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DV Act S. 2(f) - Case Law - Possibility of legal marriage is a necessary condition for a domestic relationship - Reshma Begum vs. State of Maharashtra and another

An analysis of SC judgments in Veluswamy case [AIR 2011 SC 479] and IndraSarma case [AIR 2014 SC 309] reveals that not all live-in relationships are to be deemed as a “relationship in the nature of marriage” u/s 2(f) of the DV Act. The wider interpretation of the term is aimed at welfare of unmarried women in live-in relationships who are left estranged or abused; but not at promoting adulterous relationships. The benefits provided under the Act are to be interpreted harmoniously, not violating penal provisions of adultery. Since, the applicant admitted the existence of her first marriage, negating the possibility of a legal marriage between the two contesting parties, revision was dismissed stating no “domestic relationship” subsists between them.




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Positive sign? On VE Day, Putin and Johnson agree need to improve British-Russian relationship

Victory Day brought a rare positive moment between Russia and the UK, as President Vladimir Putin and Prime Minister Boris Johnson agreed on the need to improve the badly soured relations between the two countries.
Read Full Article at RT.com




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US drone strike: Unease in New Delhi over fallout, relations with Washington, Tehran

India’s oil import bill in 2018-19 was $111.9 billion.




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An uneasy relationship between telecom & technology

For the next four days, a sprawling conference centre here will become the global hub for the telecommunications and technology industries.




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Deciphering The SWIFT-DRIDEX Relationship In Bank

This whitepaper is a study that gives an overview about what methodology a hacker uses to hack into a system, discusses a theft of millions from the central bank of Bangladesh, and more.




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FDIC: Supervisory Approach to Payment Processing Relationships with Merchant Customers

The FDIC is clarifying its policy and supervisory approach related to facilitating payment processing services directly, or indirectly through a third party, for merchant customers engaged in higher-risk activities.




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Pakistan-U.S. Relations: Insights from the Field

Pakistani and American journalists discuss insights from their March 2013 Pakistan-U.S. Journalists Exchange study tours to each other's countries.




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Court makes finding of Unfair Relationship as a consequence of Secret Commission Payments

It is reported today in the media that a Deputy District Judge in the South Shields County Court has made a finding against MBNA ("the Creditor") in respect of various aspects of the enforceability of a credit card agreement and a payment protection...




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U.S. Higher Education Leaders Call for a “Comprehensive Re-Invigoration” of the U.S.-Indonesian Higher Education Relationship

U.S. Higher Education Leaders Call for a “Comprehensive Re-Invigoration” of the U.S.-Indonesian Higher Education Relationship
For Immediate Release

Contact:

Alysson Oakley, U.S.-Indonesia Society, 202-232-1400 or aoakley@usindo.org
Sharon Witherell, Institute of International Education, 212-984-5380 or switherell@iie.org
Derek Ferrar East-West Center, 808-944-7204 or ferrard@eastwestcenter.org
Paul F. Hassen, APLU, 202-478-6073 or phassen@aplu.org




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Hiroshima Mayor to Commemorate 50 Years of Sister-City Relationship with Honolulu

Hiroshima Mayor to Commemorate 50 Years of Sister-City Relationship with Honolulu
HONOLULU (June 25) – The Mayor of Hiroshima, the Honorable Tadatoshi Akiba, will commemorate 50 years of the sister-city relationship between Hiroshima and Honolulu at a special luncheon presentation on Wednesday, July 8.

In addition to the mayor’s presentation, there will be Japanese musical entertainment and a special photo exhibit centering on Sadako Sasaki, the young Hiroshima atomic bombing victim who famously folded 1,000 cranes for peace before she died from radiation-induced leukemia.




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U.S.-Australia Relations Amid Political Change is Topic of East-West Center Luncheon

U.S.-Australia Relations Amid Political Change is Topic of East-West Center Luncheon
HONOLULU (Sept. 19) – Former Deputy Prime Minister of Australia Kim Beazley will speak on “Political Change and Alliance Continuity in U.S.-Australia Relations” at an Australian American Leadership Dialogue luncheon address on Wed., Sept. 24., at the East-West Center’s Hawai‘i Imin International Conference Center (Jefferson Hall, 1777 East-West Road).

Ten months ago, the Australian Labor Party under Kevin Rudd defeated the decade-long conservative coalition government of John Howard.  This November, the U.S. election will bring in a new American president.  These political transitions bring a new era to U.S.-Australian relations.




