Both short and long interpregnancy intervals are associated with increased risk of autism in second-born children. However, it is not known if the association is explained by unfavorable birth outcomes of the previous siblings.

Both short and long interpregnancy intervals increase risk of autism in second-born children independently of previous siblings being born premature, having low birth weight, or being born by cesarean delivery and independently of maternal antidepressant use 3 months before pregnancy. (Read the full article)

The new Trump administration rule regarding immigrants' use of federal benefits could have an indirect but significant impact on schools, education advocates warn.

Some educators and advocates fear the rule will dissuade immigrants from seeking certain government benefits, and that further burdens will fall on schools.

Saudi Arabian equities slumped on concern the U.S. may take measures against the kingdom if it’s linked to the disappearance of Washington Post writer Jamal Khashoggi.

US President Donald trump has suggested that 'rogue killers' may be behind the disappearance of journalist Jamal Khashoggi in Turkey.

US President Donald Trump says he plans to sign an executive order ending birthright citizenship for babies of non-citizens and unauthorised immigrants born on US soil.

President Donald Trump and China’s Xi Jinping will sit down for a highly anticipated dinner with investors and allies eager for a truce in the trade war between the world’s two largest economies.

The Institutes of Energy and the Environment, in collaboration with Stewarding Our Planet's Resources, announced two separate community forums aimed at providing reports on existing energy and environmental activities and strategic opportunities as well as soliciting community input and recommendations for the future.

The Central African Republic is often called a forgotten country, but that isn’t quite right. It has had a long and substantial international presence and sizable foreign investment. It’s just that those efforts haven’t made much difference. As the country rapidly descends into greater violence, the difficult truth is that more — and much better — international and regional involvement is its only hope.

QPX7728 is a new ultra-broad-spectrum inhibitor of serine and metallo beta-lactamases from a class of cyclic boronates that gave rise to vaborbactam. The spectrum and mechanism of beta-lactamase inhibition by QPX7728 were assessed using purified enzymes from all molecular classes. QPX7728 inhibits class A ESBLs (IC₅₀ range 1-3 nM) and carbapenemases such as KPC (IC₅₀ 2.9±0.4 nM) as well as class C P99 (IC₅₀ of 22±8 nM) with a potency that is comparable or higher than recently FDA approved BLIs avibactam, relebactam and vaborbactam. Unlike those other BLIs, QPX7728 is also a potent inhibitor of class D carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from A. baumannii (OXA-23/24/58, IC₅₀ range 1-2 nM) as well as MBLs such as NDM-1 (IC₅₀ 55±25 nM), VIM-1 (IC₅₀ 14±4 nM) and IMP-1 (IC₅₀ 610±70 nM). Inhibition of serine enzymes by QPX7728 is associated with progressive inactivation with a high efficiency k₂/K ranging from of 6.3 x 10⁴ (for P99) to 9.9 x 10⁵ M^-1 s^-1 (for OXA-23). This inhibition is reversible with variable stability of the QPX7728-beta-lactamase complexes with target residence time ranging from minutes to several hours: 5-20 minutes for OXA carbapenemases from A. baumanii, ~50 minutes for OXA-48 and 2-3 hours for KPC and CTX-M-15. QPX7728 inhibited all tested serine enzymes at 1:1 molar ratio. Metallo-beta-lactamases NDM, VIM, and IMP were inhibited by a competitive mechanism with fast-on-fast-off kinetics, with K_is of 7.5±2.1 nM, 32±14 nM and 240±30 nM for VIM-1, NDM-1 and IMP-1, respectively. QPX7728 ultra-broad-spectrum of BLI inhibition combined with its high potency enables combinations with multiple different beta-lactam antibiotics.

Malaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.

Since 2012, single low dose of primaquine (SLDPQ, 0.25mg/kg) has been recommended with artemisinin-based combination therapies, as first-line treatment of acute uncomplicated Plasmodium falciparum malaria, to interrupt its transmission, especially in low transmission settings of multidrug, including artemisinin, resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and lack of data on its efficacy.

