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Domain Name Industry Brief Quarterly Report: DNIB.com Announces 362.3 Million Domain Name Registrations in the Third Quarter of 2024

Today, the latest issue of The Domain Name Industry Brief Quarterly Report was released by DNIB.com, showing the third quarter of 2024 closed with 362.3 million domain name registrations across all top-level domains (TLDs), a decrease of 0.1 million domain name registrations, or less than 0.05%, compared to the second quarter of 2024. Domain name […]

The post Domain Name Industry Brief Quarterly Report: DNIB.com Announces 362.3 Million Domain Name Registrations in the Third Quarter of 2024 appeared first on Verisign Blog.




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Southeast Asia and US Delegations Meet at Jakarta Conference on US Indo-Pacific Strategy

Southeast Asia and US Delegations Meet at Jakarta Conference on US Indo-Pacific Strategy Southeast Asia and US Delegations Meet at Jakarta Conference on US Indo-Pacific Strategy
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News Release

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News Release

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East-West Center Releases Five-Year Strategic Plan

East-West Center Releases Five-Year Strategic Plan East-West Center Releases Five-Year Strategic Plan
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News Release

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News Release

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God’s Strategy for Church Growth (Selected Scriptures)

Check here each week to keep up with the latest from John MacArthur's pulpit at Grace Community Church.




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China’s Strategic Motivations in the Indo-Pacific and Implications for US-China Competition

China’s Strategic Motivations in the Indo-Pacific and Implications for US-China Competition China’s Strategic Motivations in the Indo-Pacific and Implications for US-China Competition

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Web Article

Recent online articles and analysis that have been published on the East-West Center website.

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Web Article

Recent online articles and analysis that have been published on the East-West Center website.

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

Strengthening US Relations with ASEAN: A Critical Element of the US Indo-Pacific Strategy Strengthening US Relations with ASEAN: A Critical Element of the US Indo-Pacific Strategy
Anonymous (not verified) Thu, 10/03/2019 - 12:13

East-West Wire

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News, Commentary, and Analysis
East-West Wire

The East-West Wire is a news, commentary, and analysis service provided by the East-West Center in Honolulu. Any part or all of the Wire content may be used by media with attribution to the East-West Center or the person quoted. To receive East-West Center Wire media releases via email, subscribe here.

For links to all East-West Center media programs, fellowships and services, see www.eastwestcenter.org/journalists.

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East-West Wire

Tagline
News, Commentary, and Analysis
East-West Wire

The East-West Wire is a news, commentary, and analysis service provided by the East-West Center in Honolulu. Any part or all of the Wire content may be used by media with attribution to the East-West Center or the person quoted. To receive East-West Center Wire media releases via email, subscribe here.

For links to all East-West Center media programs, fellowships and services, see www.eastwestcenter.org/journalists.

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Biden Administration Faces Daunting Task of Rebuilding US Economic Diplomacy

Biden Administration Faces Daunting Task of Rebuilding US Economic Diplomacy Biden Administration Faces Daunting Task of Rebuilding US Economic Diplomacy
ferrard Wed, 12/09/2020 - 14:49

East-West Wire

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News, Commentary, and Analysis
East-West Wire

The East-West Wire is a news, commentary, and analysis service provided by the East-West Center in Honolulu. Any part or all of the Wire content may be used by media with attribution to the East-West Center or the person quoted. To receive East-West Center Wire media releases via email, subscribe here.

For links to all East-West Center media programs, fellowships and services, see www.eastwestcenter.org/journalists.

Explore

East-West Wire

Tagline
News, Commentary, and Analysis
East-West Wire

The East-West Wire is a news, commentary, and analysis service provided by the East-West Center in Honolulu. Any part or all of the Wire content may be used by media with attribution to the East-West Center or the person quoted. To receive East-West Center Wire media releases via email, subscribe here.

For links to all East-West Center media programs, fellowships and services, see www.eastwestcenter.org/journalists.