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Derek Ferrar Joins East-West Center As Media Relations Specialist

Derek Ferrar Joins East-West Center As Media Relations Specialist

Derek Ferrar

HONOLULU (Nov. 16) — Derek Ferrar has been named Media Relations Specialist for the East-West Center. As a member of the Office of External Affairs staff, he will be authoring articles for the Center’s news wire and website, handling news releases and media inquiries, connecting journalists with expert sources on Asia Pacific issues and otherwise facilitating the dissemination of East-West Center programs, activities and resources through the media.




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Changing India-U.S. Relations Discussed at EWC Luncheon

Changing India-U.S. Relations Discussed at EWC Luncheon
HONOLULU (September 5) – India’s consul general in San Francisco, (Ambassador) B.S. Prakash will address the changing profile of India and the impact on its relationship with the United States at a luncheon gathering at the East-West Center Monday, September 10.

The luncheon will begin at noon with registration commencing at 11:30 a.m. The venue is the Garden Level of the East-West Center’s Imin International Conference Center (1777 East-West Road). The luncheon is open to the public at a cost of $22 per person. RSVP deadline is Thursday, September 6. Limited parking is available on the lawn between Lincoln Hall and the Imin Center for a cost of $3.

The luncheon forum is sponsored by the East-West Center, Pacific and Asian Affairs Council, Friends of the East-West Center, and the University of Hawai‘i Center for South Asian Studies.




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Media Alert: Perceptions and Misperceptions of Asia-U.S. Relations

Media Alert: Perceptions and Misperceptions of Asia-U.S. Relations

Satu Limaye, the newly-appointed director of East-West Center Washington, will engage in a dialogue Monday, April 30, on the Perceptions and Misperceptions of Asia-U.S. Relations. The event will get underway at 6 p.m. (registration: 5:30 p.m.) in the East-West Center Gallery located on the ground floor of John A. Burns Hall, 1601 East-West Road (mauka / Kokohead corner of Dole St. and East-West Road).

Dr. Limaye will comment on Asian views of the U.S. in light of his recent travels throughout the region, as well as Washington attitudes toward the Asia Pacific region.




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Expert Source Available on Pakistan-U.S. Relations

HONOLULU (May 2, 2011) – The U.S. discovery and killing of Osama Bin Laden in Pakistan has resulted in intensified focus on the crucial but troubled relationship between the two nations.
East-West Center research fellow Dr. Shabbir Cheema is available to comment on such issues as possible impact of the Bin Laden operation on U.S.-Pakistan relations going forward, as well as reactions within Pakistan itself. Dr. Cheema, who is originally from Pakistan and previously directed governance programs at the United Nations, is an expert on Pakistani political affairs and international relations.
His contact information is :
Shabbir Cheema , East-West Center Senior Fellow and Director of Asia Pacific Governance and Democracy Initiatives
Email : cheemas@eastwestcenter.org
Phone : 808 944-7427




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Journalists Wrestle with Complex Pakistan-U.S. Relationship

HONOLULU (April 18, 2011) — Thirteen journalists from Pakistan and America are currently visiting each other’s countries as part of the East-West Center’s inaugural Pakistan-U.S. Journalists Exchange.
At the East-West Center in Honolulu, Hawaii, the journalists participated in focused discussions on the complex U.S.-Pakistan relationship and issues facing the media in both countries. The Pakistani participants then travelled to Washington, D.C., New York City, and Columbia, Missouri, while the Americans visited Islamabad and Lahore, Pakistan.
They will meet again in Honolulu to exchange notes and impressions, and will participate in a public panel discussion on U.S. engagement in Pakistan on April 21.
The participants in the fellowship are:
Pakistan:




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North Korea In The World: A New Resource On North Korea's External Relations

The East-West Center and the National Committee on North Korea are pleased to announce the launch of a new pilot project, North Korea in the World.

For decades, American policymakers have had limited substantive information about North Korea in their consideration of U.S. policy options, with the exception of the question of North Korea’s nuclear weapons program, and in more recent times, human rights.




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The Russian Supreme Court brings clarifications to the relationship between co-owners of intellectual property

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Employee relations - working effectively with your union and employee representatives

Many senior managers lack experience of working with unions and employee representatives....




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Land Registry change of practice in relation to discharge of mortgages

The Land Registry is changing its practice on the discharge of mortgages in cases where form DS1 is not available when the application is made to the Land Registry. On 3 August 2009, the Land Registry will implement an important change in practice ...