In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. Transmission-blocking efficacy of SLDPQ was evaluated on Days 0, 1, 2, 3, 7, 14, 21, 28 and recrudescence by reverse transcriptase polymerase chain reaction (RT-PCR) (gametocyte prevalence) and membrane-feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP+SLDPQ reduced gametocyte carriage 3 fold compared to DP. Of 48 patients tested on Day 0, only three patients were infectious to mosquitoes (~6%). Post-treatment, three patients were infectious: on D14 (3.5%, 1/29), and on the first and seventh day of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission blocking efficacy.

Our study confirms effective gametocyte clearance of SLDPQ when combined with DP in multidrug resistant P. falciparum and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP and ASMQ-SLDPQ has been deployed to treat all P. falciparum symptomatic patients to further support the elimination of multidrug resistant P. falciparum in Cambodia.

Antimicrobial peptides and proteins play critical roles in the host defense against invading pathogens. We recently discovered that recombinantly expressed human and mouse serum amyloid A1 (rhSAA1 and rmSAA1) proteins have potent antifungal activities against the major human fungal pathogen Candida albicans. At high concentrations, rhSAA1 disrupts C. albicans membrane integrity and induces rapid fungal cell death. In the current study, we find that rhSAA1 promotes cell aggregation and targets the C. albicans cell wall adhesin Als3. Inactivation of ALS3 in C. albicans leads to a striking decrease in cell aggregation and cell death upon rhSAA1 treatment, suggesting that Als3 plays a critical role in SAA1 sensing. We further demonstrate that deletion of the transcriptional regulators controlling the expression of ALS3, such as AHR1, BCR1, and EFG1 in C. albicans results in similar effects to that of the als3/als3 mutant upon rhSAA1 treatment. Global gene expression profiling indicates that rhSAA1 has a discernible impact on the expression of cell wall- and metabolism-related genes, suggesting that rhSAA1 treatment could lead to a nutrient starvation effect on C. albicans cells.

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of beta-lactamase inhibition by QPX7728. The MIC of multiple IV only (ceftazidime, piperacillin, cefepime, ceftolozane and meropenem) and orally bioavailable (ceftibuten, cefpodoxime, tebipenem) antibiotics alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against the panels of laboratory strains of P. aeruginosa and K. pneumoniae expressing over 55 diverse serine and metallo beta-lactamases. QPX7728 significantly enhanced the potency of antibiotics against the strains expressing Class A extended spectrum beta-lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with beta-lactamase inhibition demonstrated in biochemical assays. It also inhibits both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) Class C beta-lactamases and Class D enzymes including carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent inhibitor of many class B metallo beta-lactamases (NDM, VIM, CcrA1, IMP, GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs in a majority of strains to the level observed for the vector alone control, indicative of complete beta-lactamase inhibition. The ultra-broad-spectrum beta-lactamase inhibition profile makes QPX7728 a viable candidate for further development.

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo beta-lactamases at a nano molar range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impact of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3 producing isogenic strains of K. pneumoniae and P. aeruginosa and OXA-23-producing strains of A. baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multi-drug resistance efflux pumps in either Enterobacteriaceae, or in non-fermenters such as P. aeruginosa or A. baumannii. In P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane is permeabilized. The potency of QPX7728 in P. aeruginosa is not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8-16-fold), QPX7728 (4 μg/ml) nevertheless completely reversed KPC-mediated meropenem resistance in strains with porin mutations, consistent with a lesser effect of these mutations on the potency of QPX7728 compared to other agents. The ultra-broad-spectrum beta-lactamase inhibition profile combined with enhancement of the activity of multiple beta-lactam antibiotics with varying sensitivity to the intrinsic resistance mechanisms of efflux and permeability indicate QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics.