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Inaugural China-Pacific Foreign Ministers' Meeting Sheds Light on Beijing’s Pacific Islands Strategy

Inaugural China-Pacific Foreign Ministers' Meeting Sheds Light on Beijing’s Pacific Islands Strategy Inaugural China-Pacific Foreign Ministers' Meeting Sheds Light on Beijing’s Pacific Islands Strategy
ferrard Thu, 12/02/2021 - 07:52

East-West Wire

Tagline
News, Commentary, and Analysis
East-West Wire

The East-West Wire is a news, commentary, and analysis service provided by the East-West Center in Honolulu. Any part or all of the Wire content may be used by media with attribution to the East-West Center or the person quoted. To receive East-West Center Wire media releases via email, subscribe here.

For links to all East-West Center media programs, fellowships and services, see www.eastwestcenter.org/journalists.

Explore

East-West Wire

Tagline
News, Commentary, and Analysis
East-West Wire

The East-West Wire is a news, commentary, and analysis service provided by the East-West Center in Honolulu. Any part or all of the Wire content may be used by media with attribution to the East-West Center or the person quoted. To receive East-West Center Wire media releases via email, subscribe here.

For links to all East-West Center media programs, fellowships and services, see www.eastwestcenter.org/journalists.

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Amsterdam police detain pro-Palestinian protesters at banned demonstration 

THE HAGUE, Netherlands —  Police detained several people Sunday for taking part in a demonstration in central Amsterdam that had been outlawed following violence targeting fans of an Israeli soccer club, a local broadcaster reported.  Amsterdam Mayor Femke Halsema banned all demonstrations over the weekend in the aftermath of the grim scenes of youths on scooters and on foot attacking Maccabi Tel Aviv supporters on Thursday and Friday in what was widely condemned as a violent outburst of antisemitism in the Dutch capital.  Israel's ambassador to the Netherlands said that 2,000 Israelis were brought home on special flights from Amsterdam over the past few days  Before the match against Ajax, Maccabi fans also tore a Palestinian flag off a building in Amsterdam and chanted anti-Arab slogans on their way to the stadium. There were also reports of Maccabi fans starting fights.  Video on local broadcaster AT5 showed police detaining one man Sunday who was taking part in a small demonstration on the central Dam Square. The protesters yelled slogans including "Free, free Palestine." AT5 reported that about 20 people were detained.  Amsterdam Municipality said on X that police had begun arresting demonstrators who refused to leave the square, which is in the heart of the city's downtown shopping area and close to the historic canal network.  Organizers of the protest went to court on Sunday morning seeking an injunction to allow the demonstration, but a judge upheld the ban imposed by the municipality.  At the hearing, senior Amsterdam police officer Olivier Dutilh said that there were again incidents overnight targeting people thought to be Jewish, including some being ordered out of taxis and others being asked to produce their passports to confirm their nationality.  Police launched a large-scale investigation Friday after gangs of youths conducted what Amsterdam's mayor called "hit and run" attacks on fans that were apparently inspired by calls on social media to target Jewish people. Five people were treated at hospitals and more than 60 suspects were arrested.  Israeli Foreign Minister Gideon Saar rushed to the Netherlands on Friday and offered Israel's help in the police investigation. He met on Saturday with Dutch Prime Minister Dick Schoof and said in a statement that the attacks and demands to show passports "were reminiscent of dark periods in history." 




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ActionSA details #Spaza4Locals strategy to combat foreign ownership and illicit trade in township spaza shops




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Special Investment Facilitation Council Reviews Progress and Strategies for Economic Stability in Pakistan

The Apex Committee of the Special Investment Facilitation Council (SIFC) met to evaluate advancements in fostering investments in Pakistan. Chaired by the caretaker prime minister, discussions encompassed strategies such as the privatization of financially struggling government institutions. In a separate interaction, the Army Chief reiterated the armed forces’ dedication to supporting the nation’s economic stability. ... Read more

The post Special Investment Facilitation Council Reviews Progress and Strategies for Economic Stability in Pakistan appeared first on Pakistan Tribune.