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EU Advocate General gives landmark opinion in relation to the VAT treatment of property services to Real Estate Funds (C-595/13)

This week, an Advocate General gave a landmark opinion that the VAT exemption for the management of certain special investment funds can apply to property management, as well as to other fund management services. The opinion represents a completely ...




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Rihan v Ernst & Young Global Ltd & Others – Duty of Care extended in relation to former partner

Summary In this case certain E&Y entities based in London were ordered to pay USD10.8 million for loss of earnings to a whistleblowing former auditor employed by an E&Y entity that was not based in the UK and not party to the proceedings. Th...




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Strengthening US Relations with ASEAN: A Critical Element of the US Indo-Pacific Strategy

By East-West Center HONOLULU (October 4, 2019)—President Donald Trump first laid out a vision for a “free and open Indo-Pacific” at the November 2017 Asia-Pacific Economic Cooperation (APEC) Summit in Vietnam. From the start, statements describing the emerging US Indo-Pacific strategy have recognized the central role of Southeast Asia. The US approach to the Indo-Pacific focuses on three vital areas: enhancing shared prosperity, championing good governance and civil society, and ensuring a peaceful and secure regional order. Two recent visitors to the East-West Center described the potential role of the 10-member Association of Southeast Asian Nations (ASEAN) in the US Indo-Pacific strategy and spelled out several steps that the United States needs to take to strengthen US-ASEAN...

This is a summary only. Click the title for the full article, or visit www.EastWestCenter.org/Research-Wire for more.




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The future of labour brokers in the face of the labour relations amendment act

The labour broker industry faces great pressure to comply with the changes to the Labour Relations Act 66 of 1995, as amended, (“LRA”) read with amendments giving effect to the ‘equal pay for work of equal value’ principle in...




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Tourism and Duty-free Industries Hopeful about Improving Korea-China Relations

As Korea and China are set to improve their relationship that was rocked by the controversy over the Terminal High Altitude Area Defense (THAAD) anti-ballistic missile system, Korea's tourism and duty-free shopping industries are raising their hopes of better days.The tourism industry believes that the Chinese government's group tour ban to Korea would be relaxed soon. A travel agency in Hebei posted an Internet ad recently for a group tour program to Korea in November at the price of 1,4...




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Based on strategic partnership, Azerbaijan-Russia bilateral friendly relations are successfully developing today in all areas (PHOTO)

(MENAFN - Trend News Agency) BAKU, Azerbaijan, May 9 Trend: The May edition of the influential Russian magazine "Natsionalnaya Oborona" (National Defe... ......




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Drivers standoff turns EAC states relations on its head

The standoff has created massive traffic jams at border control gates of member countries.




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Misinformation and leaks: The love-hate Russia-Iran relationship in Syria


We will never fully know what Iran and Russia actually think of Assad or each other’s historic role in Syria.




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Delayed South China Sea talks expose China’s complex relationship with neighbours during pandemic

Negotiations between China and its Southeast Asian neighbours for a South China Sea code of conduct have been postponed as the nations involved put their efforts into containing the Covid-19 pandemic, creating uncertainty about whether the two sides can work together amid rising tensions in the contested territory.Southeast Asian nations are increasingly caught in a dilemma whether to maintain relations with Beijing during the pandemic while also fearing that tensions over the disputed waters…




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When a tarot reader predicted Ranbir Kapoor, Alia Bhatt's relationship in 2012

A throwback video of a tarot reader predicting Ranbir Kapoor's relationship with Alia Bhatt back in 2012 is going viral




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Correlation or causation? Mathematics can finally give us an answer

Are shark attacks and ice cream sales linked? Do drugs work? Being able to distinguish cause and effect is crucial. Now we have the maths to do it reliably




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How is the Power of Voice Transforming our Relationship with Technology?

Voice-enabled technology has rapidly evolved from a novel concept to one that now plays a central role in our day-to-day lives. According to a recent report from Google, 72% of people who own voice-activated speakers say their devices are used as a part...