Recent studies highlight the abundance of commensal coagulase-negative staphylococci (CoNS) on healthy skin. Evidence suggests that CoNS actively shape the skin immunological and microbial milieu to resist colonization or infection by opportunistic pathogens, including methicillin resistant Staphylococcus aureus (MRSA), in a variety of mechanisms collectively termed colonization resistance. One potential colonization resistance mechanism is the application of quorum sensing, also called the Accessory Gene Regulator (agr) system, which is ubiquitous among staphylococci. Common and rare CoNS make autoinducing peptides (AIPs) that function as MRSA agr inhibitors, protecting the host from invasive infection. In a screen of CoNS spent media we found that Staphylococcus simulans, a rare human skin colonizer and frequent livestock colonizer, released potent inhibitors of all classes of MRSA agr signaling. We identified three S. simulans agr classes, and have shown intraspecies cross-talk between non-cognate S. simulans agr types for the first time. The S. simulans AIP-I structure was confirmed, and the novel AIP-II and AIP-III structures were solved via mass spectrometry. Synthetic S. simulans AIPs inhibited MRSA agr signaling with nanomolar potency. S. simulans in competition with MRSA reduced dermonecrotic and epicutaneous skin injury in murine models. Addition of synthetic AIP-I also effectively reduced MRSA dermonecrosis and epicutaneous skin injury in murine models. These results demonstrate potent anti-MRSA quorum sensing inhibition by a rare human skin commensal, and suggest that cross-talk between CoNS and MRSA may be important in maintaining healthy skin homeostasis and preventing MRSA skin damage during colonization or acute infection.

Klebsiella pneumoniae that produce extended spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing area under the concentration time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime 100 mg/kg q8h i.v. had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam half-maximal effect was induced with enmetazobactam 4.71 mg/kg q8h i.v. The dose fractionation study suggest both fT>threshold and fAUC:MIC are potentially relevant PD indices. The AUC_ELF:AUC_plasma for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT>MIC of ≥20% and enmetazobactam fT>2 mg/L of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

A total of 2,283 Salmonella spp. isolates were recovered from 18,334 samples including patients with diarrhea, food of animal origin and pets across 5 provinces of China. The highest prevalence of Salmonella spp. was detected in chicken meats (39.3%, 486/1,237). Fifteen serogroups and 66 serovars were identified, with Typhimurium and Enteritidis being the most dominant. Most (85.5%, 1,952/2,283) isolates exhibited resistant to ≥ 1 antimicrobial and 56.4% were multi-drug resistant (MDR). A total of 222 isolates harbored extended-spectrum β-lactamases (ESBLs), 200 of which were CTX-M-type that were mostly detected from chicken meat and turtle fecal. Overall, eight bla_CTX-M genes were identified, with bla_CTX-M-65, bla_CTX-M-123, bla_CTX-M-14, bla_CTX-M-79, and bla_CTX-M-130 being the most prevalent. Totally, 166 of the 222 ESBL-producing isolates had amino acid substitutions in GyrA (S83Y, S83F, D87G, D87N, and D87Y) and ParC (and S80I), whilst the PMQR-encoding genes oqxA/B, qepA, and qnrB/S were detected in almost all isolates. Of the fifteen sequence types (STs) identified in the 222 ESBLs, ST17, ST11, ST34, and ST26 ranked among the top 5 in the number of isolates. Our study revealed considerable serovars diversity, high prevalence of co-occurrence of MDR determinants, including CTX-M-type ESBLs, QRDRs mutations and PMQR genes. This is the first report of CTX-M-130 Salmonella spp. from patients with diarrhea and QRDRs mutations from turtle fecal samples. Our study emphasizes the importance of actions, both in the health care settings and in the veterinary medicine sector, to control the dissemination of MDR, especially the CTX-M Salmonella spp. isolates.

Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug-resistance to specific anti-influenza drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug nitazoxanide with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza potentials with 10-fold improvement, compared with nitazoxanide, and were effective against a variety of influenza subtypes including oseltamivir-resistant strains. Notably, the combination using of compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effect against oseltamivir-resistant strain. Mode of action analysis demonstrated that compounds 4a/4d acted at the late phase of viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of up-regulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, our study pointed the optimization direction of nitazoxanide as anti-influenza drug, and discovered two novel-structured candidates 4a/4d with relatively broad-spectrum antiviral potential.

