U.S. Secretary of Education Arne Duncan has been warning against a GOP NCLB rewrite bill that's slated to pass the House next week.

Washington D.C., Apr 30, 2020 / 06:00 am (CNA).- The Syrian civil war has led to one of the largest refugee crises of modern times, and presented unique problems for Syria’s ancient Christian communities. Marginalized for centuries, persecuted by ISIS, afraid to attract any attention from the West, Syrian Christians remain, by most accounts, the war’s most invisible victims.

In partnership with the Philos Project, CNA sat down with Mary Sayegh, a Syrian who lives now in the United States:

Tell me a bit about yourself.

My name is Mary Sayegh. I am 22 years old and live in the United States. I was born and raised in my beloved hometown of Aleppo, Syria. I moved to New Jersey about six years ago, running away from war to build a better future for myself. It was hard to leave my parents, family and friends behind and start all over. To be honest, it wasn’t easy to fit in a new country, even though I’m an extrovert. In America, I had to try and rebuild my social life in a strange land. As for Syria, I was involved in the scouts in church, Sunday school, computer program classes, art, and basketball.

When I came here, I started high school as a junior. I was held back for a year because I had to do ESL and take two courses in US history. During that time, I started planning for college and eventually got accepted to Montclair State University as a biology major and a public health minor. During my studies I also worked several part-time jobs in retail, as an executive office assistant and a front desk receptionist for a doctor. I tried to find balance by going to the gym, hanging out with friends and volunteering at the hospital.

When and how did you flee to the US?

Before my dad was married, he lived in the US, and therefore had American citizenship. Naturally, he passed it on to the rest of the family when he got married and settled in Aleppo again. The American citizenship made it possible for me to have a safe flight to the US when I left Aleppo. I flew from Lebanon to Spain to spend 6 weeks with my uncle and his family. Then my aunt (from New Jersey) came and took me to the States because I was too afraid to fly alone. On September 27, 2014 I landed in America. My mom and brother came three months later, and I didn’t see my dad until a couple of years later. 

When did you start recognizing that there was a war going on in Syria?

I have lost track of the years. I have no idea what happened when. In general, everything started changing when they hit my hometown and we became more in danger. We couldn’t stay out late anymore or go to certain areas. It got to the point where I would walk in the streets and couldn’t find a familiar face. I didn’t recognize anyone on the streets mainly because many Christians in my neighborhood had fled Aleppo. Bombs, shootings and noises became a daily experience for us. On the contrary, it felt weird when nothing was happening.

Tell me about Aleppo.

Aleppo was one of the most beautiful cities. It is famous for its architecture, the churches, mosques, schools, tombs and baths. As an important center for culture and as one of the oldest continuously inhabited cities in the world, Aleppo was loved by all Syrians.

The Citadel of Aleppo was one of the things that made the city special. The Citadel is considered to be one of the oldest and largest ones in the world. It is the best place to watch the sunset and learn about our ancestors’ history. During the siege, the Citadel of Aleppo was partly destroyed, unlike its surrounding buildings that were left in ruins. Today, the area is filled with locals and even tourists that enjoy nice meals in the newly built restaurants around it.

Did you ever feel like you were less valued because you were a Christian in Aleppo/Syria?

I never felt that way. Maybe back in the day. But in my days, we never felt a difference. We felt we were all equal and we treated each other as human beings, brothers and sisters, regardless of our religious differences.

What are your best and worst memories from Syria?

My best memories were every second I spent in Syria growing up until I moved to the States. I would say my worst memory was having to attend friends’ funerals at a time when I thought I would be attending their graduations and weddings.

Tell me about Aleppo when it was under siege.

I consider myself one of the lucky ones. There were obviously people who lived under better conditions during this horrible time because they were rich, and my dad owned his own business, so we were considered upper middle class. However, days passed when we would not have water or electricity. Still, we were fortunate to at least have had a roof over our heads. Close to my home, al-Assad School opened up for the people whose homes had been destroyed in the clashes. So, one really gets a perspective.

A lot of young girls and boys helped their parents to buy or bring gallons of water or fuel to their homes. I would help my dad fill up huge bottles with water so we would always have some when needed. We also filled up our bathtub as soon as water was available. We had three buckets: one for clean water, one with the soap for when we would wash our hands, and one for when we rinse our hands. The latter one was later reused as water to flush in the toilet.

We never really knew which groups were fighting, or where, unless we saw it on the news. We just heard the bombs and the shootings. There would also be snipers on buildings that would shoot as soon as someone would pass by. Once, a sniper shot at our car, but it wasn’t critical, so we just continued driving.

I was also lucky because I didn’t lose any loved ones in the war. I had a fellow peer in the church scouts who was killed by a bomb. That was really emotional because it was the first time my scout played at a funeral and not a wedding of a person belonging to the scouts. Another scout lost his mother.

If there were to be peace in Syria tomorrow would you move back?

As much as it hurts me to say this, I wouldn’t go back. I will go to visit but not live there anymore. It’s just impossible for our young generation to go and build everything all over. And to be honest, what’s left for us to even go back to? Even if I want to what would I do with my degree?

