclusive recovery. This includes an accelerated progress to a zero carbon economy, increase resilience to risk, and create fair, healthy and prosperous communities [1]. A planning concept and urban growth model known as the 20 minute neighbourhood, has gained significant traction across the world as a means of supporting this recovery, spurred on in part by the outcomes of the Covid-19 pandemic. In Scotland, 20 minute neighbourhoods have made their way into policy and political spheres with inclusion within the Programme for Government 2020-21 and explicit mention in the recently published National Planning Framework 4 Position Statement. Whilst their definition is not universally agreed upon, the basic premise is a model of urban development that creates neighbourhoods where daily services can be accessed within a 20 minute walk. The aim of such neighbourhoods is to regenerate urban centres, enhance social cohesion, improving health outcomes and support the move towards carbon net-zero targets through reducing unsustainable travel.
An array of interventions need considering to support the implementation of 20 minute neighbourhoods including active travel interventions, public realm and greenspace enhancements, traffic reduction methods, service provision and considerations of densification. Whilst 20 minute neighbourhood type interventions are recent in their deployment, there is a growing body of evidence supporting such interventions. Analysis of the impacts of active travel and traffic calming interventions in Outer London during 2016-19 have shown a modal shift away from private vehicles [2], reducing air pollution [3], improved health outcomes [4]and reduced street crime [5]. Furthermore studies have also shown that residents who spend less time traveling by car generally spend more time engaging in community activities, enhancing social cohesion [6]. 20 minute neighbourhoods could also improve our approach to inclusive design with, for example, research showing that women tend to overall drive less and rely to a greater degree on public transport and walking compared to men [7].
The fundamental tenets of 20 minute neighbourhoods are not necessarily new concepts in planning, with many already widely embedded in theory, policy and practice. This includes in a rural context, where settlement hierarchies already play an important role in allocating development in well-served settlements, alongside a general policy steer away from individual developments in isolated areas. With the renewed political and societal focus on neighbourhoods resulting from the Covid-19 pandemic, an opportunity has been provided for planning to reposition itself as a proactive and visionary discipline which will be critical in supporting post-COVID recovery and reinventing our places. The aim of this piece of work is not to try and provide a definition for 20 minute neighbourhoods or to discuss their evolution in policy and research but instead to focus thinking towards delivering their ambitions and how the planning system can support this. The implementation of 20 minute neighbourhoods will require a multifaceted approach across planning policy and practice, and the collaborative working across the public and private sector. Therefore this briefing will address a range of areas where approaches can be changed, set under three key thematic areas of consideration as follows:
Embedding 20 minute neighbourhoods in planning policy
Addressing 20 minute neighbourhood in development management
Place-based partnership delivery
2. Embedding in planning policy
As previously mentioned the aim of this briefing is not to discuss the definition of 20 minute neighbourhoods, with this been well addressed elsewhere [8]. However, it is acknowledged that in order to ensure the success of the concept a clear, holistic definition or vision needs embedding in policy. In Scotland a clear opportunity to do this lies in the impending draft of the National Planning Framework 4 and through the publication of a revised ‘Designing Streets’ [9]and ‘Creating Places’ [10]policy statement. A definition within national policy needs to be specific to provide confidence for decision makers but also a degree of flexibility to allow its application across a range of places with different context for examples across urban and rural areas.
National Planning Framework 4
Research on the adoption of Scottish Planning Policy (SPP) in Local Development Plans (LDPs) recommended greater emphasis on placemaking at the forefront of development. It recognised a need for more direction in ensuring principles are implemented with planning policy becoming more prescriptive to ensure that placemaking principles are carried through to development management [11]. RTPI Scotland recommends that any enhanced emphasis on placemaking in policy strongly integrates the fundamental principles behind 20 minute neighbourhoods. To achieve this NPF4 should give clarity on the features of a 20-minute neighbourhood to ensure a consistent place-based approach to their delivery. A strong policy steer will provide planning officers and elected members the confidence to ensure that developments show strong placemaking principles and are in keeping with 20 minute neighbourhood initiatives and to have confidence that any refusals will be upheld in the event of an appeal. Specific areas of policy which can be reformed to support 20 minute neighbourhoods will be addressed in this section of the briefing. Furthermore the NPF4 provides an opportunity to start embedding at a policy level, a broader place-based approach in the delivery of public service, a theme which is addressed further on this briefing.
Creating Places and Designing Streets Policy Statements
Creating Places is a policy statement on architecture and place for Scotland, setting out the comprehensive value that good design can deliver [12]. The statement sets out guiding principles which underpin the Scottish Government’s approach to delivering good places. These principles are expressed as the six qualities proposed of successful places as distinctive, safe and pleasant, easy to move around, welcoming, adaptable and resource efficient. The policy statement does aim to support the creation of walkable neighbourhoods however a refreshed version could highlight the value of the 20 minute neighbourhoods and focus on design considerations necessary to create them. This includes more emphasis on the connectivity of developments in terms of active transport and the provision of accessible daily services for local people.
Designing Streets is a policy statement setting out national planning, architecture and transport policy for street design. It provides guidance on how to achieve a design-led approach to street design [13]. The document provides a basis for local and site-specific policy and guidance. It advocates an approach which is underpinned by also consideration of the six qualities of successful places set out in the Creating Places guidance. Designing Streets was published in 2010 and, given the new context for design post-COVID, there is a need to review it fitness for purpose and in doing so ensure that it better incorporates the fundamental tenets of 20 minute neighbourhoods. This is an intention already signalled by Scottish Government in their National Planning Framework 4 Position Statement [14]. Specific changes to approaches to active travel will be discussed later in the briefing.
Data
LDPs set out policies and proposals to guide development, reflecting the unique characteristics of the places and communities they cover. Preparation of LDP strategies and policies needs to be informed by a robust and up-to-date evidence base. Therefore in order to support the formation of policy and delivery of 20 minute neighbourhoods, clear consideration needs made as to collection, analysis and visualisation of data relevant to achieve their output. To achieve this RTPI Scotland sees a role for the Scottish Government’s Digital Planning Strategy. This Strategy aims to unlock the value of planning data, deliver an end-to-end digital planning service experience, create the conditions for digital to flourish, use digital tools to drive collaboration and engagement and embed a culture of digital innovation [15]. Mission 1 of the strategy is to unlock the value of planning data which has a number of goals to be delivered by 2025, including to:
develop a shared data resource for planning and place data, built upon a cloud hosted platform that allows easy access to high quality data across Scotland.
build a foundation of data that is robust, trusted and can be exchanged and used across geographic boundaries, vertically (across geographic scales), and which combines data from many policy areas (such as climate, people, work, place and infrastructure) that facilitates the place-based approach.
embed a data-driven policy approach where development of policies considers data needs and opportunities at the earliest point, supporting planning policy by continuous monitoring of impact and iterative improvement.
develop a Realising Potential programme to explore data-driven innovations within planning such as scenario modelling and simulation of future policy impacts.
Research by RTPI Scotland has shown large potential economic and societal benefits arising from this digital transformation [16]. For policy initiatives such as 20 minute neighbourhoods there is a need to provide a relevant, transparent and robust evidence base and indicators for monitoring purposes, which are continuously kept up to date There are a range of existing tools and databases which could support this including the Place Standard Tool and Understanding Scotland’s Places database.
With a strong national policy steer and a robust evidence base, local circumstances can be addressed through the preparations of Local Development Plans (LDPs). The following section will address thematic areas of LDP policy development:
Density
Transport
Local Services
Open Space Strategies
Density
Compact settlement patterns help to reduce the distances between homes and jobs and makes more efficient use of existing transport infrastructure. Research has shown that larger settlements with higher densities can provide a critical mass of population to support local services, improve economic productivity, reduced transport emissions, better public health, and greater social interaction [17]. Higher densities manifest as taller buildings or terraced housing may reduce overall land take on schemes, allowing for enhanced blue and green infrastructure. It is estimated that to support 20 minute neighbourhoods an average density of at least 65 dwellings per hectare in new developments may be required, although it could be higher in some areas [18]. A stronger policy line in terms of density will be necessary to add more weight in the planning balance to the consideration of compact settlement form as opposed to existing local impact or landscape impact.
This may include readdressing existing low density neighbourhoods. Policy support needs to be continued for intensification of settlements especially through promotion of use of brownfield land. Other polices measures such as reduction in minimum parking standards will enhance opportunities to achieve gentle density and better quality placemaking.
Transport
A key policy tool in delivering 20 minute neighbourhoods is through better integrating transport and land use planning. The planning system has an important role to play in delivering active travel networks, reducing congestion and thereby creating liveable streets [19]. Despite a strong policy steer and a clear transport hierarchy prioritising active travel, uptake of active travel has stagnated in recent years in Scotland [20]with car traffic has increasing. Transport is also the largest single contributor to Scotland’s carbon emissions with private cars accounting for 39% of overall transport emissions in 2018 [21]. Car-centric design can have implications on ease of access to employment, services and facilities, which are not always located a convenient walking, cycling or public transport distance from residential neighbourhoods. In addition, with priority given to vehicle movement and access, less attention has been paid to the place function of streets and human movement through them. This has resulted in, for example, narrow footpaths, inadequate street lighting and fragmented cycle lanes.
From a development planning perspective Transport Appraisals are an important tool to assess the impact of LDP strategies on transport networks and identifying locations where transport interventions are necessary. Transport Appraisals are undertaken in line with the Development Planning and Management Transport Appraisal Guidance (DPMTAG) [22]. The DPMTAG has a clear steer within it for promoting active travel modes, including through the production of Active Travel Plans. However the implementation of national policy and guidance is not resulting in shift in travel modes on the ground. RTPI Scotland would recommend an evidence based review of the DPMTAG in advance of the producing updated guidance. A move towards a tighter consideration of 20 minute neighbourhoods in Transport Appraisals may support local transport interventions to encourage active travel for local journeys.
The need to move active travel considerations from policy through guidance to delivery is a key concern in supporting 20 minute neighbourhoods. A refreshed ‘Designing streets’ provides another opportunity to do so. Designing Streets intends to steer street design towards place-making and away from a system focused upon the dominance of motor vehicles. However the consideration of active travel infrastructure is now outdated with the inclusion of wording such as “ Only where traffic volumes and speeds are high should the need for a cycle lane be considered.” A refreshed ‘Designing Streets’ needs to better emphasise the importance of active travel when considering street design including the consideration of strategic active travel networks and core paths. An updating Designing Streets should incorporate updated guidance on active travel including a refreshed Cycling by Design and a new National Walking design standards. Local street design guidance can be subsequently produced to reflect local character.