Dihydroartemisinin-piperaquine has shown excellent efficacy and tolerability in malaria treatment. However, concerns have been raised of potentially harmful cardiotoxic effects associated with piperaquine. The population pharmacokinetics and cardiac effects of piperaquine were evaluated in 1,000 patients, mostly children enrolled in a multicentre trial from 10 sites in Africa. A linear relationship described the QTc-prolonging effect of piperaquine, estimating a 5.90ms mean QTc-prolongation per 100ng/mL increase in piperaquine concentration. The effect of piperaquine on absolute QTc-interval estimated a mean maximum QTc-interval of 456ms (EC₅₀=209ng/mL). Simulations from the pharmacokinetic-pharmacodynamic models predicted 1.98-2.46% risk of having QTc-prolongation > 60ms in all treatment settings. Although piperaquine administration resulted in QTc-prolongation, no cardiovascular adverse events were found in these patients. Thus, the use of dihydroartemisinin-piperaquine should not be limited by this concern.

Earlier genetic and inhibitor studies have shown that epigenetic regulation of gene expression is critical for malaria parasite survival in multiple life stages and a promising target for new anti-malarials. We therefore evaluated the activity of 350 diverse epigenetic inhibitors against multiple stages of Plasmodium falciparum. We observed ≥90% inhibition at 10 μM for 28% of compounds against asexual blood stages and early gametocytes, of which a third retained ≥90% inhibition at 1 μM.

You'll get a trial, but that's it. If you want any kind of free music, you'll have to stick with iTunes Radio.

Marc Tucker looks at what the world's top performers tell us about the school choice agenda likely to be pursued by President Trump and his Education Secretary nominee Betsy DeVos.

Vinod K. Bhutani
Jan 1, 1999; 103:6-14
ARTICLES

CARO RAMSAY, AUTHOR

Source: www.thegatewaypundit.com - Friday, May 08, 2020
  By Wayne Allyn Root Dear President Trump, here’s an important message from your supporters. First it was “Stormy Daniels.” Then, “Russian Collusion.” Followed by “the Ukrainian Hoax.” Now, it’s “Coronavirus pandemic” and the resulting economic catastophe. “THEY” never give up. But who is “THEY?” “THEY” can’t possibly be Pelosi, Schumer, Schiff, Nadler, Maxine Waters, AOC, et al. Their IQ totaled together and multiplied by 1000 isn’t enough brainpower to take you down, Mr. President. In my opinion “THEY” is a very wealthy, very cunning, globalist, elitist cabal- led by George Soros. Talk about Deep State. Thank God it’s you, as President of the United States, or “THEY” would have already won. There are those who think this pandemic was a planned attack. It wasn’t. It’s not a hoax. It’s very real- as I’ve said from day one. While Coronavirus is a very real pandemic, it was quickly turned into a “target of opportunity.” Likely an off-shoot of the socialist/communist Cloward- Piven plan I learned from my America-hating classmates at Columbia University three decades ago. The goal of Cloward-Piven was to overwhelm the US economic system; bury the economy under a mountain of debt; take down capitalism; bankrupt every business owner in America; and turn America into a socialist basket case like Cuba. Sound familiar? It’s all happening right now. I believe Soros and his socialist, globalist, elitist, America-hating cabal saw the Coron

Source: www.youtube.com - Thursday, May 07, 2020

Source: www.youtube.com - Wednesday, May 06, 2020

The new 50-state report from the Rural School and Community Trust, emphasizes early childhood education and college-and-career readiness.

An executive order signed this week is meant to address concerns of anti-Semitism on college and university campuses. But the legal underpinnings of that order apply to elementary and secondary schools, too.

The Delaware State Housing Authority (DSHA) will be holding a free Small Business Contractor Forum on Thursday, September 5, 2013 from 9:00 a.m. – 11:30 a.m. at the Liberty Court Community Building, 1289 Walker Road in Dover.

The four finalists for National Teacher of the Year say their fellow teachers are sharing their stories and their students' stories more than ever, and it's time for policymakers to listen.