 

 

Poultry farmer Chris Lesniowski of Marydel has been recognized for his efforts to improve water quality and reduce nutrient runoff with the 2015 Delaware Environmental Stewardship Award.

NEW CASTLE (Jan. 2, 2019) – The number of full-time equivalent primary care physicians providing direct patient care in Delaware in 2018 declined about 6 percent from 2013, a trend that resulted in a slightly lower percentage of physicians statewide who are accepting new patients, according to a new University of Delaware study of the […]

NEW CASTLE (October 9, 2019) – The Department of Health and Social Services (DHSS) is seeking applications from Delaware health care providers for one-time, health information exchange (HIE) support mini-grants to adopt the full range of health information exchange tools offered by the Delaware Health Information Network (DHIN). DHIN is Delaware’s Health Information Exchange (HIE) […]

DEPARTMENT OF INSURANCE: Office of the Commissioner

Sixth SOE modification also protects Delawareans from evictions, foreclosures    WILMINGTON, Del. – Governor John Carney on Tuesday issued a sixth modification to his State of Emergency declaration, moving Delaware’s presidential primary to June 2, and suspending residential foreclosures and evictions during the outbreak of coronavirus (COVID-19). The order goes into effect at 8:00 a.m. on […]

Wilmington. Governor Carney changed the Presidential Primary to June 2, 2020 in his 6th update to the State of Emergency.  The change caused changes in two deadlines. The  deadline to change party affiliation changed April 3, 2020. The  deadline to register to vote changed to May 8, 2020. The Governor also ordered that citizens who […]

All eligible Delaware voters will receive absentee ballot applications by mail WILMINGTON, Del. – Governor John Carney on Thursday signed the fifteenth modification to his State of Emergency declaration, rescheduling Delaware’s presidential primary for July 7. The Delaware Department of Elections will mail absentee ballot applications to all registered Democrats and Republicans in the State of […]

Haskell loses in head to head battle in fourth set on September 24, 2019. 

Hi Folks, Check out this great new video on YouTube: CDNLive SV 2014: PMC Improves Visibility and Performance with Spectre APS In this video from CDNLive Silicon Valley 2014, Jurgen Hissen, principal engineer, MSCAD, at PMC, discusses an aggressive...(read more)

Clean industry leaders celebrated the passage of the Clean Energy Jobs Act (CEJA) by state lawmakers yesterday. The bill now goes to the governor’s desk for signature.

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

On 16 October 2019, the FCA published their feedback statement FS19/6 on Climate Change and Green Finance[1]. This feedback statement summarises the responses from stakeholders to the Discussion Paper (DP18/8) on Climate Change and Green Finance[2] ...

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A number of measures have been introduced in Ireland in recent weeks in light of the impact of the Covid-19 pandemic. Irish Revenue has also published a number of welcome guidelines and confirmations in an attempt to mitigate any detrimental effects...

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In the lead-up to the Truth Matters conference in October, we will be focusing our attention on the sufficiency, authority, and clarity of Scripture. Of our previous blog series, none better embodies that emphasis than Frequently Abused Verses. The following entry from that series originally appeared on October 7, 2015. -ed.

Just as a single cell of cancer can metastasize until it spreads throughout the physical body, a single false doctrine can multiply itself and spread throughout a body of believers. A great forest fire can be started by one spark.^[1] John MacArthur, The MacArthur New Testament Commentary: Galatians (Chicago: Moody Press, 1987), 140.

Throughout this series on Scripture’s “Frequently Abused Verses,” we’ve seen how God’s Word has been misunderstood and misapplied, as well as instances when it is intentionally twisted to accommodate blasphemous lies and spurious doctrines. Today we’re going to consider how the misappropriation of one verse—3 John 2—triggered a heretical movement that has been a scourge for God’s people and blight on the testimony of the church for more than half of a century.

The Roots of the Prosperity Gospel

Not long after Oral Roberts’s death—and amidst a tidal wave of glowing praise for the pioneering televangelist—John MacArthur wrote this summation of the preacher’s life and ministry:

Oral Roberts’s influence is not something Bible-believing Christians should celebrate. Virtually every aberrant idea the Pentecostal and charismatic movements spawned after 1950 can be traced in one way or another to Oral Roberts’s influence.

One of his primary legacies is the prosperity gospel. As John explains in the article quoted above, the prosperity gospel “is the notion that God's favor is expressed mainly through physical health and material prosperity, and that these blessings are available for the claiming by anyone who has sufficient faith.”

Roberts might not have been the first person to teach that false doctrine, but through his television ministry he served as its chief herald and the primary catalyst for its rapid growth and widespread acceptance.

And according to Roberts’s biographer, David Edwin Harrell, Jr., the televangelist’s commitment to the prosperity gospel was born out of a crisis of faith and a new perspective on an overlooked verse.