As discussed above in recent years in Scotland there has been a significant increase in traffic volumes 7. This increase in traffic has not been experienced equally across roads in urban areas with studies in England showing the greatest increase in volumes on since 1994 has been almost entirely on minor roads resulting in a greater noise, air pollution and road danger on residential streets [23]. A response to this in recent years has been the deployment of low-traffic neighbourhoods (LTNs) [24]. LTNs operate whereby private motorised vehicles can still access all homes and businesses, but they cannot cross through the neighbourhood. Following a Transport Appraisal whereby problems of high congestion are identified in residential areas, there may be a role for LDPs in identifying traffic calming measures needed in areas such as LTNs and set out a policy response accordingly in alignment with any local walking and cycling strategies. In a rural context the need to drive for the foreseeable future cannot be overlooked, however on arrival to the nearest settlement, encouraging ‘park and walk’ culture through interventions could have many benefits.
Local Services
A fundamental tenet of 20 minute neighbourhoods is the provision of locally accessible services. For the purpose of this briefing services will be considered of those that meet a ‘daily’ need, although the opportunity to link a range of services to localities should not be overlooked. This includes the daily needs of a variety of stakeholders such as children, young persons and older and disabled persons. When considering the provision of services in localities development planning can provide a policy support for service access to new developments but also from a retrofit lens, whether it is supporting the provision of new services in areas deficient of them, or encouraging residential developments in areas well serviced such as town centres. Consideration need also made for any proposals for car dependent out-of-town retail and leisure that are not closely located to populated areas, which may necessitate a blanket presumption against such developments. For children and younger persons, the Planning (Scotland) 2019 Act provisions for play sufficiency assessments, where planning authorities must assess the sufficiency of play opportunities in its area for children in preparing an evidence report. The impending regulations for play sufficient assessments provide another opportunity to tie in the 20 minute neighbourhood concept.
Open Space Strategies
LDPs have a key role to play in protecting and promoting high quality open and green/blue infrastructure. Such considerations could be framed and aligned with requirements of 20 minute neighbourhoods. In the Planning (Scotland) Act 2019 provisions for Open Space Strategies require a planning authority to set out a strategic framework consisting of policies and proposals as to the development maintenance and use of open space and green infrastructure in their area. To produce these frameworks necessitates an audit of existing open space provision and an assessment of current and future requirements. There is an opportunity to integrate the 20 minute neighbourhoods specifically here with the publication of impending regulations which will make provisions about how planning authorities are to discharge this function. Such provisions could include specific reference to needs of local communities under the lens of a 20 minute neighbourhoods, identifying the need to create new open space strategies, enhance existing spaces including access to them. Forestry and Woodland strategies, another provision set out in the Planning (Scotland) Act 2019, could also be aligned to support the consideration of 20 minute neighbourhoods by identifying opportunities for community woodlands.
3. Development Management
Supported by a policy framework with clear vision and robust wording, development management will be an important process of pro-actively managing development in local areas to support 20 minute neighbourhoods. With placemaking principles of 20 minute neighbourhoods embedded in the NPF4, development management planners can have the confidence to refuse applications which do not align with the design principles and have their decisions upheld at appeal. For the purposes of this briefing three areas of development management will be considered:
Pre-application process
Planning obligations
Performance
Pre-application process
Pre-application discussions are an important part of the development management process. Through early engagement with prospective applicants, the planning authority and statutory consultees have an opportunity to discuss important issues in advance of the submission of a formal application. They can improve the quality of planning applications, mitigate potential negative impacts, address misunderstandings and where practicable, address community issues. A 20 minute neighbourhood design-led approach could be integrated into different stages of the pre-application process. Investment in upfront development frameworks, masterplans and Masterplan Consent Areas could help support formation and reinforcement of 20 minute neighbourhoods. They could do so by setting out codes and regimes which establish what can and cannot be built in terms of design, layout and phasing. This would also provide predictability for investors and developers, which in turn gives them a sound basis for making decisions. A more general criteria framework checklist process could also be harnessed, requiring developers to show how proposals meet envisioned outcomes of the 20 minute neighbourhood. There is an opportunity to align and integrate Health Impact Assessments at this stage of the planning process, provisions for which are within the Planning Scotland Act (2019). There is also an opportunity to align a revised Pre-Application Consultation process with the considerations of 20 minute neighbourhood to ensure that there is strong community buy-in secured from communities at an early stage.
Planning obligations
Planning obligations provide a mechanism by which any potential negative impacts on land use, the environment and infrastructure of development can be reduced, eliminated or compensated for. When considered essential they must be related and proportionate to the development in question. LDPs have an important role to play in setting out the potential need for and use of planning obligations and could play a role in setting out infrastructure requirements to create or reinforce successful 20 minute neighbourhoods. This could require a revised method assessment of infrastructure requirements to include considerations of:
Play and recreational facilities
Low Traffic Neighbourhoods
Urban Realm improvements
Green infrastructure provision
Daily service provision
Active travel networks
There is also an opportunity to utilise the proposed Infrastructure Levy, provisions for which are set out within the Planning (Scotland) Act 2019, with guidance still to be published on how Infrastructure Levy income should be spent. A clearer definition of what constitutes a strategic active travel networks will support consideration of this particular infrastructure requirement.
Outcomes-focused performance measures
As a means of improving the performance of planning services, a range of Key Performance Indicators (KPIs) are measured yearly and inform the production of Planning Performance Frameworks. However theses performance assessments historically have tended to be narrowly centred on process metrics such as the speed of processing applications, the number of consents given and the amount of housing units delivered. However if we are seeking better quality placemaking outcomes this will require a change in how we measure performance. The ‘Measuring What Matters; Planning Outcomes Research’ [25]published in 2020 by the RTPI provides a toolkit and routemap to moving towards an outcomes based approach to performance management. This ties in directly with the need to understand what data sets are necessary and what digital solutions are in place to monitor performance as previously discussed.
RTPI Scotland believes that the NPF4 should be structured around outcomes which are tied into planning authority performance assessment frameworks and priority strategic themes on achieving climate action, delivering a net zero carbon Scotland and improved health and wellbeing. Metrics associated with the delivery of 20 minute neighbourhoods could be incorporated into a new outcomes-focused performance framework, with a role for the new Improvement Coordinator role - provisions for which are set out in the Planning (Scotland) Act 2019 - to set out how to measure progress on new policy initiatives. An existing means of assessing the outcome of the planning process in terms of design and place quality are Design Quality Audits. These could be amended to include placemaking considerations associated with 20 minute neighbourhoods and applicants can be encouraged to use the Quality Audit as a basis for their Design Statements.
4. Place-based partnerships
The successful operationalisation of 20 minute neighbourhoods will require the collaborative work across a wide range of stakeholders in the public sector, private sector, third sector and in the communities themselves. Consideration of 20 minute neighbourhoods needs applied to a range of public sector decision making areas such as planning, Community Planning, asset management, street maintenance, investment, health and education service provision. RTPI Scotland believes that there is a clear opportunity to deliver 20 minute neighbourhoods using new place-based ways of working embedding this approach in the NPF4, in the operationalisation of the Place Principle and through new approaches to community engagement through Local Place Plans, a new provision set out in the Planning (Scotland) Act. 2019.
A place-based approach is about considering all aspects of a place when considering an intervention. The Place Standard tool provides a simple framework to structure conversations about place. This includes both physical and social elements of place structured around 14 themes. RTPI Scotland have called on the NPF4 to embed “Place and Wellbeing” themes from the Place Standard Tool to provide an evidenced, consistent framework for Scotland [26]. As a national level “Place and Wellbeing” policy requirement they provide a simple, understandable remit for how place impacts behaviour change to improve health and wellbeing, reduce carbon emissions and improve biodiversity. The themes are valuable for their contribution to all aspects of place, especially interventions underpinning 20 minute neighbourhoods. They are simple, already well understood and all sectors with an interest in place are already using them. Public Health Scotland are due to complete a full evidence review of these themes to update the initial evidence used to inform them.
Place Principle
The Scottish Government and COSLA have agreed to adopt the Place Principle to help overcome organisational and sectoral boundaries. This includes improving coordination between stakeholders, enhancing collaboration and communication across local authorities departments, key agencies, NGOs and private sector. The principle requests that all those responsible for providing services and looking after assets in a place need to work and plan together, and with local communities, to improve the lives of people, support inclusive growth and create more successful places. The Place Principle supports collaborative place-based action and the Place Standard is a commonly-used tool to help people think about the quality of their place and where action might be required. If the Place Principle is to be effective there is a need to ‘give it teeth’ and operationalise its work so it influences policy, practice and investment on the ground. RTPI Scotland believes that the planning system can be a facilitator of the Place Principle and place-based approaches. RTPI Scotland wish to see a clear articulation of how the NPF4 can embed, operationalise and champion the Place Principle. As a part of this there needs to be a stronger recognition of the role that proactive planning and place-leadership can have through the enhanced corporate influence of planning. There is an opportunity to achieve this through the Chief Planning Officer role, provisions for which are set out in the Planning (Scotland) Act 2019.
There is a need for a stronger policy framework and the introduction of measures to ensure that public authorities publicly report on how they have embedded the Place Principle in their approaches and how they have applied it in their decision making, including any reasoning. This should also apply to the Town Centre First Principle, as there needs to be greater transparency on how it these principles are considered in the decision making process. Appropriate enforcement may be required if necessary and public funding opportunities could be offered with a stipulation that there is adherence to the Place Principle and, where relevant, the Town Centre First Principle.
Once established, the Place Principle could help address many areas that would support the delivery a 20 minute neighbourhood including:
Aligning Local Place Plans, Local Outcome Improvement Plans, Locality Plans and LDPs to ensure reciprocity
Supporting the Infrastructure First Principle, Reuse First Principle and Town Centre First Principle.
Help overcome fragmented property ownership within town and city centres including a more pro-active approach to land assembly.
Develop proposals for Compulsory Sale Orders to make use of derelict and vacant land and buildings and deliver active travel networks.
Support Town Centre Actions Plans.
Co-coordinating investment across stakeholders towards place-based interventions.