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RECAP: Hong Kong solidifies global ties, strategic role in 9th Belt and Road Summit

The recent summit underscored Hong Kong's position as a "super-connector" and "super value adder," solidifying its status as a premier regional business hub and a vital link to the global market, that could support the eight major steps announced by President Xi Jinping last year to enhance the high-quality development of the Belt and Road Initiative (BRI).




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Demonstrators with Nazi flags target a Michigan production of ‘The Diary of Anne Frank’


Demonstrators held flags with Nazi swastikas and reportedly chanted a pro-Donald Trump slogan.





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EU delegation visits Sindh Assembly for Strategic plans 2024-2029

Nazir SiyalKARACHI: Jeroen Willems, Head of Cooperation at the European Union Mission to Pakistan, called upon Speaker of the Provincial Assembly of Sindh, Syed Awais Qadir Shah, here on Tuesday. CEU Mission to Pakistan leader Jeroen was accompanied by Ms. … read more




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Strategic Patience can Mitigate Conflict Between Israel & Iran

How will Israel respond to Iran’s recent ballistic missiles barrage? “Strategic patience” is the best course. Israel has its hands full with Hamas and Hezbollah. Now is not the time to escalate a new major war with Iran, which could have nuclear implications. Israeli intelligence is still chafing from its failure to preempt Hamas’ attack […]





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Police detain dozens in Amsterdam after demonstrations banned

Police detain dozens in Amsterdam after demonstrations banned




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The Ultimate Demonstration of God’s Love

God’s love for sinners is a well-documented historical fact. Its verification doesn’t hinge on the consensus of theologians, nor does its validation rest on something we feel. The apostle John points us to the cross as the consummate and undeniable proof of divine love.

READ MORE




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Corporate taxpayers frustrated with Sars over delays, aggressive penalties

Half of the participants in the Taxing Times survey still find compliance with tax obligations difficult




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ADB Launches Country Partnership Strategy for Bhutan for 2024-2028

ADB’s Country Partnership Strategy for Bhutan for 2024-2028 aims to enable inclusive, sustainable, resilient, and job-creating growth.




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Senior Administration and Communications Assistant

ADB has a vacancy for the position of Senior Administration and Communications Assistant in the Strategy, Policy and Partnerships Department. The deadline for submitting applications is on 26-NOV-2024.




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Asian Development Blog: Key Strategies to Improve Mental Health Support Across Asia and the Pacific

World Mental Health Day is a timely reminder that integrating mental health care into schools, workplaces, and communities is critical for improving health outcomes and reducing costs. Expanding digital interventions and peer-support systems are also crucial, particularly in low- and middle-income countries.




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Asian Development Blog: Five Strategic Steps to Unlock Armenia’s Data Center Potential for Economic Growth

Armenia's data center industry offers significant opportunities for economic growth, with strategic reforms in regulation, financing, and technological innovation playing crucial roles. Addressing infrastructure challenges and fostering public-private partnerships will help position Armenia as a regional digital hub.




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alm administrator guide

alm administrator guide




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bladesystem onboard administrator user guide version

bladesystem onboard administrator user guide version




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we profit from social media a social strategy

we profit from social media a social strategy




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Loan No. 2606-PRC: Shanxi Small Cities and Towns Development Demonstration Sector Project [B-YY-01-01]




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Shandong Qixia Ecological Function Conservation Demonstration Project

Extending across seven provinces and two autonomous regions, the Yellow River Ecological Corridor (YREC) comprises the second largest river basin in the People's Republic of China (PRC) with a population of 120 million. The basin is critical for food security yet faces complex ecological and environmental challenges. The region suffers from severe water scarcity, impacts from climate change and environmentally unsustainable development.