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Correlation or causation? Mathematics can finally give us an answer

Are shark attacks and ice cream sales linked? Do drugs work? Being able to distinguish cause and effect is crucial. Now we have the maths to do it reliably




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Correlation or causation? Mathematics can finally give us an answer

Are shark attacks and ice cream sales linked? Do drugs work? Being able to distinguish cause and effect is crucial. Now we have the maths to do it reliably




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Oral Health-Related Quality of Life of Children: An Assessment of the Relationship between Child and Caregiver Reporting

Purpose: Oral and craniofacial conditions or diseases can impact an individual's health and quality of life. The purpose of this study was to assess the perceived oral health related quality of life (OHRQoL) of children, and evaluate the reported level of agreement between caregivers and their children.Methods: Purposive sampling was used to recruit children ages 8-15, and their caregivers from a dental clinic in a pediatric hospital for this descriptive, cross-sectional study. A modified version of a validated measure, Child Oral Health Impact Profile-Short Form (COHIP-SF), was used for a 22-item questionnaire encompassing three subscales: oral health, functional well-being, and social emotional well-being. Two additional items were included to assess child/caregiver's level of agreement. A dental chart review was also conducted to assess the child's overbite, overjet, and decayed surfaces. Data were analyzed through descriptive statistics and examined for assumptions of normality and linearity.Results: Sixty child/caregiver pairs (n=120) participated in this study. Overbite, overjet and decayed surfaces were not found to be related to any OHRQoL variable, including child/caregiver ratings and overall agreement (p>.05). Average OHRQoL scores for caregivers found to be more positive those of their children (p=.02). Agreement between caregivers and the child's gender was shown to be significant (p=.01). Female child scores differed significantly from males with respect to their caregiver responses (p=.02). Caregivers rated a higher OHRQoL for female children, thus overestimating their female child's reported OHRQoL.Conclusions: The moderate level of agreement found between children and caregivers reinforces the importance of including the child, as well as the caregiver, when assessing OHRQoL.




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Correction to "Quantitative Proteomics of Clinically Relevant Drug-Metabolizing Enzymes and Drug Transporters and Their Intercorrelations in the Human Small Intestine" [Errata]




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Evaluation of Quantitative Relationship Between Target Expression and Antibody-Drug Conjugate Exposure Inside Cancer Cells [Articles]

Antibody-drug conjugates (ADCs) employ overexpressed cell surface antigens to deliver cytotoxic payloads inside cancer cells. However, the relationship between target expression and ADC efficacy remains ambiguous. In this manuscript, we have addressed a part of this ambiguity by quantitatively investigating the effect of antigen expression levels on ADC exposure within cancer cells. Trastuzumab-valine-citrulline-monomethyl auristatin E was used as a model ADC, and four different cell lines with diverse levels of human epidermal growth factor receptor 2 (HER2) expression were used as model cells. The pharmacokinetics (PK) of total trastuzumab, released monomethyl auristatin E (MMAE), and total MMAE were measured inside the cells and in the cell culture media following incubation with two different concentrations of ADC. In addition, target expression levels, target internalization rate, and cathepsin B and MDR1 protein concentrations were determined for each cell line. All the PK data were mathematically characterized using a cell-level systems PK model for ADC. It was found that SKBR-3, MDA-MB-453, MCF-7, and MDA-MB-468 cells had ~800,000, ~250,000, ~50,000, and ~10,000 HER2 receptors per cell, respectively. A strong linear relationship (R2 > 0.9) was observed between HER2 receptor count and released MMAE exposure inside the cancer cells. There was an inverse relationship found between HER2 expression level and internalization rate, and cathepsin B and multidrug resistance protein 1 (MDR1) expression level varied slightly among the cell lines. The PK model was able to simultaneously capture all the PK profiles reasonably well while estimating only two parameters. Our results demonstrate a strong quantitative relationship between antigen expression level and intracellular exposure of ADCs in cancer cells.

SIGNIFICANCE STATEMENT

In this manuscript, we have demonstrated a strong linear relationship between target expression level and antibody-drug conjugate (ADC) exposure inside cancer cells. We have also shown that this relationship can be accurately captured using the cell-level systems pharmacokinetics model developed for ADCs. Our results indirectly suggest that the lack of relationship between target expression and efficacy of ADC may stem from differences in the pharmacodynamic properties of cancer cells.




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Mid-Eocene giant slope failure (sedimentary melanges) in the Ligurian accretionary wedge (NW Italy) and relationships with tectonics, global climate change and the dissociation of gas hydrates

Upper Lutetian–Bartonian sedimentary mélanges, corresponding to ancient mud-rich submarine mass transport deposits, are widely distributed over an area c. 300 km long and tens of kilometres wide along the exhumed outer part of the External Ligurian accretionary wedge in the Northern Apennines. The occurrence of methane-derived carbonate concretions (septarians) in a specific tectonostratigraphic position below these sedimentary mélanges allows us to document the relationships among a significant period of regional-scale slope failure, climate change (the Early and Mid-Eocene Optimum stages), the dissociation of gas hydrates and accretionary tectonics during the Ligurian Tectonic Phase (early–mid-Lutetian). The distribution of septarians at the core of thrust-related anticlines suggests that the dissociation of gas hydrates was triggered by accretionary tectonics rather than climate change. The different ages of slope failure emplacement and the formation of the septarians support the view that the dissociation of gas hydrates was not the most important trigger for slope failure. The latter occurred during a tectonic quiescence stage associated with a regressive depositional trend, and probably minor residual tectonic pulses, which followed the Ligurian Tectonic Phase, favouring the dynamic re-equilibrium of the External Ligurian accretionary wedge. Our findings provide useful information for a better understanding of the factors controlling giant slope failure events in modern accretionary settings, where they may cause tsunamis.