Local Place Plans
Local Place Plans (LPPs) were introduced as a provision in the 2019 Planning (Scotland) Act. They are an exciting new type of plan providing opportunities for communities to develop proposals and ideas for the development of where they live. LPPs can help community planning and land-use planning achieve better outcomes for communities. RTPI Scotland believe there is a clear opportunity to integrate emerging Local Place Plans with the aspirations of 20 minute neighbourhoods, especially through the drafting of impending guidance. Local Place Plans and 20 minute neighbourhoods are both concerned with making everyday neighbourhoods and environments better places to live, work and play. They can help planners to communicate strategic overarching considerations and allow communities plan priorities for interventions, conveying detailed local understanding. A lot of these strategic considerations could be covered by many of the fundamental aspirations of 20 minute neighbourhoods, tailored to the specific circumstance and context of localities. Planners can in turn bring the vital links to other departments, agendas and organisations that help to navigate the system and turn community aspirations into reality.
Local community-led planning has been around for many years in the form of Community Action Planning and there are a range of existing projects that could be tied into LPPs and 20 minute neighbourhoods. For example the Sustaining Choices is pilot project delivered by Paths for All and Planning Aid Scotland [27]. The projects aim to produce a series of community-led active travel plans across Scotland. In the future similar approaches could be integrated into the LPP process.
However, for LPPs to succeed there needs to be funding set aside to support communities to develop them. There is currently no designated funding in place to support them to do this, although their success may well depend on this. It has been estimated that each LPP could cost between £10,000 - £30,000 each [28]. There is also a need to secure on-going funding for maintenance of any interventions identified. Full consideration also needs made as to how a diverse range of ages can be involved and how both geographic communities and communities of interest be engaged in the LPP preparation process.
[1]RTPI (2020) Plan The World We Need. June. Available here:http://bit.ly/2OvMyaf
[2]Aldred, R and Goodman, A (2020) Low Traffic Neighbourhoods, Car Use, and Active Travel: Evidence from the People and Places Survey of Outer London Active Travel Interventions. Transport Findings. September. Available here:https://bit.ly/38maKTn
[3]Dajnak, D et al. (2018) Air Quality: concentrations, exposure and attitudes in Waltham Forest .July. Available here:https://bit.ly/3sWUjoo
[4]Dajnak, D and Walton, H (2018) Waltham Forest study of life expectancy benefits of increased physical activity from walking and cycling. September. Available here:http://bit.ly/3enFw1Z
[5]Goodman, A, and Aldred R. (2021) The Impact of Introducing a Low Traffic Neighbourhood on Street Crime, in Waltham Forest, London. February. Available here:http://bit.ly/3s0wLyP
[6]Morris, E et al. (2020) Which activities do those with long commutes forego, and should we care? Transportation Research Interdisciplinary Perspectives.May. Available here:https://bit.ly/3sY2nVZ
[7]Criado-Perez (2019) Invisible Women: Exposing Data Bias in a World Designed for Men
[8]Improvement Service (2021) 20 Minute Neighbourhoods, Elected Member Briefing Note. January. Available here:https://bit.ly/3bw62Da
[9]Scottish Government (2010) Designing Streets: A Policy Statement for Scotland. March. Available here: http://bit.ly/3lHXCNJ
[10]Scottish Government (2013) Creating Places: A policy statement on architecture and place for Scotland. June. Available here:http://bit.ly/3fjEMf1
[11]Scottish Government (2019) Adoption of Scottish planning policy in local development plans: research. October. Available here:https://bit.ly/3kZUw7L
[12]Scottish Government (2013) Creating Places: A policy statement on architecture and place for Scotland. June. Available here:https://bit.ly/2N0n6cu
[13]Scottish Government (2010) Designing Streets: A Policy Statement for Scotland. March. Available here:https://bit.ly/3binnRi
[14]Scottish Government (2020) Fourth National Planning Framework: position statement. November. Available here:https://bit.ly/38l85cG
[15]Scottish Government (2020) Transforming Places Together: digital strategy for planning. November. Available here:https://bit.ly/2OBWVcj
[16]RTPI Scotland (2020) Transforming Planning, Places and Scotland - The benefits of investing in a digital planning service. November. Available here:https://bit.ly/3bgyDgW
[17]RTPI (2018) Settlement Patterns, Urban Form and Sustainability. May. Available here:https://bit.ly/3srnL5B
[18]Improvement Service (2020) Comparing the 20 Minute Neighbourhood and Traditional Scenarios in Edinburgh Local Development Plan: a Rapid Scoping Assessment. September. Available here:https://bit.ly/2P1cqL9
[19]RTPI (2021) Net Zero Transport: the role of spatial planning and place-based solutions. January. Available here:http://bit.ly/2OvBPfN
[20]https://nationalperformance.gov.scot/chart/journeys-active-travel
[21]Transport Scotland (2020) Scottish Transport Statistics No. 39 2020 edition. Available here:https://bit.ly/2On8LqM
[22]Transport Scotland (2009) Development Planning and Management Transport Appraisal Guidance. Available here:https://bit.ly/3biJPd7
[23]UK Government Department for Transport (2020) Road Traffic Estimates: Great Britain 2019. Available here:https://bit.ly/3kMzuJm
[24]Scottish Parliament Information Centre (2020) SPICe briefing - Low traffic neighbourhoods. October. Available here:https://bit.ly/3c8fygo
[25]RTPI (2020) Measuring What Matters: Planning Outcomes Research. November. Available here:https://bit.ly/3c8jzBc
[26]RTPI Scotland (2020) 10 Big Ideas for National Planning Framework 4 - RTPI Scotland response to Scottish Government’s call for ideas. May. Available here:https://bit.ly/3lqSD3S
[27]https://www.pas.org.uk/sustainingchoices/
[28]RTPI Scotland (2019) Financial Implications of Implementing the Planning (Scotland) Act 2019. August. Available here:https://bit.ly/3uRbtFT
| https://www.rtpi.org.uk/research/2021/march/20-minute-neighbourhoods/?fbclid=IwAR3p3ERMN83moWovVnM0bGpfgmJwYfeHG6CzgkA1UMDTkblvClWVghD1_tY |
The Horn Book | Fanfare 2020 Annotations
The Horn Book's choices of the best books of 2020.
Fanfare 2020 Annotations
Welcome to Fanfare, our choices of the best books of 2020.
Welcome to Fanfare, our choices of the best books of 2020. When The Horn Book’s tiny office went from wall-to-wall books, ARCs,effin’ jeez, and piles and piles of still more booksto fully remote, there was a lot of uncertainty. Overnight, our digital tag line — It’s virtually a whole new Horn Book — became the necessary new normal (the howof it being another story). Through it all, we had books to see us through; andthe titles on our annual Fanfare list— thirty in all, our best of the best — offer comfort, hope, inspiration, laughter, escapism, realism, community, sustenance, challenge, warmth, and more. With thisholiday seasonlike no other, wear a mask,support an indie, and share our Fanfare recommendations with people you love.
Picture Books
I Am Every Good Thingwritten by Derrick Barnes, illustrated by Gordon C. James; Paulsen/Penguin(Preschool, Primary)
“I am a roaring flame of creativity. / I am a lightning round of questions, and / a star-filled sky of solutions.” Barnes’s powerful first-person present-tense text affirms the limitless possibilities of Black boys’ lives, while James’s vibrant oil-paint illustrations harmoniously depict Black boys in motion, in contemplation, and in full vitality. Beautiful and necessary. Review 9/20.
In the Woodswritten by David Elliott, illustrated by Rob Dunlavey; Candlewick(Primary)
Fifteen thoughtful, pithy poems — some funny, some elegiac — capture the essence of the forest and its inhabitants. Expansive watercolor and mixed-media spreads are absolutely immersive in their realism. Spread by spread, readers can take in the whole scene from afar and be rewarded anew by looking closely. Review 3/20.
A Girl like Mewritten by Angela Johnson, illustrated by Nina Crews; Millbrook(Preschool, Primary)
It seems not even the sky’s the limit for the imaginative, adventurous, inventive girls depicted in Crews’s innovative, exuberant photo collages, paired with Johnson’s upbeat, encouraging text. They fly, stand atop tall buildings, and dive deep into oceans; but, most importantly, they resist others’ warnings, denials, and chastisements about “a girl like you.” Review 3/20.
Black Is a Rainbow Colorwritten by Angela Joy, illustrated by Ekua Holmes; Roaring Brook(Primary)
“My color is black.” A lyrical, metaphor-rich text uses familiar motifs and allusions to Black artistic contributions to highlight what black is. Heavy lines, strong colors, and soft touches of collage in the striking illustrations create a mosaic of a thriving culture. A wealth of back matter further enhances this treasure trove of positivity. Review 1/20.
The Camping Tripwritten and illustrated by Jennifer K. Mann; Candlewick(Primary)
Ernestine’s first camping trip, with her aunt and cousin, brings joy and thrills — but bedtime brings homesickness. “Let’s go look at the stars,” suggests her aunt, which does the trick. First-person, present-tense narration combines with superbly paced panel art for a warmhearted (and welcome)story about an African American family enjoying nature together. Review 5/20.
Hikewritten and illustrated by Pete Oswald; Candlewick(Preschool, Primary)
In this heartwarming wordless ode to nature and tradition, a brown-skinned father and child embark on an eventful daylong hike, the culmination of which connects them to previous generations. Gorgeous textured, earth-toned illustrations carry the narrative, with varied perspectives highlighting action or offering moments for reflection. Review 3/20.
A New Green Daywritten and illustrated by Antoinette Portis; Porter/Holiday(Preschool)
In this exuberant celebration of a summer day, readers engage with propulsive page-turns to solve simple nature riddles. “Morning lays me on your pillow, an invitation square and warm. Come out and play!” Hand-stamped lettering, leaf prints, sumi ink, vine charcoal, and digital color produce art that is tantalizingly evocative; summertime encapsulated. Review 5/20.
The Old Truckwritten and illustrated by Jarrett Pumphrey and Jerome Pumphrey; Norton(Preschool, Primary)
A hard-working truck and a young girl grow older, in parallel, on the family farm. The child, as an adult, becomes the “new farmer” and rehabilitates the long-broken-down vehicle. An African American farming family is depicted in the Pumphreys’ retro, earth-toned illustrations — technically masterful, uncluttered, and infused with cheer and playfulness. Review 3/20.
I Talk like a Riverwritten by Jordan Scott, illustrated by Sydney Smith; Porter/Holiday(Primary)
A boy who struggles with stuttering narrates this profound and empowering picture book. One day, the boy’s father takes him for a walk by a river and tells him that his speech is like the river — sometimes “churning, whirling, and crashing,” sometimes calm. Smith’s illustrations are a tour de force, showing both the boy’s internal emotions and the stunning beauty of the natural world — notably in a spectacular gatefold of the boy standing in the river’s embrace. Review 11/20.