Out of this period of spiritual trauma came a sequence of instantaneous insights, revelations as Oral viewed them. The first occurred one morning as he read III John 2: “I wish above all things that thou mayest prosper and be in health, even as they soul prospereth.” Oral had rushed out of his house one morning to catch the bus to class when he realized he had not read his Bible as was his custom. He returned, hastily grabbed his Bible, opened it “at random,” and read III John 2. He had read his New Testament, he reported, at least a hundred times, but this verse seemed brand-new. He called Evelyn and read it to her. “That is not in the Bible,” she challenged. “It is,” Oral replied, “I just read it.” “Evelyn,” he said, “we have been wrong. I haven’t been preaching that God is good. And Evelyn, if this verse is right, God is a good God.” The idea seemed revolutionary, liberating. They had been nurtured in a belief system that insisted “you had to be poor to be a Christian.” Perhaps it was not so. They talked excitedly about the verse’s implications. Did it mean they could have a “new car,” a “new house,” a “brand-new ministry?” In later years, Evelyn looked back on that morning as the point of embarkation: “I really believe that that very morning was the beginning of this worldwide ministry that he has had, because it opened up his thinking.”

Oral’s new-found insight was soon put to a practical test. The agent was a Mr. Gustavus, a neighbor who owned the Buick automobile dealership in Enid. Mr. Gus liked Oral, and, although he was a “nonreligious” man, he listened to his neighbor’s preaching occasionally and liked his emphasis on the “here and now.” One morning Mr. Gus noted that Oral’s car looked “pretty bad” and suggested that he buy a new one. It seemed a preposterous idea. Cars were still “practically unobtainable” in these postwar months, and there was no slack in the Robertses’ tight budget. But Mr. Gus showed them a way; he sold their old car for the “highest ceiling” price and acquired a new Buick for Oral at “dealer’s cost.” Mr. Gus, Oral, and Evelyn drove together to Detroit to pick up the car. As they drove back to Enid in their “brand new . . . long, green slick Buick,” Oral and Evelyn pondered the significance of this seemingly impossible turn. Evelyn asked Oral to stop: “We have just got to hold hands and praise the Lord for this car.” For Oral, the “new car became a symbol to me of what a man could do if he would believe God.” Nor was Mr. Gus through. He kept egging Oral on. “Son, the message you are preaching is too big for one town,” he told Oral, “the country is waiting for it. . . . Preach it, son. And you will stir this generation.” ^[2] David Edwin Harrell, Jr., Oral Roberts: An American Life (Bloomington, IN: Indiana University Press, 1985) 65-66.

Of course there are plenty of other Bible verses that have been contorted by prosperity preachers to support their false teaching—we looked at one of them earlier in this series. But 3 John 2 is the textual soil that sprouted Roberts’s prosperity gospel, and the massive family tree of prosperity preachers who have carried on his heretical legacy.

And when you consider how the lies of the prosperity gospel have permeated and poisoned the church, you understand why the details matter, and the damage that can be done when we play fast and loose with God’s Word. The careless reading and application of this one verse has spawned multiple generations of false prophets and fraudulent healers who have feasted on the spiritually naïve and theologically shallow. And by continuing to perpetuate Roberts’s false teaching, they further tarnish the testimony of God’s Word and His people. In many parts of the world, the face of Christianity is a sneering charlatan with his hand out, preaching the get-rich gospel of health and wealth to people who have neither.

When it comes to biblical interpretation, the details are vitally important.

True Prosperity

And in the case of 3 John 2, the details make the true meaning of the verse abundantly clear. In his short letter to a man named Gaius, the apostle John wrote, “Beloved, I pray that in all respects you may prosper and be in good health, just as your soul prospers.”

The reality is that the apostle’s words are not a prophecy of blessing. As John MacArthur explains in his commentary on 3 John, “The phrase ‘I pray that in all respects you may prosper and be in good health’ was a standard greeting in ancient letters.” ^[3] John MacArthur, The MacArthur New Testament Commentary: 1-3 John (Chicago: Moody Press, 2007) 245.

The salutations of the epistles are rich with doctrinal truth (cf. Romans 1:1-7; Galatians 1:1-5; 1 Peter 1:1-2). But it’s not theologically safe or hermeneutically sound to turn a greeting to a specific audience into a promise for all believers.

Moreover, the apostle’s words here don’t support an emphasis on physical blessings like health and wealth, since that’s the opposite of the point John was making. He was praising God for the good report on the quality of Gaius’s character. As John MacArthur explains, the apostle’s focus was spiritual prosperity.

“Prosper” translates a form of the verb euodoō. The term, used only here, Romans 1:10, and 1 Corinthians 16:2, means “to succeed,” “to have things go well,” or “to enjoy favorable circumstances.” The first use of prosper in verse 2 refers to Gaius’s physical health, as the contrast with the last part of the verse makes clear. The apostle’s wish was that Gaius’s physical health would be as good as that of his spiritual.

John’s concern for Gaius is a pastoral desire that he be free from the turmoil, pain, and debilitation of illness so as to be unrestricted in his service to the Lord and His church. . . .

But [in contrast to his physical condition] Gaius’s healthy soul brought far more delight to John. He knew he had a vibrant spiritual life. To borrow from some other apostles, Gaius was among those who are “sound in the faith” (Titus 1:13); constantly “grow[ing] in the grace and knowledge of our Lord and Savior Jesus Christ” (2 Peter 3:18); “walk[ing] in a manner worthy of the Lord, to please him in all respects, bearing fruit in every good work and increasing in the knowledge of God” (Colossians 1:10). ^[4] The MacArthur New Testament Commentary: 1-3 John, 245-246.