Coalition of 21 attorneys general argues changes violate federal law and judicial precedent Attorney General Kathy Jennings joined Friday a group of 21 state attorneys general to challenge the Trump administration’s proposed changes to asylum standards. If implemented, these changes would allow the Executive branch to arbitrarily deny asylum claims to immigrants seeking haven from […]

Attorney General Kathy Jennings today announced that she is joining a lawsuit opposing the Trump Administration’s new rule circumventing the Flores Settlement Agreement, which has governed the treatment of children in immigration custody since 1997. In the complaint before the U.S. District Court for the Central District of California, the coalition argues that the rule eliminates several critical protections […]

US President Donald Trump on Monday nominated an Indian-American attorney to a federal court in New York.

US President Donald Trump has nominated senior Indian-American diplomat Manisha Singh as his envoy to the Organization for Economic Cooperation and Development (OECD).

Four top Republican senators have urged US President Donald Trump to suspend all new guest worker visas for 60 days and some of its categories, including the H-1B visa, for at least the next year or...

President Donald Trump evoked the coronavirus crisis ahead of a wreath-laying ceremony Friday at the World War II memorial in Washington to mark the 75th anniversary of the Allied victory in Europe.

The US is working to temporarily ban the issuance of some work-based visas like H-1B, popular among highly-skilled Indian IT professionals, as well as students visas and work authorisation that...

Democratic Party's presumptive presidential nominee and former US vice president Joe Biden alleged on Friday that President Donald Trump utterly failed to prepare for the COVID-19 pandemic and said...

US President Donald Trump on Friday said that he will soon make an announcement on the World Health Organisation, which he alleged has become a puppet of China.

Ivanka Trump's personal assistant has tested positive for the deadly coronavirus, making her the third White House staff member to be infected from COVID-19, a media report said on Saturday.

Home Minister Amit Shah today tweeted to say he is healthy and not suffering from any disease, dismissing recent speculations on social media about his health.

Every year hundreds of dedicated SAS® users and event volunteers work tirelessly to create an amazing conference experience for SAS Global Forum attendees. This year, as you know, COVID-19 changed our plans. But our devoted team of volunteers, including our conference chairs and session presenters, was still determined to provide [...]

Introducing the first virtual SAS® Global Forum was published on SAS Voices by Jenn Chase

While for the latter the companies, including Vodafone Idea, have sought the facility to pay in installments spread over some 20 years which is currently before the SC, there's been no such demand for current payments.

Once the clinical trials are over and successful, SII will release its vaccine. If the clinical trials by Oxford are not successful then the loss will be of SII. Some limited clinical trials will be done by SII also.

DNREC’s Polly Drummond Hill Yard Waste site in New Castle County will close for the season on Friday, Feb. 28, 2020. Normally, the site closes earlier – at the end of January – but due to mild weather, DNREC extended the site’s operation into 2020 to accommodate yard waste activities. Area residents who wish to recycle their yard waste while the Polly Drummond Hill Road site is closed have other options for yard waste disposal.

DOVER, Del. – The Polly Drummond Hill yard waste drop-off site near Newark, which opened for the season on Saturday, April 18, was closed to further drop-offs about noon on Sunday because of material capacity and traffic issues. DNREC will work this week to have its contractor shred and remove all the material that was dropped off until the closure, and create a traffic plan with the goal of reopening the site on Saturday, April 25. The site operates Saturdays and Sundays.

Input sought on how funding will be distributed in Delaware for humanities-based organizations facing financial hardship due to the coronavirus. Deadline: April 20, 2020

The post Delaware Humanities Forum seeks input on funding for coronavirus relief appeared first on Division of Historical and Cultural Affairs - State of Delaware.

After careful consideration of the evolving COVID-19 situation, SAS made the decision in March to cancel the in-person SAS Global Forum 2020 conference in Washington, DC. The health and well-being of SAS customers and employees was the company's top priority in making that decision, and while it's unfortunate that we [...]

SAS Global Forum 2020: Hybrid marketing with SAS Customer Intelligence 360 was published on Customer Intelligence Blog.