Our Little Kitchenwritten and illustrated by Jillian Tamaki; Abrams(Primary)
A celebration of community, togetherness, creativity, and food, this book, set in a communal urban kitchen, exudes effervescence: “Beans from the food bank? Third week in a row! But it’s what we’ve got, we’ll use ’em somehow.” The characters — of all shapes, sizes, races, religions, abilities, and genders — radiate warmth, vibrancy, individuality, and purpose. Review 11/20.
Fiction
Clap When You Landwritten by Elizabeth Acevedo; Quill Tree/HarperCollins(High School)
After their father perishes in a plane crash, newly revealed half-sisters Camino (who lives in the Dominican Republic) and Yahaira (a native New Yorker) grapple with grief, the sting of deception, and the meaning of family. Acevedo ( The Poet X) again excels in this sharp and compelling verse novel centering Latinx young women. Review 7/20.
Fighting Wordswritten by Kimberly Brubaker Bradley; Dial(Intermediate, Middle School)
Ten-year-old Della has learned to be tough from her fiercely protective older sister Suki. Placed in a new foster home, the girls’ lives are looking up — but Suki is hiding a devastating secret. Narrated with pathos (and some humor) by audacious Della, the story showcases the astonishing strength and resilience of children as it cheers the bonds of sisterhood. Review 9/20.
King and the Dragonflieswritten by Kacen Callender; Scholastic(Intermediate, Middle School)
African American twelve-year-old King, sad and mourning, believes his late brother Khalid has “left his body behind like a second skin” and become a dragonfly. Dragonfly-Khalid guides King to his former best friend, Sandy — scared, bullied, and in hiding. Sandy is gay, and so, King gradually accepts, is he. Unflinchingly honest, uncommonly sensitive, and beautifully complex. Review 1/20.
Flamerwritten and illustrated by Mike Curato; Godwin/Holt(Middle School, High School)
Aiden hopes high school will provide some relief from being bullied, but meanwhile, there is summer Boy Scout camp to get through. This graphic novel, in black and white with judicious and effective splashes of an impassioned red, winningly captures the joys of camp and young love while at the same time exploring the hopes and fears of the human heart. Review 11/20.
Twinswritten by Varian Johnson, illustrated by Shannon Wright; Graphix/Scholastic(Intermediate, Middle School)
Sixth grade brings changes for African American twins Maureen (“the thinker”) and Francine (“the talker”). Francine expands her horizons by running for class president…and, for better or worse, her sister follows suit. A highly relatable middle-grade graphic novel, perfect for anyone who’s struggled with self-doubt or yearned to stand out. Review 11/20.
We Dream of Spacewritten by Erin Entrada Kelly; Greenwillow(Intermediate, Middle School)
In 1986, siblings Fitch, Bird, and Cash see their lives reflected and changed by a school project devoted to the upcoming (and ill-fated) Challenger space shuttle mission. As chapters alternate between each of the kids in turn, Kelly’s acuity and empathy for family and middle-school dynamics are on full display. Review 5/20.
Loretta Little Looks Back: Three Voices Go Tell Itwritten by Andrea Davis Pinkney, illustrated by Brian Pinkney; Little, Brown(Intermediate, Middle School)
Three members of a Mississippi family tell their stories in a lyrical “monologue novel” with insight into the complex African American experience of Jim Crow and the long fight for voting rights. Through a mix of drama, gospel, and rhythm and blues, and with great immediacy, author Pinkney presents a compelling testimony of resilience. Review 11/20.
Kent Statewritten by Deborah Wiles; Scholastic(Middle School, High School)
In somber free verse, a passionate imagined conversation among disembodied voices recalls the heart-wrenching 1970 Kent State shootings of university students by the National Guard. All the speakers bicker and lay blame but eventually sincerely wish that the murdered students “rest in peace.” The format vividly evokes the pain, confusion, and conflicting perspectives of the era, while also making timely connections. Review 5/20.
Echo Mountainwritten by Lauren Wolk; Dutton(Intermediate, Middle School)
Via poetic prose and brief, steadily paced chapters, Wolk immerses readers in the Maine woods setting where twelve-year-old Ellie’s family is forced to move during the Great Depression. Following a devastating accident that leaves her father in a coma, budding naturalist and healer Ellie makes some new and surprising friendships. An exemplary work of historical fiction. Review 7/20.
Nonfiction
Sharuko: El arqueólogo Peruano Julio C. Tello / Peruvian Archaeologist Julio C. Tellowritten by Monica Brown, illustrated by Elisa Chavarri, translated into Spanish by Adriana Domínguez; Children’s/Lee & Low(Primary, Intermediate)
This narratively engaging, visually spectacular picture-book biography of a groundbreaking archaeologist and educator forefronts Indigenous Peruvian science, knowledge systems, and art. Gouache and watercolor illustrations highlight panoramic Andean vistas; vignettes focus on resplendent brown faces. Notes from Brown and Chavarri affirm their commitment to perpetuating Peru’s Indigenous culture. Review 7/20.
Your Place in the Universewritten and illustrated by Jason Chin; Porter/Holiday(Primary, Intermediate)
Chin’s exceptional science picture book compares the relative sizes of things — including a group of children, famous tall buildings, and objects in space — in increasingly large units of measurement and to scale (where possible!). Stunning watercolor and gouache art helps elucidate the complex concepts, all clearly defined in the text. Review 11/20.
Honeybee: The Busy Life ofApis Melliferawritten by Candace Fleming, illustrated by Eric Rohmann; Porter/Holiday(Primary)
This up-close-and-personal look at the life cycle of one worker bee delivers an epic amount of information and packs a surprising emotional punch. With each stage of growth, Fleming’s text builds anticipation, while Rohmann’s detailed honey-toned art immerses readers in the life of the hive — and, in a climactic gatefold illustration, follows Apis as she flies for the first time. Review 3/20.
The Rise and Fall of Charles Lindberghwritten by Candace Fleming; Schwartz & Wade/Random(Middle School, High School)
With a fair-minded accounting of Lindbergh’s achievements (as an aviator and inventor) and his failings (as a racist and xenophobe), Fleming brings Lindbergh to three-dimensional life and asks us to think about what it means — tous as well as aboutus — to call someone a “hero.” Review 1/20.
The Next President: The Unexpected Beginnings and Unwritten Future of America’s Presidentswritten by Kate Messner, illustrated by Adam Rex; Chronicle(Primary, Intermediate)
Sure, George Washington was our first president, but did you know there were ninefuture presidents alive when his presidency began? This chronological but unique approach to presidential history invites us to consider the office as well as the — so far — men who have held it. Review 3/20.
How We Got to the Moon: The People, Technology, and Daring Feats of Science Behind Humanity’s Greatest Adventurewritten and illustrated by John Rocco; Crown(Intermediate, Middle School)
Rocco provides a clear, comprehensive, enthralling account of the scientific and historical factors involved in the U.S.’s effort to send humans to the moon. Breathtaking full-color pencil, watercolor, and digital illustrations and frequent elucidating side panels support the conversational text, culminating in a thrilling minute-by-minute chronicle of the Apollo 11 mission. Review 11/20.
Chance: Escape from the Holocaustwritten and illustrated by Uri Shulevitz; Farrar(Intermediate, Middle School)
Caldecott Medalist Shulevitz recounts his wartime childhood of displacement, discrimination, and hunger as his Jewish refugee family fled the Nazis — from Poland, to Russia, to Turkestan, and eventually Paris. Frequent expressive and lively grayscale illustrations illuminate poignant and emotional moments. Truly a portrait of an artist as a young man thrown into the maelstrom of a world gone mad. Review 11/20.
Exquisite: The Poetry and Life of Gwendolyn Brookswritten by Suzanne Slade, illustrated by Cozbi A. Cabrera; Abrams(Primary, Intermediate)
This picture-book biography of the Pulitzer Prize–winning poet lives up to its title. Cabrera’s acrylic paintings burst with creativity and joy, mixing realism — even the hard times — with idiosyncratic, expressionistic moments. With Slade’s attention to detail, vigorous prose, and judicious use of Brooks’s own words, both this “exquisite” biography and its subject stand out. Review 7/20.
All Thirteen: The Incredible Cave Rescue of the Thai Boys’ Soccer Teamwritten by Christina Soontornvat; Candlewick(Intermediate, Middle School)
Lucid prose in an immediate present tense gives a journalistic account of the difficult, complicated 2018 rescue of twelve members of a youth soccer team and their coach from a flooded cave in Thailand. Soontornvat clearly lays out the technical and engineering challenges while keeping a tight focus on the unfolding edge-of-your-seat drama. Review 9/20.
How to Find a Birdwritten by Jennifer Ward, illustrated by Diana Sudyka; Beach Lane/Simon(Preschool, Primary)
Ward’s enticing text pulls readers in with its welcoming and encouraging tone as two children demonstrate that “there are a lot of ways to find a bird.” Sudyka’s motion-filled watercolor gouache and digital illustrations manage to be both informative and beautiful, with bird names unobtrusively labeled throughout. This inspiring picture book reminds readers that “we can all be birdwatchers!” Review 7/20.
Dragon Hoopswritten and illustrated by Gene Luen Yang, color by Lark Pien; First Second/Roaring Brook(High School)
Yang’s latest comics-format book brilliantly combines journalism, memoir, and sports history. A math teacher at the school, he recounts the events of Bishop O’Dowd High School’s 2015 basketball season as the team attempted to win the California State Championship. While the action on the court is transfixing, portrayed in dynamic panels, the story shines just as brightly when Yang’s focus shifts to his own profound insights regarding art and storytelling. Review 5/20.
| https://www.hbook.com/story/Publications/fanfare-2020-annotations |
KLEIN TOOLS NCVT-1XTKIT Non Contact Voltage and GFCI Receptacle Electrical Test Kit Instructions
Instructions for KLEIN TOOLS models including: NCVT-1XTKIT, Non Contact Voltage and GFCI Receptacle Electrical Test Kit, NCVT-1XTKIT Non Contact Voltage and GFCI Receptacle Electrical Test Kit, GFCI Receptacle Electrical Test Kit, Receptacle Electrical Test Kit, Electrical Test Kit
NCVT1XTKIT Manual web
Klein Tools
Instructions
Non-Contact Voltage and GFCI Receptacle Premium Test Kit - NCVT1XTKIT | Klein Tools - For Professionals since 1857
Edmondson Supply | Klein Tools NCVT1XTKIT Non-Contact Voltage and GFCI Receptacle Premium Test Kit
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NCVT1XTKIT manual web
INSTRUCTIONS Non-Contact Voltage and GFCI Receptacle Electrical Test Kit (English: Page 2)
INSTRUCCIONES Kit de prueba eléctrica de receptáculos GFCI y voltaje sin contacto (Español: página 3) INSTRUCTIONS Trousse de test électrique pour les tensions sans contact et les prises avec disjoncteur de fuite de terre (Français : page 4)
NCVT-1XTKIT
4 3 9 2 1 5
6
8
7
ENGLISH
1. Power On / Off Button 2. Power On / Low Battery Indicator 3. Voltage Detection LEDs (Inside Tip) 4. Non-Contact Tip 5. Pocket Clip 6. O-ring Seal 7. Battery Cap 8. 2x AAA Batteries (Included) 9. Keep hand and fingers below this line while using tester NOTE: No user-serviceable parts inside. ESPAÑOL
1. Botón de encendido y apagado "NCV"
2. Indicador de encendido y batería baja
3. LED de detección de voltaje (en el interior de la punta)
4. Punta para detección y medición sin contacto
5. Clip de bolsillo
6. Junta tórica
7. Tapa del compartimento de baterías
8. 2 baterías AAA (incluidas)
9. Mantenga la mano y los dedos debajo de esta línea mientras
usa el probador
NOTA: No contiene piezas que el usuario pueda reparar.