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High-resolution carbon isotope stratigraphy of the Lower and Middle Ordovician succession of the Yangtze Platform, China: implications for global correlation

The Lower and Middle Ordovician of the Yangtze Platform, China, is characterized by a sedimentary succession dominated by carbonate rocks. Three sections spanning the Nantsinkuan/Lunshan, Fenhsiang, Hunghuayuan, and Dawan/Zitai formations, corresponding to the Tremadocian–Dapingian in age, have been sampled for high-resolution 13C chemostratigraphy (542 samples in total). Our new 13C data reveal five tie-points with the potential for global correlation: (1) a positive 13C excursion in the lower Nantsinkuan Formation within the Tremadocian Rossodus manitouensis Zone; (2) an excursion with two peaks roughly within the late Tremadocian Paltodusdeltifer’ Zone; (3) a positive 13C shift in the lower Hunghuayuan Formation, within the early Floian Serratognathus diversus Zone; (4) a gradual positive 13C shift in the late Floian, ranging from the uppermost S. diversus Zone to the basal Oepikodus evae Zone; (5) a minor negative shift in the lower Dawan/Zitai Formation, within the early Dapingian Baltoniodus triangularis Zone. These excursions are herein used for correlation of the Yangtze Platform strata with successions from South China, North China, the Argentine Precordillera, North America and Baltica. From a palaeogeographical perspective the Gudongkou, Xiangshuidong and Daling sections represent depositional environments along an inner to outer ramp profile. 13C data from these sections show successively heavier (higher) 13C values with increasing depositional depth. This is interpreted as due to remineralization of organic carbon within the carbonate rocks.

Supplementary material: Carbon and oxygen isotope data are available at: https://doi.org/10.6084/m9.figshare.c.4767080




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Basement-cover relationships and deformation in the Northern Paraguai Belt, central Brazil: implications for the Neoproterozoic-early Paleozoic history of western Gondwana

The Northern Paraguai Belt, at the SE border of the Amazonian Craton, central Brazil, has been interpreted as a Brasiliano–Pan-African (c. 650–600 Ma) belt with a foreland basin, recording collisional polyphase tectonism and greenschist-facies metamorphism extending from the late Precambrian to the Cambrian–Ordovician. New structural investigations indicate that the older metasedimentary rocks of the Cuiabá Group represent a Tonian–Cryogenian basement assemblage deformed in two contemporaneous fault-bounded structural sub-domains of wrench-dominated (rake <10°) and contraction-dominated (rake ~30–40°) sinistral transpression, with tectonic vergence towards the SE. The younger late Cryogenian to early Cambrian sedimentary rocks lying to the NW of the Cuiabá Group are non-metamorphic and display only pervasive brittle transtension characterized by normal-oblique faults, fractures and forced drag folds with no consistent vergence pattern. Our analyses suggest that an unconformity separates the metasedimentary Cuiabá Group basement of the Northern Paraguai Belt from the unmetamorphosed sedimentary cover. It is proposed that the latter units were deposited during a post-glacial marine transgression (after c. 635 Ma) in a post-collisional basin. The Paraguai Belt basement and its post-collisional sedimentary cover share a number of significant geological similarities with sequences in the Bassarides Belt and Taoudéni Basin in the SW portion of the West African Craton.