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South Asia Subregional Economic Cooperation Customs Administration Reform and Modernization Project




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Simple Strategies Aren't Always Enough for Bedwetting

Title: Simple Strategies Aren't Always Enough for Bedwetting
Category: Health News
Created: 8/27/2013 12:35:00 PM
Last Editorial Review: 8/28/2013 12:00:00 AM




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Obama Administration Offers New Rules for Religious Objections to Health Care Law

Title: Obama Administration Offers New Rules for Religious Objections to Health Care Law
Category: Health News
Created: 8/25/2014 9:35:00 AM
Last Editorial Review: 8/25/2014 12:00:00 AM




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Evolutionary dynamics of polyadenylation signals and their recognition strategies in protists [RESEARCH]

The poly(A) signal, together with auxiliary elements, directs cleavage of a pre-mRNA and thus determines the 3' end of the mature transcript. In many species, including humans, the poly(A) signal is an AAUAAA hexamer, but we recently found that the deeply branching eukaryote Giardia lamblia uses a distinct hexamer (AGURAA) and lacks any known auxiliary elements. Our discovery prompted us to explore the evolutionary dynamics of poly(A) signals and auxiliary elements in the eukaryotic kingdom. We use direct RNA sequencing to determine poly(A) signals for four protists within the Metamonada clade (which also contains G. lamblia) and two outgroup protists. These experiments reveal that the AAUAAA hexamer serves as the poly(A) signal in at least four different eukaryotic clades, indicating that it is likely the ancestral signal, whereas the unusual Giardia version is derived. We find that the use and relative strengths of auxiliary elements are also plastic; in fact, within Metamonada, species like G. lamblia make use of a previously unrecognized auxiliary element where nucleotides flanking the poly(A) signal itself specify genuine cleavage sites. Thus, despite the fundamental nature of pre-mRNA cleavage for the expression of all protein-coding genes, the motifs controlling this process are dynamic on evolutionary timescales, providing motivation for future biochemical and structural studies as well as new therapeutic angles to target eukaryotic pathogens.




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Home Respiratory Strategies in Patients With COPD With Chronic Hypercapnic Respiratory Failure

BACKGROUND:Home noninvasive ventilation (NIV) may improve chronic hypercarbia in COPD and patient-important outcomes. The efficacy of home high-flow nasal cannula (HFNC) as an alternative is unclear.METHODS:We searched MEDLINE, Embase, Cochrane CENTRAL, Scopus, and ClinicalTrials.gov for randomized trials of subjects from inception to March 31, 2023, and updated the search on July 14, 2023. We performed a frequentist network meta-analysis and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We analyzed randomized controlled trials (RCTs) comparing NIV, HFNC, or standard care in adult subjects with COPD with chronic hypercapnic respiratory failure. Outcomes included mortality, COPD exacerbations, hospitalizations, and quality of life (St George Respiratory Questionnaire [SGRQ]).RESULTS:We analyzed 24 RCTs (1,850 subjects). We found that NIV may reduce the risk of death compared to standard care (relative risk 0.82 [95% CI 0.66–1.00]) and probably reduces exacerbations (relative risk 0.71 [95% CI 0.58–0.87]). HFNC probably reduces exacerbations compared to standard care (relative risk 0.77 [0.68–0.88]), but its effect on mortality is uncertain (relative risk 1.20 [95% CI 0.63–2.28]). HFNC probably improves SGRQ scores (mean difference −7.01 [95% CI −12.27 to −1.77]) and may reduce hospitalizations (relative risk 0.87 [0.69–1.09]) compared to standard care. No significant difference was observed between HFNC and NIV in reducing exacerbations.CONCLUSIONS:Both NIV and HFNC reduce exacerbation risks in subjects with COPD compared to standard care. HFNC may offer advantages in improving quality of life.




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A Strategic Guide to Improve and De-Risk Vaccine Development: CEPIs CMC Framework

The Coalition for Epidemic Preparedness Innovations (CEPI) has developed a robust CMC (Chemistry, Manufacturing, and Controls) Framework to enhance the likelihood of successful vaccine development. This Framework serves as a comprehensive guide, aiding developers in building effective strategies to overcome the challenges posed by the different phases of vaccine development, including the ones often referred to as the "valleys of death". The Framework lists stage-appropriate deliverables, categorized and refined, spanning five key areas: manufacturing process, formulation and stability, analytics, supply chain, and compliance. By emphasizing the critical aspects of CMC development, CEPI's objective is to expedite the progression of vaccine candidates from research to deployment, reducing delays, mitigating risks, and optimizing the overall development process, all while upholding uncompromising quality standards, ultimately increasing the probability of success.