FRANÇAIS
1. Bouton marche/arrêt NCV (test de tension sans contact) 2. Voyant de mise sous tension/piles faibles 3. Voyants DEL de détection de tension (dans la pointe) 4. Pointe sans contact 5. Agrafe pour poche 6. Joint torique 7. Couvercle de piles 8. 2 piles AAA (comprises) 9. Gardez la main et les doigts sous cette ligne pendant l'utilisation
REMARQUE : Ne contient pièce réparable par l'utilisateur.
NCVT-1XT · Non-contact detection of 70 to 1000V AC in cables, cords, circuit breakers, lighting fixtures, switches, outlets, and wires · When voltage is detected, a high intensity, bright red LED illuminates and a beeping sound is generated
·· CDuetaencdcoiónsesidnecteocnttaactetonsdieón7,0sVe aen1c0i0e0ndVeCuAnepnocteanblteesL, EcaDbdlees ccoolnodrurcotjoorebsr,ilclaonrttaecyircsueitooyse, aucnceinsdoircioasdodresilounmoirnoación, interruptores, tomacorrientes y alambres
·· DSiégtnecatlisoonnsoarnesectovnotyaacnttdDeElaL treonusgioenàdheau7t0e àin1te0n0s0itVé qc.uai.sdigannsalelenst cloârbslqesu,'ulensecteonrdsoionns,elsetsddéitsejcotnéceteurs, les luminaires, les interrupteurs, les prises et les fils
SYMBOLS ON TESTER / SÍMBOLOS DEL PROBADOR / SYMBOLES SUR LE TESTEUR
Warning Risk of electric shock / Advertencia: riesgo de choque eléctrico / Avertissement Risque d'électrocution
mRiasnkuoafldbaenfogreer.oImpeproatritnagntoirnsfoerrvmicaintigonth: iIst
is important that users tester. Failure to follow
of this tester read, instructions could
understand, and follow all warnings, result in death or serious injury.
cautions,
safety
information,
and
instructions
in
this
Riesgo de peligro. Información importante: Es importante que el usuario de este probador lea, comprenda y respete todas las advertencias, precauciones, instrucciones e información de seguridad incluidas en este manual, antes de poner en funcionamiento el probador o de realizarle servicios de mantenimiento. No seguir estas instrucciones puede dar lugar a lesiones graves o mortales.
sRéiscquurietédeetdinasntgruecr.tiIonnfosrdmoantnioéns dimanpsorletapnrtées:enIltegsutiidmepaovratannttdqeufeairleesfounticlistiaotnenuersr odue dceetreésptaeruerrlciseentets,tceoumr.pLreennonnen-rteestpseucitvpeonut trorauist elenstraavîneerrtisdseesmbelenstssu, rmesisgesraevnesg,avrodiere, ilnafomrmorat.tions de
Double insulated / Doble aislamiento / Double isolation
Read instructions / Lea las instrucciones / Lire les instructions
Conformité Européenne: Conforms with European Economic Area directives. Cumple con las normas del Área Económica Europea. Conforme aux directives de l'Espace économique Européen.
UKCA: UK Conformity Assessment Conformidad evaluada por el Reino Unido Évaluation de la conformité du Royaume-Uni
This product has been independently tested by Intertek and meets applicable published standards. Este producto ha sido probado de manera independiente por Intertek y cumple con las normas publicadas vigentes. Ce produit a été testé de manière indépendante par Intertek et répond aux exigences des normes applicables.
CAT For measurements performed at the source of low-voltage installation and outside lines. IV Para mediciones realizadas en la fuente de la instalación de bajo voltaje y líneas externas.
Pour des mesures prises à la source d'une installation à faible tension et des lignes extérieures.
5001748
DURABILITY / DURABILIDAD / DURABILITÉ
Ingress Protection
Protección contra el ingreso
IP67
Protection contre les infiltrations
Drop Protection Protección ante caídas Protection contre les chutes
9.8 ft. (3 m)
Safety Rating Clasificación de seguridad Cote de sécurité
CAT IV 1000V
FIG. 1 Indicator Indicador Voyant
RT210
Indicator Illuminated Indicador iluminado Voyant allumé
Indicator Not Illuminated Indicador no iluminado Voyant éteint
Fault
Explanation
Falla
Explicación
Anomalie
Explication
Open Ground
Ground contact is not connected
Conexión a tierra abierta
El contacto a tierra no está conectado
Mise à la terre non connectée Le contact de mise à la terre n'est pas connecté
Open Neutral
Neutral contact is not connected
Neutro abierto
El contacto neutro no está conectado
Neutre ouvert
Le contact neutre n'est pas connecté
Open Hot
Hot contact is not connected
Vivo abierto
El contacto vivo no está conectado
Phase ouverte
Le contact de phase n'est pas connecté
Hot/Ground Reversed
Hot and ground connections are reversed
Vivo/Tierra invertidos
Las conexiones viva y de tierra están invertidas
Phase/mise à la terre inversées Les connexions de phase et de mise à la terre sont inversées
Hot/Neutral Reversed
Hot and neutral connections are reversed
Vivo/Neutro invertidos
Las conexiones viva y neutra están invertidas
Phase/neutre inversés
Les connexions de phase et de neutre sont inversées
Correct
Receptacle is wired correctly
Correcto
El receptáculo está cableado correctamente
Correct
La prise est câblée correctement
· Designed to detect the most common wiring problems in standard and GhoFtC/gIrroeucnedptraecvleerss:eOdpen ground, reverse polarity, open hot, open neutral,
· Diseñado para detectar los problemas de cableado más comunes en receptáculos estándar y GFCI: puesta a tierra abierta, polaridad inversa, vivo abierto, neutro abierto y vivo/tierra invertidos
· Conçu pour détecter les problèmes de câblage les plus fréquents dans des prises standard et GFCI : mise à la terre ouverte, polarité inversée, phase ouverte, neutre ouvert, phase/mise à la terre inversées
Neutral (White) Neutro (blanco) Neutre (blanc)
Hot (Black) Vivo (negro) Phase (noir)
Ground (Green) Tierra (verde) / Mise à la terre (vert)
CAT II 5001748 300V
BASED ON: 1330999 Rev 04/22 B
ENGLISH
NCVT-1XT
RT210
GENERAL SPECIFICATIONS
The Klein Tools NCVT-1XT is a durable 70 to 1000V AC non-contact voltage tester with IP67 rating and a 3m (9.8') drop protection. · Environment: Indoor · Measurement Range: 70 to 1000V AC · Frequency Range: 50 to 500 Hz · Batteries: 2x AAA 1.5V Alkaline · Operating and Storage Altitude: Up to 6562 ft. (2000 m) · Operating and Storage Temp: 14° to 122°F (-10° to 50°C) · Relative Humidity: <95% non-condensing · Dimensions: 5.34" x 1.08" x 0.97" (135.6 x 27.4 x 22.1 mm) · Weight: 1.65 oz (46.7 g) with batteries · Pollution degree: 2 · Safety Rating: CAT IV 1000V AC · Drop Protection: 9.8 ft. (3 m) · Ingress Protection: IP67 · Standards: EN 61010-1:2010+A1: 2019,
EN IEC 61010-2-030:2021+A11:2021. Conforms to UL STD. 61010-1, 61010-2-030 Certified to CSA STD. C22.2 No. 61010-1, 61010-2-030.
5001748
Specifications subject to change.
WARNINGS
FToaielunrseurtoe osabfseerovpeetrhaetisoenwaanrdnsinegrvsicceanofrethsueltteisntesre,vfeorleloiwnjtuhreysoeridnesatrtuhc.tions. · Risk of electric shock and burn. Contact with live circuits could result in death or serious
injury. · Use caution with voltages above 25V AC as a shock hazard may exist. · A blinking LED or a steadily illuminated LED in the tip and audible beeps indicate presence
of voltage. If no indication, voltage could still be present. · Before and after each use, verify operation by testing a known working circuit that is within
the rating of this unit. · Never assume neutral or ground wires are de-energized. Neutrals in multi-wire branch
circuits may be energized when disconnected and must be retested before handling. · The tester WILL NOT detect voltage if:
· The wire is shielded. · The operator is not grounded or is otherwise isolated from an effective earth ground. · The voltage is DC. · The tester MAY NOT detect voltage if: · The user is not holding the tester. · The user is insulated from the tester with a glove or other materials. · The wire is partially buried or in a grounded metal conduit. · The tester is at a distance from the voltage source. · The field created by the voltage source is being blocked, dampened, or otherwise
interfered with. · The frequency of the voltage is not a perfect sine wave between 50 and 500Hz. · The tester is outside of operating conditions (listed in Specifications section). · Operation may be affected by differences in socket design and insulation thickness and type; tester may not be compatible with some types of standard or tamper resistant (TR) electrical outlets. · In bright light conditions, the LED visual indicators will be less visible. · When powered-ON, one of the "power-ON" LED's will be illuminated, and a green light wILiLllUilMluImNiAnTaEteDt.he tip. DO NOT USE TESTER UNLESS ONE OF THE "POWER-ON" LEDs IS · Do not use if tester appears damaged or is not operating properly. If in doubt, replace the tester. · Do not apply more than the rated voltage as marked on the tester (1000V). · Do not apply to uninsulated hazardous live conductors. · Detection above 70V AC is specified under "normal" conditions as detailed below. The tester may detect at a different threshold at different conditions, or may not detect at all unless: · The tip of the tester is within 0.25" (6 mm) of an AC voltage source radiating unimpeded. · The user is holding the body of the tester with his or her bare hand. · The user is standing on or connected to earth ground. · The air humidity is nominal (50% relative humidity non-condensing). · The tester is held still. · Always wear approved eye protection. · Comply with local and national safety requirements. · If this product is used in a manner not specified by the manufacturer, protection provided by the product may be affected.