When considering how the Lord might bless us, we need to keep in mind that His blessings are not merely for our benefit. As long as He grants us breath, He has use of us for the work of His kingdom. It stands to reason then that even the physical blessings we enjoy have eternal purposes—and for the sake of His glory and His church, we need to pursue those purposes.

God is in the business of building His church, not handing out Buicks.

The Roman Catholic Church has committed the error of promoting a mere citizen of heaven to an improper place of authority and honor. Despite the overwhelming testimony of Scripture, the Catholic Church has elevated Mary—a self-described servant of the Lord (Luke 1:38)—to the same level as God, if not higher.

Bongo (onge) is what has given rise to the Luo name Obong’o, which also means the only begotten child.

This paper documents the Chair's Summary of the Development Effectiveness Committee (DEC) discussion held on 7 February 2020.  DEC and the Independent Evaluation Department (IED) discussed three topics presented by IED: Evaluation Capacity Development (ECD), Independent Evaluation Methods, and DEC-IED Retrospective/Prospective Exchange.

This paper documents the Chair's Summary of the Development Effectiveness Committee (DEC) discussion held on 25 March 2020. The commitee discussed the sector-wide evaluation report ADB Support for Transport, 2010-2018.

This paper documents the Chair's Summary of the Development Effectiveness Committee (DEC) discussion held on 14 April 2020. The commitee discussed the 2019 Development Effectiveness Review (DEfR), and the 2019 Annual Portfolio Performance Report (APPR).

This publication provides estimates of purchasing power parities (PPPs) and real expenditures for 22 economies in Asia and the Pacific. These are summary regional results from the 2017 cycle of the International Comparison Program (ICP).

HYDERABAD: Forcible land acquisition has returned to haunt property owners on St Mary’s Road in Secunderabad, who are likely to face the bulldozers for the second time in less than eight years. Incidentally, a sweet shop owner had committed suicide after the lost his only means of livelihood in the first round of acquisition. The arterial road from Secunderabad railway station to Clock Tower was expanded in 2005 by acquiring the properties from 70 owners so that it could be widened from 60 feet to 120 feet. This time, the acquisition is because the metro rail corridor II (JBS-Falaknuma) passes through this road. The Greater Hyderabad Municipal Corporation (GHMC) has […]

Title: U.S. Primary Care Docs Unprepared for Surge in Alzheimer's Cases
Category: Health News
Created: 3/11/2020 12:00:00 AM
Last Editorial Review: 3/11/2020 12:00:00 AM

Title: The Doctor Gap: In Areas of Greatest Need, Primary Care Is a Team Effort
Category: Health News
Created: 3/19/2020 12:00:00 AM
Last Editorial Review: 3/20/2020 12:00:00 AM

2-fluorofucose (2FF) inhibits protein and cellular fucosylation. Afucosylation of IgG antibodies enhances antibody-dependent cell-mediated cytotoxicity by modulating antibody affinity for FcRIIIa, which can impact secondary T-cell activation. Immune responses toward most common solid tumors are dominated by a humoral immune response rather than the presence of tumor-infiltrating cytotoxic T cells. IgG antibodies directed against numerous tumor-associated proteins are found in the sera of both patients with breast cancer and transgenic mice bearing mammary cancer. We questioned whether 2FF would have antitumor activity in two genetically distinct transgenic models; TgMMTV-neu (luminal B) and C3(1)-Tag (basal) mammary cancer. 2FF treatment significantly improved overall survival. The TgMMTV-neu doubled survival time compared with controls [P < 0.0001; HR, 7.04; 95% confidence interval (CI), 3.31–15.0], and survival was significantly improved in C3(1)-Tag (P = 0.0013; HR, 3.36; 95% CI, 1.58–7.14). 2FF treated mice, not controls, developed delayed-type hypersensitivity and T-cell responses specific for syngeneic tumor lysates (P < 0.0001). Serum IgG from 2FF-treated mice enhanced tumor lysis more efficiently than control sera (P = 0.004). Administration of 2FF for prophylaxis, at two different doses, significantly delayed tumor onset in both TgMMTV-neu; 20 mmol/L (P = 0.0004; HR, 3.55; 95% CI, 1.60–7.88) and 50 mmol/L (P = 0.0002; HR: 3.89; 95% CI, 1.71–8.86) and C3(1)-Tag; 20 mmol/L (P = 0.0020; HR, 2.51; 95% CI, 1.22–5.18), and 50 mmol/L (P = 0.0012; HR, 3.36; 95% CI, 1.57–7.18). Mammary cancer was prevented in 33% of TgMMTV-neu and 26% of C3(1)-Tag. 2FF has potent antitumor effects in mammary cancer models. The agent shows preclinical efficacy for both cancer treatment and prevention.