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Simplified Method for Kinetic and Thermodynamic Screening of Cardiotonic Steroids through the K+-Dependent Phosphatase Activity of Na+/K+-ATPase with Chromogenic pNPP Substrate [Article]

The antitumor effect of cardiotonic steroids (CTS) has stimulated the search for new methods to evaluate both kinetic and thermodynamic aspects of their binding to Na+/K+-ATPase (IUBMB Enzyme Nomenclature). We propose a real-time assay based on a chromogenic substrate for phosphatase activity (pNPPase activity), using only two concentrations with an inhibitory progression curve, to obtain the association rate (kon), dissociation rate (koff), and equilibrium (Ki) constants of CTS for the structure-kinetics relationship in drug screening. We show that changing conditions (from ATPase to pNPPase activity) resulted in an increase of Ki of the cardenolides digitoxigenin, essentially due to a reduction of kon. In contrast, the Ki of the structurally related bufadienolide bufalin increased much less due to the reduction of its koff partially compensating the decrease of its kon. When evaluating the kinetics of 15 natural and semisynthetic CTS, we observed that both kon and koff correlated with Ki (Spearman test), suggesting that differences in potency depend on variations of both kon and koff. A rhamnose in C3 of the steroidal nucleus enhanced the inhibitory potency by a reduction of koff rather than an increase of kon. Raising the temperature did not alter the koff of digitoxin, generating a H (koff) of –10.4 ± 4.3 kJ/mol, suggesting a complex dissociation mechanism. Based on a simple and inexpensive methodology, we determined the values of kon, koff, and Ki of the CTS and provided original kinetics and thermodynamics differences between CTS that could help the design of new compounds.

SIGNIFICANCE STATEMENT

This study describes a fast, simple, and cost-effective method for the measurement of phosphatase pNPPase activity enabling structure-kinetics relationships of Na+/K+-ATPase inhibitors, which are important compounds due to their antitumor effect and endogenous role. Using 15 compounds, some of them original, this study was able to delineate the kinetics and/or thermodynamics differences due to the type of sugar and lactone ring present in the steroid structure.




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Documenting the Provision of Emergency Contraceptive Pills Through Youth-Serving Delivery Channels: Exploratory Mixed Methods Research on Malawi’s Emergency Contraception Strategy

ABSTRACTIntroduction:Emergency contraceptive pills (ECPs) are effective and can be used safely at any age repeatedly within the same cycle. They are often favored by youth yet are underutilized. Private facilities can increase ECP access but present barriers including cost. Identifying effective public-sector ECP distribution models can help ensure equitable access. The Malawi Ministry of Health developed a strategy to improve ECP access in 2020. We documented ECP provision through select public, youth-serving channels recommended by the strategy: general and youth-specific outreach, paid and unpaid community health workers (CHWs), and youth clubs.Methods:We conducted this mixed methods study from November 2022–March 2023 in 2 rural districts (Mchinji and Phalombe) implementing the strategy. We conducted qualitative interviews with 10 national stakeholders, 46 providers, and 24 clients aged 15–24 years about ECP service delivery. Additionally, 25 providers collected quantitative tally data about clients seeking ECPs. We analyzed qualitative data using grounded theory and quantitative data descriptively.Results:Stakeholders and providers reported ECP uptake increased in geographies where the strategy was implemented, especially among youth. Providers documented 3,988 client visits for ECPs over 3 months. Of these visits, 26% were from male clients, 36% were from clients aged younger than 20 years, and 64% received ECPs for the first time. Across channels, youth club leaders and unpaid CHWs reported the most client visits per provider and served the youngest clients. However, no ECPs were dispensed during 29% of visits due to stock-outs. While many providers were supportive of youth accessing ECPs, most held unfavorable attitudes toward repeat use.Conclusion:ECP access should be expanded through provision in the studied channels, especially youth clubs and CHWs. However, to meet demand, the supply chain must be strengthened. We recommend addressing providers’ attitudes about repeat use to ensure informed method choice.