FUNCTION BUTTONS NCV POWER ON/OFF BUTTON 1 Press and release the NCV Power button 1 . The tester will emit a single beep, the Power On Indicator 2 and green LED 3 in the tip will illuminate. To power-OFF the tester, press and release the Power On / Off button 1 . The tester will emit a double beep. NOTE: The tester will automatically power-OFF following 4 minutes of inactivity to conserve battery life.
OPERATING INSTRUCTIONS CHECKING FOR THE PRESENCE OF AC VOLTAGE 1. Press the Power On / Off button. After performing a self-test,
a green LED 3 will illuminate the tip when no voltage is detected. 2. Prior to use, test on a known live circuit to verify tester functionality. 3. Place tip of the tester 4 near AC voltage. If voltage is present, the unit will emit audible beeps and the red LED 3 in the tip will illuminate.
SILENT OPERATION To activate silent operation, power-ON by pressing and holding the NCV Power-ON button 1 for more than 2 seconds. PowerON in this manner each time silent operation is desired.
MAINTENANCE BATTERY REPLACEMENT When the battery is low, the unit will power-on with a blinking red LED 2 . When this happens, the batteries must be replaced:
1. Unscrew the battery cap 7 and remove/recycle spent batteries.
2. Install two new AAA batteries. Note proper polarity. 3. Screw battery cap tightly to ensure a tight seal with the O-Ring 6 .
CLEANING Be sure tester is turned off and wipe with a clean, dry lintfree cloth. Do not use abrasive cleaners or solvents.
STORAGE Remove the batteries when not in use for a prolonged period of time. Do not expose to high temperatures or humidity. After a period of storage in extreme conditions exceeding the limits mentioned in the General Specifications section, allow the tester to return to normal operating conditions before using.
GENERAL SPECIFICATIONS
· Environment: Indoor · Operating and Storage Altitude: Up to 6562 ft. (2000 m) · Operating Temperature: 32° to 140°F (0° to 40°C) · Storage Temperature: 14° to 122°F (-10° to 50°C) · Relative Humidity: <85% non-condensing
· Weight: 1.2 oz (33 g) · Pollution degree: 2 · Safety Rating: CAT II 300V · Drop Protection: 6.6 ft. (2 m)
· Mains supply voltage fluctuations: ±10%
· Nominal Voltage: 110 - 125V AC at 50/60Hz in 3-wire outlet
· Standards: Conforms to UL Std 61010-1, 61010-2-030,1436.
Certified to CSA Std C22.2 #61010-1, 61010-2-030,160.
Specifications subject to change.
5001748
WARNINGS
Read, understand, and follow all warnings and instructions before operating testers. Failure to follow instructions could result in death or serious injury. Before each use, verify tester operation by testing on a known live and correctly wired receptacle. Do not use if the tester appears damaged in any way. The tester is intended for indoor use only. Other equipment or devices attached to the circuit being tested could interfere with the tester, clear the circuit before testing. This tester only detects common wiring problems. Always consult a qualified electrician to resolve wiring problems.
WIRING CONFIGURATION TESTING
Conditions indicated: wiring correct, open ground, reverse polarity, open hot, open neutral and hot/ ground reversed. Conditions NOT indicated: quality of ground, multiple hot wires, combinations of defects, reversal of grounded and grounding conductors. All appliances or equipment on the circuit being tested should be unplugged to help reduce the possibility of erroneous readings.
STANDARD RECEPTACLES 1. Verify tester operation by testing on a known live and correctly wired receptacle. 2. Plug tester into receptacle. 3. Compare the illuminated lights on the tester to the key code printed on the tester. 4. If the tester indicates that the receptacle is not wired correctly, consult a qualified electrician.
GFCI RECEPTACLES 1. Check the GFCI receptacle user manual for information on how the specific receptacle operates prior to
using this tester. 2. Insert the tester into the receptacle under test to check for correct wiring (See FIG. 1). Lights on the
tester should illuminate. 3. Press the "TEST" button on the GFCI receptacle.
Did the GFCI trip and the lights on the tester go dark? YES: Reset the GFCI by pressing the reset button. Proceed to step 4. NO: The GFCI is not operating properly or the receptacle is miswired. Consult a qualified electrician.
4. Press and hold the test button on the tester for 7 seconds. Did the GFCI trip and the lights on the tester go dark? YES: Reset the GFCI by pressing the reset button. The GFCI appears to be operating properly. NO: The GFCI is not operating properly or the receptacle is miswired. Consult a qualified electrician.
FCC AND IC COMPLIANCE
See this product's page at www.kleintools.com for FCC compliance information. Canada ICES-003 (B) / NMB-003 (B)
CLEANING Wipe with a clean, dry lint-free cloth. Do not use abrasive cleaners or solvents.
DISPOSAL / RECYCLE Do not place equipment and its accessories in the trash. Items must be properly disposed of in accordance with local regulations. Please see www.epa.gov/recycle for additional information.
CAUTION · DO NOT attempt to repair this tester. It contains no serviceable parts. · DO NOT expose tester to extremes in temperature or high humidity.
450 Bond Street, Lincolnshire, IL 60069
CUSTOMER SERVICE KLEIN TOOLS, INC.
1-800-553-4676 customerservice@kleintools.com
www.kleintools.com
ESPAÑOL
NCVT-1XT
RT210
ESPECIFICACIONES GENERALES
El NCVT-1XT de Klein Tools es un probador de voltaje sin contacto que detecta de 70 a 1000 V CA que cuenta con una clasificación IP67 y protección ante caídas de 3 m (9,8').
· Entorno: Interior
· Rango de medición: 70 a 1000 V CA
· Rango de frecuencia: 50 a 500 Hz
· Baterías: 2 baterías alcalinas AAA de 1,5 V
· Altitud de funcionamiento y almacenamiento: hasta 6562' (2000 m)
· Temperatura de funcionamiento y almacenamiento: 14 a 122 °F (-10 a 50 °C)
· Humedad relativa: <95 %, sin condensación
· Dimensiones: 5,34" × 1,08" × 0,97" (135,6 × 27,4 × 22,1 mm)
· Peso: 1,65 oz (46,7 g) con baterías
· Grado de contaminación: 2
· Clasificación de seguridad: CAT IV 1000 V CA
· Protección ante caídas: 9,8' (3 m)
· Protección de ingreso: IP67
· Normas: EN 61010-1:2010+A1: 2019,
EN IEC 61010-2-030:2021+A11:2021.
Cumple con la norma UL. 61010-1, 61010-2-030
Certificado según la norma. C22.2 n.º 61010-1, 61010-2-030.
5001748
Especificaciones sujetas a cambios.
ADVERTENCIAS
Para garantizar el funcionamiento y servicio seguros del probador, siga estas instrucciones. El incumplimiento de estas advertencias puede provocar lesiones graves o la muerte. · Riesgo de choque eléctrico y quemaduras. El contacto con los circuitos activos podría provocar la muerte o
lesiones graves. · Tenga precaución con los voltajes superiores a 25 V CA, ya que podría existir riesgo de choque eléctrico. · Un LED intermitente o fijo en la punta y la emisión de pitidos indican la presencia de voltaje. Aun cuando
el instrumento no lo indique, es posible que haya voltaje. · Antes y después de cada uso, verifique el funcionamiento realizando una prueba en un circuito activo que
se encuentre dentro de la capacidad de esta unidad. · Nunca suponga que los cables neutro y de puesta a tierra están desenergizados. Los neutros en circuitos
derivados de cables de múltiples alambres pueden estar energizados aunque estén desconectados y deben volver a probarse antes de manipularlos. · El probador NO detectará voltaje en las siguientes situaciones: · Si el cable está blindado. · Si el operador no está conectado a tierra o está aislado de alguna manera de una toma de tierra eficaz. · Si el voltaje es de CD. · El probador POSIBLEMENTE NO detecte voltaje en las siguientes situaciones: · Si el usuario no sostiene el probador. · Si el usuario está aislado del probador mediante un guante u otro material. · Si el cable está parcialmente enterrado o en un conducto de metal conectado a tierra. · Si el probador se encuentra a cierta distancia de la fuente de voltaje. · Si el campo creado por la fuente de voltaje está bloqueado, amortiguado o sometido a interferencia de
alguna otra manera. · Si la frecuencia de voltaje no es una onda sinusoidal perfecta entre 50 y 500 Hz. · Si el probador se encuentra fuera de las condiciones de funcionamiento (descritas en la sección
Especificaciones). · El funcionamiento puede llegar a verse afectado por diferencias en el diseño del enchufe y el tipo y grosor
del aislamiento. Es posible que el probador no sea compatible con algunos tipos de tomacorrientes estándar o inviolables. · En condiciones de mucha luz, los indicadores visuales LED serán menos visibles. · Al encenderse la unidad, se iluminará uno de los LED de "encendido" y una luz verde iluminará la punta. NO UTILICE EL PROBADOR A MENOS QUE UNO DE LOS LED DE "ENCENDIDO" ESTÉ ILUMINADO. · No use el probador si parece dañado o si no funciona correctamente. Si tiene dudas, reemplace el probador. · No aplique un voltaje nominal mayor al indicado en el probador (1000 V). · No lo utilice en conductores activos peligrosos sin aislamiento. · La detección de más de 70 V CA en el modo 1 o de más de 12 V CA en el modo 2 se especifica en condiciones "normales" como se indica a continuación. El probador puede detectar voltaje en un umbral diferente, en diferentes condiciones, o puede no detectar voltaje en absoluto a menos que: · La punta del probador está dentro de 0,25" (6 mm) de una fuente de voltaje de CA que irradia sin
impedimento. · El usuario sostiene el cuerpo del probador con la mano descubierta. · El usuario está parado sobre una toma de tierra o conectado a ella. · La humedad del aire es de valor nominal (50 % de humedad relativa, sin condensación). · El probador se sostiene firmemente para mantenerlo inmóvil. · Siempre debe usar protección para los ojos aprobada. · Cumpla con los requisitos locales y nacionales de seguridad. · Si este producto se usa de una manera contraria a lo especificado por el fabricante, la protección proporcionada por el producto puede verse afectada.