Despite advances in oral health care, inequalities in oral health outcomes persist due to problems in access. With proper training, primary care providers can mitigate this inequality by providing oral health education, screening, and referral to advanced dental treatment. Diverging sets of oral health competencies and guidelines have been released or endorsed by multiple primary care disciplines. The aim of this study was to transform multiple sets of competencies into Entrustable Professional Activities (EPAs) for oral health integration into primary care training. A scoping review of the literature between January 2000 and December 2016 was conducted according to PRISMA methodology to identify all existing sets of competencies. The following primary care disciplines were included in the search: allopathic/osteopathic medical schools and residency programs in family medicine, internal medicine, and pediatrics; physician assistant programs; and nurse practitioner programs. Competencies were compared using the Health Resources and Services Administration Integration of Oral Health and Primary Care Practice competencies as the foundational set and translated into EPAs. The resulting EPAs were tested with a reactor panel. The scoping review produced 1,466 references, of which 114 were selected for full text review. Fourteen competencies were identified as being central to the integration of oral health into primary care. These were converted to seven EPAs for oral health integration into primary care and were mapped onto Accreditation Council for Graduate Medical Education residency competency domains as well to the Association of American Medical Colleges EPAs for graduating medical students. The resulting EPAs delineate the essential, observable work required of primary care providers to ensure that oral health is treated as a critical determinant of overall health.

ABSTRACT

In the absence of a vaccine, multidrug-resistant Neisseria gonorrhoeae has emerged as a major human health threat, and new approaches to treat gonorrhea are urgently needed. N. gonorrhoeae pili are posttranslationally modified by a glycan that terminates in a galactose. The terminal galactose is critical for initial contact with the human cervical mucosa via an interaction with the I-domain of complement receptor 3 (CR3). We have now identified the I-domain galactose-binding epitope and characterized its galactose-specific lectin activity. Using surface plasmon resonance and cellular infection assays, we found that a peptide mimic of this galactose-binding region competitively inhibited the N. gonorrhoeae-CR3 interaction. A compound library was screened for potential drugs that could similarly prohibit the N. gonorrhoeae-CR3 interaction and be repurposed as novel host-targeted therapeutics for multidrug-resistant gonococcal infections in women. Two drugs, methyldopa and carbamazepine, prevented and cured cervical cell infection by multidrug-resistant gonococci by blocking the gonococcal-CR3 I-domain interaction.

IMPORTANCE Novel therapies that avert the problem of Neisseria gonorrhoeae with acquired antibiotic resistance are urgently needed. Gonococcal infection of the human cervix is initiated by an interaction between a galactose modification made to its surface appendages, pili, and the I-domain region of (host) complement receptor 3 (CR3). By targeting this crucial gonococcal–I-domain interaction, it may be possible to prevent cervical infection in females. To this end, we identified the I-domain galactose-binding epitope of CR3 and characterized its galactose lectin activity. Moreover, we identified two drugs, carbamazepine and methyldopa, as effective host-targeted therapies for gonorrhea treatment. At doses below those currently used for their respective existing indications, both carbamazepine and methyldopa were more effective than ceftriaxone in curing cervical infection ex vivo. This host-targeted approach would not be subject to N. gonorrhoeae drug resistance mechanisms. Thus, our data suggest a long-term solution to the growing problem of multidrug-resistant N. gonorrhoeae infections.

Kaposi sarcoma-associated herpesvirus (KSHV) is necessary but not sufficient for primary effusion lymphoma (PEL) development. Alterations in cellular signaling pathways are also a characteristic of PEL. Other B cell lymphomas have acquired an oncogenic mutation in the myeloid differentiation primary response 88 (MYD88) gene. The MYD88 L265P mutant results in the activation of interleukin-1 receptor associated kinase (IRAK). To probe IRAK/MYD88 signaling in PEL, we employed CRISPR/Cas9 technology to generate stable deletion clones in BCBL-1Cas9 and BC-1Cas9 cells. To look for off-target effects, we determined the complete exome of the BCBL-1Cas9 and BC-1Cas9 cells. Deletion of either MYD88, IRAK4, or IRAK1 abolished interleukin-1 beta (IL-1β) signaling; however, we were able to grow stable subclones from each population. Transcriptome sequencing (RNA-seq) analysis of IRAK4 knockout cell lines (IRAK4 KOs) showed that the IRAK pathway induced cellular signals constitutively, independent of IL-1β stimulation, which was abrogated by deletion of IRAK4. Transient complementation with IRAK1 increased NF-B activity in MYD88 KO, IRAK1 KO, and IRAK4 KO cells even in the absence of IL-1β. IL-10, a hallmark of PEL, was dependent on the IRAK pathway, as IRAK4 KOs showed reduced IL-10 levels. We surmise that, unlike B cell receptor (BCR) signaling, MYD88/IRAK signaling is constitutively active in PEL, but that under cell culture conditions, PEL rapidly became independent of this pathway.