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Development and Piloting of Implementation Strategies to Support Delivery of a Clinical Intervention for Postpartum Hemorrhage in Four sub-Saharan Africa Countries

ABSTRACTIntroduction:Postpartum hemorrhage (PPH) remains the leading cause of maternal mortality. A new clinical intervention (E-MOTIVE) holds the potential to improve early PPH detection and management. We aimed to develop and pilot implementation strategies to support uptake of this intervention in Kenya, Nigeria, South Africa, and Tanzania.Methods:Implementation strategy development: We triangulated findings from qualitative interviews, surveys and a qualitative evidence synthesis to identify current PPH care practices and influences on future intervention implementation. We mapped influences using implementation science frameworks to identify candidate implementation strategies before presenting these at stakeholder consultation and design workshops to discuss feasibility, acceptability, and local adaptations. Piloting: The intervention and implementation strategies were piloted in 12 health facilities (3 per country) over 3 months. Interviews (n=58), case report forms (n=1,269), and direct observations (18 vaginal births, 7 PPHs) were used to assess feasibility, acceptability, and fidelity.Results:Implementation strategy development: Key influences included shortages of drugs, supplies, and staff, limited in-service training, and perceived benefits of the intervention (e.g., more accurate PPH detection and reduced PPH mortality). Proposed implementation strategies included a PPH trolley, on-site simulation-based training, champions, and audit and feedback. Country-specific adaptations included merging the E-MOTIVE intervention with national maternal health trainings, adapting local PPH protocols, and PPH trollies depending on staff needs. Piloting: Intervention and implementation strategy fidelity differed within and across countries. Calibrated drapes resulted in earlier and more accurate PPH detection but were not consistently used at the start. Implementation strategies were feasible to deliver; however, some instances of limited use were observed (e.g., PPH trolley and skills practice after training).Conclusion:Systematic intervention development, piloting, and process evaluation helped identify initial challenges related to intervention fidelity, which were addressed ahead of a larger-scale effectiveness evaluation. This has helped maximize the internal validity of the trial.




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Alternative Reinforcers Enhance the Effects of Opioid Antagonists, but Not Agonists, on Oxycodone Choice Self-Administration in Nonhuman Primates [Behavioral Pharmacology]

Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of Food and Drug Administration–approved opioid antagonist or agonist medications, as well as the nonopioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys (n = 7; four females) responded under concurrent second-order fixed-ratio (FR)-3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1 mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032–1.0 mg/kg), nalbuphine (0.32–10 mg/kg), buprenorphine (0.0032–0.032 mg/kg), methadone (0.32–1.0 mg/kg), or flumazenil (1–3.2 mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a μ-opioid receptor antagonist, was >30-fold more potent when milk was available compared with water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low-efficacy μ-agonist nalbuphine was most effective in the presence of milk compared with water, decreasing oxycodone preference to <50% of control values. The higher efficacy μ-agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse–related behaviors.

SIGNIFICANCE STATEMENT

Clinical treatment programs for opioid use disorder use a combination of pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective have not been fully characterized. This study examined whether the effectiveness of μ-opioid medications to decrease oxycodone self-administration is altered in the presence of an alternative reinforcer. The results suggest that alternative reinforcers enhance the effects of antagonist or low-efficacy partial agonists, suggesting they may be a more effective strategy to curtail opioid use.




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Chronic Administration of Cannabinoid Agonists ACEA, AM1241, and CP55,940 Induce Sex-Specific Differences in Tolerance and Sex Hormone Changes in a Chemotherapy-Induced Peripheral Neuropathy [Special Section: Cannabinoid Signaling in Human Health and Dise

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB1)-selective, cannabinoid receptor type 2 (CB2)-selective, and CB1/CB2 mixed agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects.

SIGNIFICANCE STATEMENT

CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.




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Efficacy and Toxicity of [177Lu]Lu-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: Results from the U.S. Expanded-Access Program and Comparisons with Phase 3 VISION Data

The phase 3 VISION trial demonstrated that [177Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]–positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor–signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [177Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [177Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [177Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [177Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients.