PRECAUCIÓN
· NO intente reparar el probador. No contiene piezas que se puedan reparar. · NO exponga el probador a condiciones de temperatura extrema o de humedad alta.
BOTONES DE FUNCIONES BOTÓN DE ENCENDIDO Y APAGADO NCV 1 Presione y suelte el botón de encendido NCV 1 . El probador emitirá un solo pitido y se encenderá el indicador de encendido 2 y el LED 3 verde en la punta. Para apagar el probador, mantenga presione y suelte el botón de encendido y apagado 1 . El probador emitirá dos pitidos. NOTA: El probador se apagará automáticamente después de 4 minutos de inactividad para preservar la vida útil de las baterías.
INSTRUCCIONES DE FUNCIONAMIENTO VERIFICACIÓN DE PRESENCIA DE VOLTAJE CA 1. Presione el botón de encendido y apagado. Después de realizar una autoprueba,
un LED verde 3 iluminará la punta cuando no se detecta ningún voltaje. 2. Antes de utilizar el probador, realice pruebas en un circuito activo para comprobar
que funcione correctamente. 3. Coloque la punta del probador 4 cerca del voltaje CA. Si se detecta voltaje, la
unidad emitirá pitidos y se encenderá el LED rojo 3 en la punta. FUNCIONAMIENTO EN MODO SILENCIOSO Para activar el modo silencioso, mantenga presionado el botón de encendido NCV 1 durante más de 2 segundos. Encienda el probador de esta manera cada vez que desee hacerlo funcionar en modo silencioso.
MANTENIMIENTO REEMPLAZO DE LAS BATERÍAS Cuando la batería tiene poca carga, la unidad se enciende mostrando un LED rojo intermitente 2 . Cuando esto ocurre, las baterías deben reemplazarse: 1. Desenrosque la tapa del compartimiento de las baterías 7 y retire y envíe las
baterías agotadas a reciclaje. 2. Instale dos baterías AAA nuevas. Tenga en cuenta la polaridad correcta. 3. Enrosque la tapa del compartimiento de las baterías firmemente para garantizar un
cierre estanco con la junta tórica 6 .
LIMPIEZA Asegúrese de que el probador esté apagado y límpielo con un paño limpio y seco que no deje pelusas. No utilice solventes ni limpiadores abrasivos.
ALMACENAMIENTO Retire las baterías si no va a utilizar el instrumento durante un tiempo prolongado. No lo exponga a la humedad ni a altas temperaturas. Luego de un período de almacenamiento en condiciones extremas que sobrepasen los límites mencionados en la sección Especificaciones generales, deje que el probador vuelva a las condiciones de funcionamiento normales antes de utilizarlo.
CONFORMIDAD CON LA NORMATIVA FCC/IC Puede leer la información sobre la normativa FCC para este producto en www. kleintools.com. ICES-003 (B)/NMB-003 (B) de Canadá
ESPECIFICACIONES GENERALES
· Entorno: Interior
· Altitud de funcionamiento y almacenamiento: hasta 6562' (2000 m)
· Temperatura de operaón: 32° a 140°F (0° a 40°C)
· Peso: 1,2 oz (33 g)
· Temperatura de almacenamiento: 14° a 122°F (-10° a 50°C) · Grado de contaminación: 2
· Humedad relativa: < 85% sin condensación
· Clasificación de seguridad: CAT II 300V
· Fluctuaciones de voltaje de suministro de redes: ±10% · Protección ante caídas: 6,6 pies (2 m)
· Voltaje nominal: 110 V CA - 125 V CA a 50 Hz/60 Hz en tomacorriente de 3 alambres
· Normas: Cumple con la norma UL Std 61010-1, 61010-2-030,1436.
Certificado según la norma CSA Std C22.2 #61010-1, 61010-2-030,160.
Especificaciones sujetas a cambios.
5001748
ADVERTENCIAS Antes de utilizar los probadores, lea, comprenda y respete todas las advertencias e instrucciones. No seguir estas instrucciones puede dar lugar a lesiones graves o mortales. Antes de cada uso, verifique el funcionamiento del probador realizando una prueba en un receptáculo con corriente conocida y correctamente cableado. No utilice el probador si está dañado. El probador está diseñado solo para uso en ambientes interiores. Es posible que otros equipos o dispositivos conectados al circuito sometido a prueba causen interferencia con el probador. Despeje el circuito antes de realizar la prueba. Este probador solo detecta problemas de cableado comunes. Siempre consulte a un electricista calificado para solucionar problemas de cableado.
PRUEBAS DE CONFIGURACIÓN DE CABLEADO Antes de utilizar los probadores, lea, comprenda y respete todas las advertencias e instrucciones. No seguir estas instrucciones puede dar lugar a lesiones graves o mortales. Antes de cada uso, verifique el funcionamiento del probador realizando una prueba en un receptáculo con corriente conocida y correctamente cableado. No utilice el probador si está dañado. El probador está diseñado solo para uso en ambientes interiores. Es posible que otros equipos o dispositivos conectados al circuito sometido a prueba causen interferencia con el probador. Despeje el circuito antes de realizar la prueba. Este probador solo detecta problemas de cableado comunes. Siempre consulte a un electricista calificado para solucionar problemas de cableado. Condiciones indicadas por el probador: cableado correcto, puesta a tierra abierta, polaridad inversa, vivo abierto, neutro abierto y vivo/tierra invertidos. Condiciones NO indicadas por el probador: calidad de tierra, múltiples cables vivos, combinaciones de defectos, inversión de conductor conectado a tierra y conductor de conexión a tierra. Se deben desenchufar todos los electrodomésticos y equipos conectados al circuito sometido a prueba para ayudar a reducir la posibilidad de que se produzcan lecturas erróneas. RECEPTÁCULOS ESTÁNDAR 1. Compruebe el funcionamiento del probador realizando una prueba en un receptáculo con
corriente conocida y correctamente cableado. 2. Enchufe el probador en el receptáculo. 3. Compare las luces encendidas en el probador con el código de colores impreso en el probador. 4. Si el probador indica que el receptáculo no está correctamente cableado, comuníquese con un
electricista calificado. RECEPTÁCULOS GFCI 1. Antes de usar este probador, lea el manual del usuario del receptáculo GFCI para obtener
información sobre su funcionamiento. 2. Inserte el probador en el receptáculo sometido a prueba para verificar si el cableado es
correcto. (Consulte la FIG. 1). Las luces del probador deben encenderse. 3. Presione el botón "TEST" ("PROBAR") en el receptáculo GFCI. ¿Se accionó el GFCI y se
oscurecieron las luces del probador? SÍ: Reinicie el GFCI presionando el botón de reinicialización. Siga con el paso 4. NO: El GFCI no funciona correctamente o el receptáculo tiene errores de cableado. Comuníquese con un electricista calificado. 4. Mantenga presionado el botón de prueba en el probador durante 7 segundos. ¿Se accionó el GFCI y se oscurecieron las luces del probador? SÍ: Reinicie el GFCI presionando el botón de reinicialización. Parece que el GFCI funciona correctamente. NO: El GFCI no funciona correctamente o el receptáculo tiene errores de cableado. Comuníquese con un electricista calificado.
LIMPIEZA Límpielo con un paño limpio y seco que no deje pelusas. No utilice solventes ni limpiadores abrasivos
ELIMINACIÓN/RECICLAJE No arroje el equipo ni sus accesorios a la basura. Los elementos se deben desechar correctamente de acuerdo con las regulaciones locales. Para obtener más información, consulte www.epa.gov/recycle.
450 Bond Street, Lincolnshire, IL 60069
SERVICIO AL CLIENTE KLEIN TOOLS, INC.
1-800-553-4676 customerservice@kleintools.com
www.kleintools.com
FRANÇAIS
NCVT-1XT
RT210
CARACTÉRISTIQUES GÉNÉRALES
BOUTONS DE FONCTION
CARACTÉRISTIQUES GÉNÉRALES
Le NCVT-1XT de Klein Tools est un testeur de tension sans contact durable de 70 à 1000 V c.a. BOUTON MARCHE/ARRÊT NCV (TEST DE TENSION SANS CONTACT) 1
doté d'une cote IP67 et d'une protection contre les chutes de 3 m (9,8 pi). · Environnement : intérieur · Plage de mesure : 70 à 1000 V c.a. · Plage de fréquences : 50 à 500 Hz · Piles : 2 piles alcalines AAA de 1,5 V
Appuyez sur le bouton marche/arrêt NCV (test de tension sans contact) 1 et relâchez-le. Le testeur émettra un signal sonore, et le voyant de mise sous tension 2 et le voyant DEL 3 vert de la pointe s'allumeront. Pour éteindre le testeur, appuyez sur le bouton marche/arrêt NCV (test
· Altitude de fonctionnement et d'entreposage : jusqu'à 2000 m (6562 pi) · Température de fonctionnement et d'entreposage : -10 °C à 50 °C (14 °F à 122 °F) · Humidité relative : <95 % sans condensation · Dimensions : 135,6 x 27,4 x 22,1 mm (5,34 x 1,08 x 0,97 po) · Poids : 46,7 g (1,65 oz) avec les piles
de tension sans contact) 1 et relâchez-le. Le testeur émettra un double signal sonore. REMARQUE : Le testeur s'arrêtera automatiquement après 4 minutes d'inactivité pour préserver la charge de la pile.
· Niveau de pollution : 2
· Cote de sécurité : CAT IV 1000 V c.a. · Protection contre les chutes : 3 m (9,8 pi) · Protection contre les infiltrations : IP67
INSTRUCTIONS D'UTILISATION VÉRIFICATION DE LA PRÉSENCE D'UNE TENSION C.A.
·
Normes : EN 61010-1:2010+A1:2019,
IEC EN 61010-2-030:2021+A11:2021.
Conforme aux normes UL n° 61010-1 et 61010-2-030
Certifié conforme aux normes CSA C22.2 n° 61010-1 et 61010-2-030
5001748
Les caractéristiques techniques peuvent faire l'objet de modifications.
1. 2.
Appuyez sur le bouton marche/arrêt NCV (test de tension sans contact). Le testeur effectuera un autotest, puis le voyant DEL 3 vert dans la pointe s'illuminera si aucune tension n'est détectée. Avant l'utilisation, testez sur un circuit alimenté connu pour vérifier la fonctionnalité du testeur.