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Geochronology and geochemistry of the Tabaquito batholith (Frontal Cordillera, Argentina): geodynamic implications and temporal correlations in the SW Gondwana margin

The Tabaquito batholith (Frontal Cordillera, western Argentina), is mainly composed of shallowly emplaced granodiorite to minor monzogranite with abundant mafic microgranular enclaves. New sensitive high-resolution ion microprobe U–Pb zircon ages of c. 337 Ma (biotite granodiorite) and c. 284 Ma (mafic dyke) along with previously published geochronological data suggest that a long-lived magmatic system formed through at least two magmatic pulses at c. 337 and c. 322 Ma with later superimposition of Permian magmatism. The Tabaquito granitoids are metaluminous, calc-alkalic and magnesian with I-type affinity. Elevated Th/Nb, Y/Nb and La/Nb ratios along with negative Nb–Ta and positive Pb anomalies are consistent with a continental arc setting. Hf, Nd and Sr isotopic composition of the Tabaquito granitoids suggests that their source could result from mixing of an old felsic crustal component and a juvenile mafic to intermediate component. New geochronological and geochemical data together with published data reveal a continuous arc setting from the Carboniferous to the Permian in Argentina, and important magmatic compositional variations through time and space controlled by episodic fluctuations in the subduction angle of the oceanic plate. Reported and compiled data allow us to infer the continuity of the Carboniferous magmatic arc along the west margin of Gondwana.

Supplementary material: Detailed petrography, analytical methods and data, zircon cathodoluminescence images and supplementary figures are available at https://doi.org/10.6084/m9.figshare.c.4763993




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Void ratio-permeability relations for clays

In spite of the Kozeny–Carman formula having been applied effectively to sands, there is at present no generally accepted explanation for why it is inadequate for clays. The impermeable adsorbed water layer surrounding the soil particles throws further light on the issue. By introducing the pervious void ratio, which accounts for the effective voids that a fluid flows through, a modified Kozeny–Carman formula is presented. The results presented here show that the modified Kozeny–Carman formula predicts fairly well the hydraulic conductivity of clays, especially for fine-grained soils.




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Imaging Inflammation in Atherosclerosis with CXCR4-Directed 68Ga-Pentixafor PET/CT: Correlation with 18F-FDG PET/CT

C-X-C motif chemokine receptor 4 (CXCR4) is expressed on the surface of various cell types involved in atherosclerosis, with a particularly rich receptor expression on macrophages and T cells. First pilot studies with 68Ga-pentixafor, a novel CXCR4-directed PET tracer, have shown promise to noninvasively image inflammation within atherosclerotic plaques. The aim of this retrospective study was to investigate the performance of 68Ga-pentixafor PET/CT for imaging atherosclerosis in comparison to 18F-FDG PET/CT. Methods: Ninety-two patients (37 women and 55 men; mean age, 62 ± 10 y) underwent 68Ga-pentixafor and 18F-FDG PET/CT for staging of oncologic diseases. In these subjects, lesions in the walls of large arteries were identified using morphologic and PET criteria for atherosclerosis (n = 652). Tracer uptake was measured and adjusted for vascular lumen (background) signal by calculation of target-to-background ratios (TBRs) by 2 investigators masked to the other PET scan. On a lesion-to-lesion and patient basis, the TBRs of both PET tracers were compared and additionally correlated to the degree of arterial calcification as quantified in CT. Results: On a lesion-to-lesion basis, 68Ga-pentixafor and 18F-FDG uptake showed a weak correlation (r = 0.28; P < 0.01). 68Ga-pentixafor PET identified more lesions (n = 290; TBR ≥ 1.6, P < 0.01) and demonstrated higher uptake than 18F-FDG PET (1.8 ± 0.5 vs. 1.4 ± 0.4; P < 0.01). The degree of plaque calcification correlated negatively with both 68Ga-pentixafor and 18F-FDG uptake (r = –0.38 vs. –0.31, both P < 0.00001). Conclusion: CXCR4-directed imaging of the arterial wall with 68Ga-pentixafor PET/CT identified more lesions than 18F-FDG PET/CT, with only a weak correlation between tracers. Further studies to elucidate the underlying biologic mechanisms and sources of CXCR4 positivity, and to investigate the clinical utility of chemokine receptor–directed imaging of atherosclerosis, are highly warranted.




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Markers of Early Life Infection in Relation to Adult Diabetes: Prospective Evidence From a National Birth Cohort Study Over Four Decades




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Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients

Pharmacokinetic-based prophylaxis of replacement factor VIII (FVIII) products has been encouraged in recent years, but the relationship between exposure (factor VIII activity) and response (bleeding frequency) remains unclear. The aim of this study was to characterize the relationship between FVIII dose, plasma FVIII activity, and bleeding patterns and individual characteristics in severe hemophilia A patients. Pooled pharmacokinetic and bleeding data during prophylactic treatment with BAY 81-8973 (octocog alfa) were obtained from the three LEOPOLD trials. The population pharmacokinetics of FVIII activity and longitudinal bleeding frequency, as well as bleeding severity, were described using non-linear mixed effects modeling in NONMEM. In total, 183 patients [median age 22 years (range, 1-61); weight 60 kg (11-124)] contributed with 1,535 plasma FVIII activity observations, 633 bleeds and 11 patient/study characteristics [median observation period 12 months (3.1-13.1)]. A parametric repeated time-to-categorical bleed model, guided by plasma FVIII activity from a 2-compartment population pharmacokinetic model, described the time to the occurrence of bleeds and their severity. Bleeding probability decreased with time of study, and a bleed was not found to affect the time of the next bleed. Several covariate effects were identified, including the bleeding history in the 12-month pre-study period increasing the bleeding hazard. However, unexplained inter-patient variability in the phenotypic bleeding pattern remained large (111%CV). Further studies to translate the model into a tool for dose individualization that considers the individual bleeding risk are required. Research was based on a post-hoc analysis of the LEOPOLD studies registered at clinicaltrials.gov identifiers: 01029340, 01233258 and 01311648.




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Novel Insights into the Classification of Staphylococcal {beta}-Lactamases in Relation to the Cefazolin Inoculum Effect [Mechanisms of Resistance]

Cefazolin has become a prominent therapy for methicillin-susceptible Staphylococcus aureus (MSSA) infections. However, an important concern is the cefazolin inoculum effect (CzIE), a phenomenon mediated by staphylococcal β-lactamases. Four variants of staphylococcal β-lactamases have been described based on serological methodologies and limited sequence information. Here, we sought to reassess the classification of staphylococcal β-lactamases and their correlation with the CzIE. We included a large collection of 690 contemporary bloodstream MSSA isolates recovered from Latin America, a region with a high prevalence of the CzIE. We determined cefazolin MICs at standard and high inoculums by broth microdilution. Whole-genome sequencing was performed to classify the β-lactamase in each isolate based on the predicted full sequence of BlaZ. We used the classical schemes for β-lactamase classification and compared it to BlaZ allotypes found in unique sequences using the genomic information. Phylogenetic analyses were performed based on the BlaZ and core-genome sequences. The overall prevalence of the CzIE was 40%. Among 641 genomes, type C was the most predominant β-lactamase (37%), followed by type A (33%). We found 29 allotypes and 43 different substitutions in BlaZ. A single allotype, designated BlaZ-2, showed a robust and statistically significant association with the CzIE. Two other allotypes (BlaZ-3 and BlaZ-5) were associated with a lack of the CzIE. Three amino acid substitutions (A9V, E112A, and G145E) showed statistically significant association with the CzIE (P = <0.01). CC30 was the predominant clone among isolates displaying the CzIE. Thus, we provide a novel approach to the classification of the staphylococcal β-lactamases with the potential to more accurately identify MSSA strains exhibiting the CzIE.




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Activity of Imipenem-Relebactam against Carbapenem-Resistant Escherichia coli Isolates from the United States in Relation to Clonal Background, Resistance Genes, Coresistance, and Region [Epidemiology and Surveillance]

Imipenem-relebactam (I-R) is a recently developed carbapenem–beta-lactamase inhibitor combination agent that can overcome carbapenem resistance, which has now emerged in Escherichia coli, including sequence type 131 (ST131) and its fluoroquinolone-resistant H30R subclone, the leading cause of extraintestinal E. coli infections globally. To clarify the likely utility of I-R for carbapenem-resistant (CR) E. coli infections in the United States, we characterized 203 recent CR clinical E. coli isolates from across the United States (years 2002 to 2017) for phylogroup, clonal group (including ST131, H30R, and the CTX-M-15-associated H30Rx subset within H30R), relevant beta-lactamase genes, and broth microdilution MICs for I-R and 11 comparator agents. Overall, I-R was highly active (89% susceptible), more so than all comparators except tigecycline and colistin (both 99% susceptible). I-R’s activity varied significantly in relation to phylogroup, clonal background, resistance genotype, and region. It was greatest among phylogroup B2, ST131-H30R, H30Rx, Klebsiella pneumoniae carbapenemase (KPC)-positive, and northeast U.S. isolates and lowest among phylogroup C, New Delhi metallo-β-lactamase (NDM)-positive, and southeast U.S. isolates. Relebactam improved imipenem’s activity against CR isolates within each phylogroup—especially groups A, B1, and B2—and particularly against isolates containing KPC. I-R remained substantially active against isolates coresistant to comparator agents, albeit somewhat less so than against the corresponding susceptible isolates. These findings suggest that I-R should be useful for treating most CR E. coli infections in the United States, largely independent of coresistance, although this likely will vary in relation to the local prevalence of specific E. coli lineages and carbapenem resistance mechanisms.