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Initial Experience with [177Lu]Lu-PSMA-617 After Regulatory Approval for Metastatic Castration-Resistant Prostate Cancer: Efficacy, Safety, and Outcome Prediction

[177Lu]Lu-PSMA-617 was approved by the U.S. Food and Drug Administration for patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC). Since the time of regulatory approval, however, real-world data have been lacking. This study investigated the efficacy, safety, and outcome predictors of [177Lu]Lu-PSMA-617 at a major U.S. academic center. Methods: Patients with mCRPC who received [177Lu]Lu-PSMA-617 at the Johns Hopkins Hospital outside clinical trials were screened for inclusion. Patients who underwent [177Lu]Lu-PSMA-617 and had available outcome data were included in this study. Outcome data included prostate-specific antigen (PSA) response (≥50% decline), PSA progression-free survival (PFS), and overall survival (OS). Toxicity data were evaluated according to the Common Terminology Criteria for Adverse Events version 5.03. The study tested the association of baseline circulating tumor DNA mutational status in homologous recombination repair, PI3K alteration pathway, and aggressive-variant prostate cancer–associated genes with treatment outcome. Baseline PSMA PET/CT images were analyzed using SelectPSMA, an artificial intelligence algorithm, to predict treatment outcome. Associations with the observed treatment outcome were evaluated. Results: All 76 patients with PSMA-positive mCRPC who received [177Lu]Lu-PSMA-617 met the inclusion criteria. A PSA response was achieved in 30 of 74 (41%) patients. The median PSA PFS was 4.1 mo (95% CI, 2.0–6.2 mo), and the median OS was 13.7 mo (95% CI, 11.3–16.1 mo). Anemia of grade 3 or greater, thrombocytopenia, and neutropenia were observed in 9 (12%), 3 (4%), and 1 (1%), respectively, of 76 patients. Transient xerostomia was observed in 23 (28%) patients. The presence of aggressive-variant prostate cancer–associated genes was associated with a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P = 0.040). No other associations were observed between circulating tumor DNA mutational status and treatment outcomes. Eighteen of 71 (25%) patients classified by SelectPSMA as nonresponders had significantly lower rates of PSA response than patients classified as likely responders (6% vs. 51%; P < 0.001), a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P < 0.001), and a shorter OS (median, 6.3 vs. 14.5 mo; P = 0.046). Conclusion: [177Lu]Lu-PSMA-617 offered in a real-world setting after regulatory approval in the United States demonstrated antitumor activity and a favorable toxicity profile. Artificial-intelligence–based analysis of baseline PSMA PET/CT images may improve patient selection. Validation of these findings on larger cohorts is warranted.




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Academic Neuroradiology: 2023 Update on Turnaround Time, Financial Recruitment, and Retention Strategies [CLINICAL PRACTICE]

SUMMARY:

The ASNR Neuroradiology Division Chief Working Group's 2023 survey, with responses from 62 division chiefs, provides insights into turnaround times, faculty recruitment, moonlighting opportunities, and academic funds. In emergency cases, 61% aim for a turnaround time of less than 45–60 minutes, with two-thirds meeting this expectation more than 75% of the time. For inpatient CT and MR imaging scans, 54% achieve a turnaround time of 4–8 hours, with three-quarters meeting this expectation at least 50% of the time. Outpatient scans have an expected turnaround time of 24–48 hours, which is met in 50% of cases. Faculty recruitment strategies included 35% offering sign-on bonuses, with a median of $30,000. Additionally, 23% provided bonuses to fellows during fellowship to retain them in the practice upon completion of their fellowship. Internal moonlighting opportunities for faculty were offered by 70% of divisions, with a median pay of $250 per hour. The median annual academic fund for a full-time neuroradiology faculty member was $6000, typically excluding license fees but including American College of Radiology and American Board of Radiology membership, leaving $4000 for professional expenses. This survey calls for further dialogue on adapting and innovating academic institutions to meet evolving needs in neuroradiology.