AVERTISSEMENTS
3. Placez la pointe du testeur 4 près d'une tension c.a. Si une tension
Pour garantir une utilisation et un entretien sécuritaires du testeur, respectez ces consignes. Le non-respect de ces avertissements peut entraîner des blessures graves, voire la mort.
est présente, il produit un signal sonore et le voyant DEL 3 rouge dans la pointe s'allume.
· Risque de choc électrique et de brûlures. Tout contact avec un circuit sous tension peut provoquer des blessures graves, voire la mort.
· Faites preuve de prudence lorsque vous travaillez avec des tensions supérieures à 25 V c.a., en raison du risque de choc électrique.
· Un voyant DEL clignotant ou un voyant DEL illuminé de façon continue dans la pointe et un signal sonore indiquent la présence d'une tension. Même lorsqu'il n'y a pas de signal, une tension peut être présente.
FONCTIONNEMENT SILENCIEUX Pour activer le fonctionnement silencieux, appuyez sur le bouton marche/ arrêt NCV (test de tension sans contact) 1 et tenez-le enfoncé pendant plus de 2 secondes. Procédez de cette façon chaque fois que vous désirez activer le fonctionnement silencieux.
· Avant et après chaque utilisation, vérifiez le fonctionnement de l'appareil sur un circuit dont vous connaissez l'état de fonctionnement se trouvant à proximité de l'unité.
ENTRETIEN
· Ne supposez jamais que le fil de mise à la terre et le fil neutre sont hors tension. Les fils neutres des circuits de dérivation à câbles multiples peuvent être sous tension lorsqu'ils sont débranchés; il faut les retester avant de les manipuler.
· Le testeur NE DÉTECTERA PAS de tension si : · Le fil est blindé. · L'utilisateur n'est pas mis à la terre ou est isolé d'une mise à la terre efficace. · La tension est une tension c.c.
· Le testeur POURRAIT NE PAS détecter de tension si : · L'utilisateur ne tient pas le testeur. · L'utilisateur est isolé du testeur à l'aide de gants ou d'autres matières. · Le fil est partiellement enterré ou se trouve dans un conduit métallique mis à la terre.
REMPLACEMENT DES PILES Lorsque les piles sont faibles, un voyant DEL 2 rouge clignote lors de la mise sous tension du testeur. Lorsque cela se produit, les piles doivent être remplacées. 1. Dévissez le couvercle de piles 7 , puis retirez et recyclez les
piles usagées. 2. Placez deux nouvelles piles AAA. Tenez compte de la polarité. 3. Vissez solidement le couvercle de piles pour assurer l'étanchéité
avec le joint torique 6 .
· Le testeur est trop loin de la source de tension. · Le champ créé par la source de tension est bloqué, atténué ou perturbé. · La fréquence du courant n'est pas une onde sinusoïdale parfaite de 50 à 500 Hz. · Le testeur n'est pas utilisé dans les conditions de fonctionnement définies dans la section
NETTOYAGE Essuyez-le à l'aide d'un linge non pelucheux propre. N'utilisez pas de nettoyant abrasif ni de solvant.
Caractéristiques générales. · Le fonctionnement peut être influencé par les différences dans la conception des prises et dans l'épaisseur
ENTREPOSAGE
et le type de blindage; le testeur pourrait ne pas être compatible avec certains types de prises électriques Retirez les piles lorsque vous prévoyez ne pas utiliser le testeur pendant
standard ou inviolables. · Dans des conditions de forte luminosité ambiante, les voyants DEL pourraient être moins visibles. · Lorsque le testeur est mis sous tension, l'un des voyants DEL de mise sous tension s'allume et la pointe
s'illumine en vert. N'UTILISEZ PAS LE TESTEUR À MOINS QU'UN DES VOYANTS DEL DE MISE SOUS TENSION SOIT ALLUMÉ. · N'utilisez pas le testeur s'il semble être endommagé ou s'il ne fonctionne pas correctement. Dans le doute,
une longue période. N'exposez pas l'appareil à des températures ou à un taux d'humidité élevés. Après une période d'entreposage dans des conditions extrêmes (hors des limites mentionnées dans la section Caractéristiques générales), laissez le testeur revenir à des conditions d'utilisation normales avant de l'utiliser.
remplacez le testeur. · Évitez d'appliquer une tension supérieure à la tension nominale indiquée sur le testeur (1000 V). · N'appliquez pas l'appareil sur des conducteurs non isolés, sous tension et potentiellement dangereux. · La détection d'une tension supérieure à 70 V c.a. en mode 1 ou supérieure à 12 V c.a. en mode 2 est
définie dans les conditions « normales » mentionnées ci-dessous. Le testeur pourrait détecter la tension à partir d'un seuil différent, ou même ne rien détecter, lorsque les conditions sont différentes, sauf si : · La pointe du testeur se trouve à moins de 6 mm (0,25 po) d'une source de tension c.a. produisant un
CONFORMITÉ FCC ET IC Consultez la page de ce produit à l'adresse www.kleintools.com pour obtenir des renseignements sur la conformité à la Federal Communications Commission (FCC). Canada ICES-003 (B) / NMB-003 (B)
champ non atténué.
· L'utilisateur tient le boîtier du testeur dans ses mains nues.
· L'utilisateur est debout sur une surface mise à la terre ou est relié à la terre.
· L'humidité de l'air est nominale (50 % d'humidité relative sans condensation).
· Environnement : intérieur
· Poids : 33 g (1,2 oz)
· Altitude de fonctionnement et fonctionnement : Jusqu'à 2000 m (6562 pi) · Température de fonctionnement : 0 °C à 40 °C (32 °F à 140 °F) · Température d'entreposage : -10 °C à 50 °C (14 °F à 122 °F)
· Niveau de pollution : 2 · Cote de sécurité : CAT II 300V · Protection contre les chutes : 2 m (6,6 pi)
· Humidité relative : < 85 % (sans condensation)
· Fluctuations de tension d'alimentation du réseau : ± 10 %
· Tension nominale : 110 - 125 V c.a. à 50/60 Hz dans une prise à trois fils
· Certification: Conforme à la norme UL Std 61010-1, 61010-2-030,1436.
Certifié conforme à la norme CSA Std C22.2 #61010-1, 61010-2-030,160.
5001748
Les caractéristiques techniques peuvent faire l'objet de modifications.
AVERTISSEMENTS Veuillez lire, comprendre et tenir compte de tous les avertissements et de toutes les directives avant d'utiliser un testeur. Le non-respect pourrait entraîner des blessures graves, voire la mort. Avant chaque utilisation, vérifiez le fonctionnement de l'appareil en effectuant un test sur une prise dont le fonctionnement est connu et dont le câblage est correct. N'utilisez pas l'appareil s'il semble avoir été endommagé de quelque manière que ce soit. Cet appareil est destiné à une utilisation à l'intérieur seulement. D'autres équipements ou appareils branchés au circuit vérifié peuvent interférer avec l'appareil; libérez le circuit avant de débuter la vérification. Ce testeur ne détecte que les problèmes de câblage les plus fréquents. Communiquez toujours avec un électricien qualifié pour résoudre les problèmes de câblage.
VÉRIFICATION DE LA CONFIGURATION DE CÂBLAGE Conditions indiquées : câblage adéquat, mise à la terre ouverte, polarité inversée, phase ouverte, neutre ouvert et phase/mise à la terre inversées. Conditions NON indiquées : qualité de la mise à la terre, fils de phase multiples, combinaisons de défauts, inversement des conducteurs mis à terre et des conducteurs de mise à la terre. Tous les électroménagers et l'équipement électrique branchés sur le circuit vérifié doivent être débranchés pour réduire le risque de lecture erronée. PRISES STANDARD 1. Vérifiez le fonctionnement de l'appareil en effectuant un test sur une prise dont le fonctionnement est connu et
dont le câblage est correct. 2. Branchez l'appareil dans la prise. 3. Comparez les voyants allumés sur le testeur au code de référence imprimé sur celui-ci. 4. Si le testeur indique que le câblage de la prise est incorrect, consultez un électricien qualifié. PRISES GFCI 1. Consultez le manuel de l'utilisateur de la prise GFCI pour connaître le fonctionnement de la prise avant
d'utiliser ce testeur. 2. Insérez le testeur dans la prise pour vérifier si le câblage est adéquat (voir la FIG. 1). Les voyants sur
le testeur devraient s'allumer. 3. Appuyez sur le bouton « TEST » de la prise GFCI. La prise GFCI s'est-elle déclenchée et les voyants sur le
testeur se sont-ils éteints? OUI : Réinitialisez la prise GFCI en appuyant sur le bouton de réenclenchement sur celle-ci. Passez à l'étape 4. NON : La prise GFCI ne fonctionne pas correctement ou le câblage n'est pas adéquat. Consultez un électricien qualifié. 4. Appuyez sur le bouton de test du testeur pendant 7 secondes. La prise GFCI s'est-elle déclenchée et les voyants sur le testeur se sont-ils éteints? OUI : Réinitialisez la prise GFCI en appuyant sur le bouton de réenclenchement sur celle-ci. La prise GFCI semble fonctionner correctement. NON : La prise GFCI ne fonctionne pas correctement ou le câblage n'est pas adéquat. Consultez un électricien qualifié.
NETTOYAGE Assurez-vous d'éteindre le testeur, puis essuyez-le à l'aide d'un linge non pelucheux propre. N'utilisez pas de nettoyant abrasif ni de solvant.
· Le testeur est tenu immobile. · Portez toujours une protection oculaire approuvée. · Respectez les normes de sécurité locales et nationales. · Si ce produit est utilisé d'une manière n'ayant pas été indiquée par le fabricant, la protection offerte par le produit
MISE AU REBUT/RECYCLAGE Ne mettez pas l'appareil et ses accessoires au rebut. Ces articles doivent être éliminés conformément aux règlements locaux. Pour de plus amples renseignements, consultez le site www.epa.gov/recycle.
pourrait être réduite.
MISES EN GARDE
· N'ESSAYEZ PAS de réparer ce testeur. Il ne contient aucune pièce pouvant être réparée. · N'EXPOSEZ PAS ce produit aux températures extrêmes ou à une humidité élevée.
450 Bond Street, Lincolnshire, IL 60069
SERVICE À LA CLIENTÈLE KLEIN TOOLS, INC.
1-800-553-4676 customerservice@kleintools.com
www.kleintools.com
References
Klein Tools - For Professionals since 1857
Reduce, Reuse, Recycle | US EPA
Klein Tools - For Professionals since 1857 | Klein Tools
Adobe PDF Library 16.0.7
| https://manuals.plus/m/dab0a90035ef15690fa8df3246156413fff4adef8d85d757997ac90aba9950ce |
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