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Prediagnostic Circulating Levels of Sex Steroid Hormones and SHBG in Relation to Risk of Ductal Carcinoma In Situ of the Breast among UK Women

Background:

Sex steroid hormones and sex hormone–binding globulin (SHBG) have been implicated in the etiology of invasive breast cancer, but their associations with risk of the precursor lesion, ductal carcinoma in situ (DCIS) of the breast, remain unclear.

Methods:

We used Cox proportional hazards regression models to estimate the associations of serum levels of estradiol (premenopausal women only), testosterone, and/or SHBG with DCIS risk among 182,935 women. After a median follow-up of 7.1 years, 186 and 531 DCIS cases were ascertained in premenopausal and postmenopausal women, respectively.

Results:

Total and free estradiol were positively associated with risk of DCIS among premenopausal women. The HRs for the highest versus the lowest tertiles were 1.54 (1.06–2.23) and 1.72 [95% confidence interval (CI), 1.15–2.57], respectively. Among postmenopausal women, elevated levels of free testosterone (FT), and to a lesser extent, total testosterone, were positively associated with DCIS risk. The HRs for the highest versus the lowest quartiles were 1.42 (95% CI, 1.09–1.85) and 1.16 (95% CI, 0.91–1.48), respectively. Serum SHBG levels were inversely associated with risk of DCIS among postmenopausal women (HRq4 vs. q1: 0.75; 95% CI, 0.56–0.99).

Conclusions:

This study suggests that elevated levels of estradiol are associated with increased risk of DCIS among premenopausal women, and that among postmenopausal women, elevated levels of testosterone, and particularly those of FT, are associated with increased DCIS risk, while elevated levels of SHBG are associated with reduced risk.

Impact:

These findings may be helpful in developing prevention strategies aimed at reducing breast cancer risk among premenopausal and postmenopausal women.




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Alcohol and Tobacco Use in Relation to Mammographic Density in 23,456 Women

Background:

Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood.

Methods:

We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis.

Results:

Alcohol use was positively associated with PD (Ptrend = 0.01), unassociated with DA (Ptrend = 0.23), and inversely associated with NDA (Ptrend = 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (Ptrend = 0.0008), unassociated with DA (Ptrend = 0.93), and positively associated with NDA (Ptrend<0.0001). These trends were stronger in normal and overweight women than in obese women.

Conclusions:

These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA.

Impact:

PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health.




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Pancreatic Cancer Risk in Relation to Lifetime Smoking Patterns, Tobacco Type, and Dose-Response Relationships

Background:

Despite smoking being a well-established risk factor for pancreatic cancer, there is a need to further characterize pancreatic cancer risk according to lifespan smoking patterns and other smoking features, such as tobacco type. Our aim was to deeply investigate them within a large European case–control study.

Methods:

Tobacco smoking habits and other relevant information were obtained from 2,009 cases and 1,532 controls recruited in the PanGenEU study using standardized tools. Multivariate logistic regression analysis was performed to evaluate pancreatic cancer risk by smoking characteristics and interactions with other pancreatic cancer risk factors. Fractional polynomials and restricted cubic splines were used to test for nonlinearity of the dose–response relationships and to analyze their shape.

Results:

Relative to never-smokers, current smokers [OR = 1.72; 95% confidence interval (95% CI), 1.39–2.12], those inhaling into the throat (OR = 1.48; 95% CI, 1.11–1.99) or chest (OR = 1.33; 95% CI, 1.12–1.58), and those using nonfiltered cigarettes (OR = 1.69; 95% CI, 1.10–2.61), were all at an increased pancreatic cancer risk. Pancreatic cancer risk was highest in current black tobacco smokers (OR = 2.09; 95% CI, 1.31–3.41), followed by blond tobacco smokers (OR = 1.43; 95% CI, 1.01–2.04). Childhood exposure to tobacco smoke relative to parental smoking was also associated with increased pancreatic cancer risk (OR = 1.24; 95% CI, 1.03–1.49). Dose–response relationships for smoking duration, intensity, cumulative dose, and smoking cessation were nonlinear and showed different shapes by tobacco type. Effect modification by family history of pancreatic cancer and diabetes was likely.

Conclusions:

This study reveals differences in pancreatic cancer risk by tobacco type and other habit characteristics, as well as nonlinear risk associations.

Impact:

This characterization of smoking-related pancreatic cancer risk profiles may help in defining pancreatic cancer high-risk populations.