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Prostate cancer patient stratification by molecular signatures in the Veterans Precision Oncology Data Commons [RESEARCH REPORT]

Veterans are at an increased risk for prostate cancer, a disease with extraordinary clinical and molecular heterogeneity, compared with the general population. However, little is known about the underlying molecular heterogeneity within the veteran population and its impact on patient management and treatment. Using clinical and targeted tumor sequencing data from the National Veterans Affairs health system, we conducted a retrospective cohort study on 45 patients with advanced prostate cancer in the Veterans Precision Oncology Data Commons (VPODC), most of whom were metastatic castration-resistant. We characterized the mutational burden in this cohort and conducted unsupervised clustering analysis to stratify patients by molecular alterations. Veterans with prostate cancer exhibited a mutational landscape broadly similar to prior studies, including KMT2A and NOTCH1 mutations associated with neuroendocrine prostate cancer phenotype, previously reported to be enriched in veterans. We also identified several potential novel mutations in PTEN, MSH6, VHL, SMO, and ABL1. Hierarchical clustering analysis revealed two subgroups containing therapeutically targetable molecular features with novel mutational signatures distinct from those reported in the Catalogue of Somatic Mutations in Cancer database. The clustering approach presented in this study can potentially be used to clinically stratify patients based on their distinct mutational profiles and identify actionable somatic mutations for precision oncology.




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Chest Pain in Primary Care: A Systematic Review of Risk Stratification Tools to Rule Out Acute Coronary Syndrome [Systematic Review]

PURPOSE

Chest pain frequently poses a diagnostic challenge for general practitioners (GPs). Utilizing risk stratification tools might help GPs to rule out acute coronary syndrome (ACS) and make appropriate referral decisions. We conducted a systematic review of studies evaluating risk stratification tools for chest pain in primary care settings, both with and without troponin assays. Our aims were to assess the performance of tools for ruling out ACS and to provide a comprehensive review of the current evidence.

METHODS

We searched PubMed and Embase for articles up to October 9, 2023 concerning adult patients with acute chest pain in primary care settings, for whom risk stratification tools (clinical decision rules [CDRs] and/or single biomarker tests) were used. To identify eligible studies, a combination of active learning and backward snowballing was applied. Screening, data extraction, and quality assessment (following the Quality Assessment of Diagnostic Accuracy Studies-2 tool) were performed independently by 2 researchers.

RESULTS

Of the 1,204 studies screened, 14 were included in the final review. Nine studies validated 7 different CDRs without troponin. Sensitivities ranged from 75.0% to 97.0%, and negative predictive values (NPV) ranged from 82.4% to 99.7%. None of the CDRs outperformed the unaided judgment of GP’s. Five studies reported on strategies using troponin measurements. Studies using high-sensitivity troponin showed highest diagnostic accuracy with sensitivity 83.3% to 100% and NPV 98.8% to 100%.

CONCLUSION

Clinical decision rules without troponin and the use of conventional troponin showed insufficient sensitivity to rule out ACS in primary care and are not recommended as standalone tools. High-sensitivity troponin strategies are promising, but studies are limited. Further prospective validation in primary care is needed before implementation.




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Correction to "Validity of diagnoses of SARS-CoV-2 infection in Canadian administrative health data: a multiprovince, population-based cohort study"





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SNP ministers urged to 'mitigate' UK Government's ‘chilling’ anti-terror strategy

Human rights campaigners are calling on SNP ministers to do all they can to “mitigate” Prevent, the UK Government's controversial anti-terror strategy.




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RPG Cast – Episode 677: “My Parents Thought Final Fantasy Tactics Was a Strategy Guide”

Kelley "accidentally" barbecues her horse. Josh slaps "Trails" onto Horizon: Forbidden West to get Americans to play it. Jason has to go get a tako taco.

The post RPG Cast – Episode 677: “My Parents Thought Final Fantasy Tactics Was a Strategy Guide” appeared first on RPGamer.



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Bangladesh next in Seek strategy

ONLINE jobs and education group Seek will continue expansion into international markets.