IMPORTANCE One hundred percent of primary effusion lymphoma (PEL) cases are associated with Kaposi sarcoma-associated herpesvirus (KSHV). PEL cell lines, such as BCBL-1, are the workhorse for understanding this human oncovirus and the host pathways that KSHV dysregulates. Understanding their function is important for developing new therapies as well as identifying high-risk patient groups. The myeloid differentiation primary response 88 (MYD88)/interleukin-1 receptor associated kinase (IRAK) pathway, which has progrowth functions in other B cell lymphomas, has not been fully explored in PEL. By performing CRISPR/Cas9 knockout (KO) studies targeting the IRAK pathway in PEL, we were able to determine that established PEL cell lines can circumvent the loss of IRAK1, IRAK4, and MYD88; however, the deletion clones are deficient in interleukin-10 (IL-10) production. Since IL-10 suppresses T cell function, this suggests that the IRAK pathway may serve a function in vivo and during early-stage development of PEL.

The Epstein-Barr virus (EBV) causes human cancers, and epidemiological studies have shown that lytic replication is a risk factor for some of these tumors. This fits with the observation that EBV M81, which was isolated from a Chinese patient with nasopharyngeal carcinoma, induces potent virus production and increases the risk of genetic instability in infected B cells. To find out whether this property extends to viruses found in other parts of the world, we investigated 22 viruses isolated from Western patients. While one-third of the viruses hardly replicated, the remaining viruses showed variable levels of replication, with three isolates replicating at levels close to that of M81 in B cells. We cloned one strongly replicating virus into a bacterial artificial chromosome (BAC); the resulting recombinant virus (MSHJ) retained the properties of its nonrecombinant counterpart and showed similarities to M81, undergoing lytic replication in vitro and in vivo after 3 weeks of latency. In contrast, B cells infected with the nonreplicating Western B95-8 virus showed early but abortive replication accompanied by cytoplasmic BZLF1 expression. Sequencing confirmed that rMSHJ is a Western virus, being genetically much closer to B95-8 than to M81. Spontaneous replication in rM81- and rMSHJ-infected B cells was dependent on phosphorylated Btk and was inhibited by exposure to ibrutinib, opening the way to clinical intervention in patients with abnormal EBV replication. As rMSHJ contains the complete EBV genome and induces lytic replication in infected B cells, it is ideal to perform genetic analyses of all viral functions in Western strains and their associated diseases.

IMPORTANCE The Epstein-Barr virus (EBV) infects the majority of the world population but causes different diseases in different countries. Evidence that lytic replication, the process that leads to new virus progeny, is linked to cancer development is accumulating. Indeed, viruses such as M81 that were isolated from Far Eastern nasopharyngeal carcinomas replicate strongly in B cells. We show here that some viruses isolated from Western patients, including the MSHJ strain, share this property. Moreover, replication of both M81 and of MSHJ was sensitive to ibrutinib, a commonly used drug, thereby opening an opportunity for therapeutic intervention. Sequencing of MSHJ showed that this virus is quite distant from M81 and is much closer to nonreplicating Western viruses. We conclude that Western EBV strains are heterogeneous, with some viruses being able to replicate more strongly and therefore being potentially more pathogenic than others, and that the virus sequence information alone cannot predict this property.

Our study in PNAS (1) applies a mathematically based framework to the study of reported emotional experience evoked by music in the United States and China. Germane to theoretical debate, our methods reveal how specific emotions such as “triumph” are more primary across cultures than valence and arousal, a finding...

Background:

Patient identification is an important step for advance care planning (ACP) discussions.

Purpose:

Clinical evidence shows minimal benefit to vitamin D screening and subsequent treatment in the general population. This study aims to assess the effectiveness of 2 light-touch interventions on reducing vitamin D test orders.

Background

Arteriovenous fistulas placed surgically for dialysis vascular access have a high primary failure rate resulting from excessive inward remodeling, medial fibrosis, and thrombosis. No clinically established pharmacologic or perisurgical therapies currently address this unmet need. Statins’ induction of multiple anti-inflammatory and antithrombotic effects suggests that these drugs might reduce arteriovenous fistula failure. Yet, the in vivo physiologic and molecular effects of statins on fistula patency and maturation remain poorly understood.

¹⁸F-rhPSMA-7 (radiohybrid prostate-specific membrane antigen [PSMA]) is a novel ligand for PET imaging. Here, we present data from a retrospective analysis using PET/CT and PET/MRI examinations to investigate the efficacy of ¹⁸F-rhPSMA-7 PET for primary N-staging of patients with prostate cancer (PC) compared with morphologic imaging (CT or MRI) and validated by histopathology. Methods: Data from 58 patients with high-risk PC (according to the D’Amico criteria) who were staged with ¹⁸F-rhPSMA-7 PET/CT or PET/MRI at our institution between July 2017 and June 2018 were reviewed. The patients had a median prescan prostate-specific antigen value of 12.2 ng/mL (range, 1.2–81.6 ng/mL). The median injected activity of ¹⁸F-rhPSMA-7 was 327 MBq (range, 132–410 MBq), with a median uptake time of 79.5 min (range, 60–153 min). All patients underwent subsequent radical prostatectomy and extended pelvic lymph node dissection. The presence of lymph node metastases was determined by an experienced reader independently for both the PET and the morphologic datasets using a template-based analysis on a 5-point scale. Patient-level and template-based results were both compared with histopathologic findings. Results: Lymph node metastases were present in 18 patients (31.0%) and were located in 52 of 375 templates (13.9%). Receiver-operating-characteristic analyses showed ¹⁸F-rhPSMA-7 PET to perform significantly better than morphologic imaging on both patient-based and template-based analyses (areas under curve, 0.858 vs. 0.649 [P = 0.012] and 0.765 vs. 0.589 [P < 0.001], respectively). On patient-based analyses, the sensitivity, specificity, and accuracy of ¹⁸F-rhPSMA-7 PET were 72.2%, 92.5%, and 86.2%, respectively, and those of morphologic imaging were 50.0%, 72.5%, and 65.5%, respectively. On template-based analyses, the sensitivity, specificity, and accuracy of ¹⁸F-rhPSMA-7 PET were 53.8%, 96.9%, and 90.9%, respectively, and those of morphologic imaging were 9.6%, 95.0%, and 83.2%, respectively. Conclusion: ¹⁸F-rhPSMA-7 PET is superior to morphologic imaging for N-staging of high-risk primary PC. The efficacy of ¹⁸F-rhPSMA-7 is similar to published data for ⁶⁸Ga-PSMA-11.

Therapeutic inertia is a prevalent problem in people with type 2 diabetes in primary care and affects clinical outcomes. It arises from a complex interplay of patient-, clinician-, and health system–related factors. Ultimately, clinical practice guidelines have not made an impact on improving glycemic targets over the past decade. A more proactive approach, including focusing on optimal combination agents for early glycemic durability, may reduce therapeutic inertia and improve clinical outcomes.

Human bone marrow stromal cells (BMSC) are key elements of the hematopoietic environment and they play a central role in bone and bone marrow physiology. However, how key stromal cell functions are regulated is largely unknown. We analyzed the role of the immediate early response transcription factor EGR1 as key stromal cell regulator and found that EGR1 was highly expressed in prospectively-isolated primary BMSC, down-regulated upon culture, and low in non-colony-forming CD45^neg stromal cells. Furthermore, EGR1 expression was lower in proliferative regenerating adult and fetal primary cells compared to adult steady-state BMSC. Overexpression of EGR1 in stromal cells induced potent hematopoietic stroma support as indicated by an increased production of transplantable CD34⁺CD90⁺ hematopoietic stem cells in expansion co-cultures. The improvement in bone marrow stroma support function was mediated by increased expression of hematopoietic supporting genes, such as VCAM1 and CCL28. Furthermore, EGR1 overexpression markedly decreased stromal cell proliferation whereas EGR1 knockdown caused the opposite effects. These findings thus show that EGR1 is a key stromal transcription factor with a dual role in regulating proliferation and hematopoietic stroma support function that is controlling a genetic program to co-ordinate the specific functions of BMSC in their different biological contexts.

BackgroundAutistic people are at increased risk of developing mental health problems. To reduce the negative impact of living with autism in a non-autistic world, efforts to improve take-up and access to care, and support in early years, which will typically start with a GP appointment, must be grounded in the accounts of autistic young adults.AimTo explore how autistic young adults understand and manage mental health problems; and to consider help seeking as a focus.Design and settingA cross-sectional, qualitative study. Autistic participants were purposively selected to represent a range of mental health conditions including anxiety and depression. A subsample were recruited from a population cohort screened for autism in childhood. The study concerns access to primary care.MethodNineteen autistic young adults without learning disabilities, aged 23 or 24 years, were recruited. In-depth, semi-structured interviews explored how they understood and managed mental health problems. Data were analysed thematically.ResultsYoung adults preferred self-management strategies. Multiple factors contributed to a focus on self-management, including: beliefs about the aetiology of mental health difficulties and increased vulnerability with the context of a diagnosis of autism, knowledge of self-management, and a view that formal support was unavailable or inadequate. Families had limited awareness of professional support.ConclusionYoung autistic adults without learning disabilities, and their families, may hold erroneous beliefs about autism and mental health. This may affect help seeking and contribute to an exacerbation of symptoms. GPs need to be alert to the fact that autistic young adults in their care may be experiencing mental health difficulties but may not recognise them as such.

BackgroundA brief intervention whereby GPs opportunistically facilitate an NHS-funded referral to a weight loss programme is clinically and cost-effective.AimTo test the acceptability of a brief intervention and attendance at a weight loss programme when GPs facilitate a referral that requires patients to pay for the service.Design and settingAn observational study of the effect of a GP encouraging attendance at a weight loss programme requiring self-payment in the West Midlands from 16 October 2018 to 30 November 2018, to compare with a previous trial in England in which the service was NHS-funded.MethodSixty patients with obesity who consecutively attended primary care appointments received an opportunistic brief intervention by a GP to endorse and offer a referral to a weight loss programme at the patient’s own expense. Participants were randomised to GPs who either stated the weekly monetary cost of the programme (basic cost) or who compared the weekly cost to an everyday discretionary item (cost comparison). Participants were subsequently asked to report whether they had attended a weight loss programme.ResultsOverall, 47% of participants (n = 28) accepted the referral; 50% (n = 15) in the basic cost group and 43% (n = 13) in the cost comparison group. This was significantly less than in a previous study when the programme was NHS-funded (77%, n = 722/940; P<0.0001). Most participants reported the intervention to be helpful/very helpful and appropriate/very appropriate (78%, n = 46/59 and 85%, n = 50/59, respectively) but scores were significantly lower than when the programme was NHS-funded (92% n = 851/922 and 88% n = 813/922, respectively; P = 0.004). One person (2%) attended the weight loss programme, which is significantly lower than the 40% of participants who attended when the programme was NHS-funded (P<0.0001).ConclusionGP referral to a weight loss programme that requires patients to pay rather than offering an NHS-funded programme is acceptable; however, it results in almost no attendance.

BackgroundAwareness of the importance of shared decision making (SDM) is widespread; however, little research has focused on discussions surrounding investigations, despite increasing laboratory testing in primary care.AimTo explore the discussion of blood tests in routine primary care consultations.Design and settingA secondary analysis of 50 video-recorded routine primary care consultations, linked surveys, and records data (all from the One in a Million [OiaM] archive). The consultations were taken by 22 GPs across 12 practices.MethodA coding scheme was developed, using qualitative content analysis, to explore discussion of blood tests in transcripts of recorded consultations. Codes focused on instigating testing, the extent of SDM, and how results were explained. Survey data were used to compare patients’ pre-visit expectations with consultation content. Medical records were reviewed to compare tests discussed with those ordered.ResultsIn 36 out of 50 consultations that discussed ordering blood tests, 11 patients (31%) hinted that they wanted a blood test; however, none asked explicitly. Only four patients (11%) were offered alternative options. In 29 cases (81%) the GP gave some explanation of the indication, but only in six cases (17%) were the limitations of testing explained. Only 10 out of 31 patients (32%) were informed about all blood tests ordered. Of the 23 out of 50 consultations in which results were conveyed, the GP gave no explanation of the results in six cases (26%). Thirteen patients (57%) were only informed of an assessment of the results (for example, ‘normal’), rather than the actual results.ConclusionA lack of information dissemination and SDM exists around ordering tests and conveying results. Promoting SDM could reduce unnecessary testing and improve patient-centred care.

BackgroundUrinary tract infections (UTIs) are one of the most common bacterial infections managed in general practice. Many women with symptoms of uncomplicated UTI may not benefit meaningfully from antibiotic treatment, but the evidence base is complex and there is no suitable shared decision-making resource to guide antibiotic treatment and symptomatic care for use in general practice consultations.AimTo develop an evidence-based, shared decision-making intervention leaflet to optimise management of uncomplicated UTI for women aged <65 years in the primary care setting.Design and settingQualitative telephone interviews with GPs and patient focus group interviews.MethodIn-depth interviews were conducted to explore how consultation discussions around diagnosis, antibiotic use, self-care, safety netting, and prevention of UTI could be improved. Interview schedules were based on the Theoretical Domains Framework.ResultsBarriers to an effective joint consultation and appropriate prescribing included: lack of GP time, misunderstanding of depth of knowledge and miscommunication between the patient and the GP, nature of the consults (such as telephone consultations), and a history of previous antibiotic therapy.ConclusionConsultation time pressures combined with late symptom presentation are a challenge for even the most experienced of GPs: however, it is clear that enhanced patient–clinician shared decision making is urgently required when it comes to UTIs. This communication should incorporate the provision of self-care, safety netting, and preventive advice to help guide patients when to consult. A shared decision-making information leaflet was iteratively co-produced with patients, clinicians, and researchers at Public Health England using study data.

BackgroundIn the context of a variable condition such as asthma, patient recognition of deteriorating control and knowing what prompt action to take is crucial. Yet, implementation of recommended self-management strategies remains poor.AimTo explore how patients with asthma and parents/carers of children with asthma develop and establish recommended self-management strategies for living with asthma, and how clinicians can best support the process.Design and settingA qualitative study in UK primary care.MethodPatients with asthma and parents/carers of children with asthma from 10 general practices were purposively sampled (using age, sex, and duration of asthma) to participate in focus groups or interviews between May 2016 and August 2016. Participants’ experiences of health care, management of asthma, and views on supported self-management were explored. Interviews and focus group sessions were audio-recorded and transcribed verbatim. Iterative thematic analysis was conducted, guided by the research questions and drawing on habit theory in discussion with a multidisciplinary research team.ResultsA total of 49 participants (45 patients; 4 parents/carers) took part in 32 interviews and five focus groups. Of these, 11 reported using an action plan. Patients learnt how to self-manage over time, building knowledge from personal experience and other sources, such as the internet. Some regular actions, for example, taking medication, became habitual. Dealing with new or unexpected scenarios required reflective abilities, which may be supported by a tailored action plan.ConclusionPatients reported learning intuitively how to self-manage. Some regular actions became habitual; dealing with the unexpected required more reflective cognitive skills. In order to support implementation of optimal asthma self- management, clinicians should consider both these aspects of self-management and support, and educate patients proactively.