Discussing end-of-life (EoL) care with adolescents and young adults (AYAs) is difficult. Often, such conversations are delayed or avoided, but AYAs contemplate EoL issues and want to make decisions about their care. Few established resources exist to help this process.

Results support the use of a developmentally appropriate document that allows AYAs an opportunity to share their choices about EoL care and how they would like to be remembered in the future. (Read the full article)

Juice consumption among 2- to 5-year-old children exceeds dietary recommendations. In 2007, the US Department of Agriculture revised the composition and quantities of prescribed foods in WIC food packages to align them with dietary guidelines. Juice allowances were reduced by approximately half.

WIC participants purchased about a quarter less juice volume after implementation of the revised WIC packages. Large reductions in WIC-provided juice were only partly compensated for by extra juice purchases with non-WIC funds. Little compensation occurred for other beverages. (Read the full article)

Allostatic load (AL), a biomarker of cardiometabolic risk, predicts the onset of the chronic diseases of aging including cardiac disease, diabetes, hypertension, and stroke. Socioeconomic-related stressors, such as low family income, are associated with AL.

African American youth who grow up in neighborhoods in which poverty levels increase across adolescence evince high AL. The study also highlights the benefits of emotional support in ameliorating this association. (Read the full article)

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.

Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo β-lactamase (MBL) families. The recent introduction of SBL carbapenemase-inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n=234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ~30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modelling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor, capable of operating in a functional space not presently filled by any clinically approved compound.

Multi-drug resistance among Gram-negative bacteria is a major global public health threat. Metallo-β-lactamases (MBLs) target the most widely-used antibiotic class, the β-lactams, including the most recent-generation carbapenems. Interspecies spread renders these enzymes a serious clinical threat and there are no clinically-available inhibitors. We present crystal structures of IMP-13, a structurally-uncharacterized MBL from Gram-negative Pseudomonas aerugionasa found in clinical outbreaks globally, and characterize the binding using solution NMR-spectroscopy and molecular-dynamics simulations. Crystal structures of apo IMP-13 and bound to four clinically-relevant carbapenem antibiotics (doripenem, ertapenem, imipenem and meropenem) are presented. Active site plasticity and the active-site loop, where a tryptophan residue stabilizes the antibiotic core scaffold, are essential to the substrate-binding mechanism. The conserved carbapenem scaffold plays the most significant role in IMP-13 binding, explaining the broad substrate specificity. The observed plasticity and substrate-locking mechanism provide opportunities for rational drug design of novel metallo-β-lactamase inhibitors, essential in the fight against antibiotic resistance.

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.

Treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP+Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) at 4-day intervals, plus allopurinol at 30 mg/kg/12 h p.o. during 130 days; LC+Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose), plus allopurinol during 130 days; Allop, treated with allopurinol only; non-treated control. Parasite loads were evaluated by quantitative PCR in liver, spleen and bone marrow and by immunohistochemistry in the ear skin, before, just after treatment and 4 months later. LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen and bone marrow 4 months after treatment, compared to the pre-treatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin, in comparison to the control group. On the basis of clinical staging and parasitological evaluations, LCP formulation exhibited a more favorable therapeutic profile, when compared to LC one, being therefore promising for treatment of canine visceral leishmaniasis.

Allegations that some students lied about having disabilities so they could get special accommodations on college entrance exams have the disabilities community worried about a backlash.

"This is the moment of truth," says the Spain midfielder ahead of his second U21 EURO final against Germany.

The UEFA Super Cup ticket ballot has been conducted and applicants notified via email.

South Carolina grants Google permission to pump up to 549 million gallons of groundwater every year to cool servers at its Berkeley County data center.

If this was a review, these AirPods would definitely earn a passing grade.

Fans have found out if they have secured tickets for UEFA EURO 2020 after a record-breaking 19.3 million requests.

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 […]

“Who Did In the Delaware Ducks?” and “Mysteries of History” to be featured

Activities will include tours of the home, games and crafts.

Trick-or-treaters invited to the governor's home on Tuesday, Oct. 31, 2017, between 5 p.m. and 8 p.m.

As currently funded, $278 million project would unfairly burden electric ratepayers on Delmarva WILMINGTON, Del. – Delaware Governor John Carney and Maryland Governor Larry Hogan on Tuesday sent a letter to members of the Federal Energy Regulatory Commission, urging commissioners to expedite their review of the $278 million Artificial Island transmission line project and consider a […]

The Orlando Magic have approval from the NBA to begin testing players for the deadly virus after getting written approval from area health officials, according to the report.

Google has released an update for its Authenticator app to allow users to manage their account security keys easily while switching to a different phone.

The US Department of Commerce is close to signing off on a new rule that would allow US companies to work with China's Huawei Technologies on setting standards for next generation 5G networks, people...

DOVER – The Delaware Supreme Court, by decision dated Dec. 7, 2017 in the matter of Bridgeville Rifle & Pistol Club, LTD, overturned a Superior Court ruling and ended a ban on visitors’ possessing firearms in Delaware’s state parks and state forests. Pursuant to the ruling, visitors may now possess firearms unless they are prohibited by law due to a past conviction for a violent crime, active Protection from Abuse Order, or mental health commitment. Following the Court’s decision to invalidate the existing regulations limiting firearms in state parks and forests, and some Division of Fish & Wildlife properties, the Delaware Department of Natural Resources and Environmental Control and the Delaware Department of Agriculture (DDA) anticipate issuing interim firearm regulations. The interim regulations would respect the State Constitutional provisions on firearms cited by the Court, by implementing the State’s interest in ensuring the safety of the public in a less restrictive manner.

The Safe Kids Delaware Coalition reminds parents to take precautions to keep their children safe while trick-or-treating.

Dr Gallo and Dr Chumakov briefly talk about research showing non-specific protection from vaccines such as BCG, measles and other live attenuated (weakened) vaccines.

Out-of-state visitors must self-quarantine for 14 days before engaging in fishing, hunting, golf, visiting state parks and wildlife areas.

DNREC announced today it will take steps when necessary to limit the numbers of visitors within state parks and wildlife areas.

Retail, hair dressers able to resume limited services while maintaining health guidelines WILMINGTON, Del. – Governor John Carney on Tuesday announced a series of interim steps allowing small businesses to resume limited operations effective 8:00 a.m. on Friday, May 8. The goal of the interim steps is to provide economic relief to Delaware citizens and […]

OHS Activates Operation Checkpoint StrikeForce For All 3 counties This Weekend Dover, Del. (October 25, 2019) – The Delaware Office of Highway Safety is coordinating Operation Checkpoint Strikeforce in each county statewide for Halloween weekend. This zero-tolerance initiative in Delaware, implemented since 2002, is designed to get impaired drivers off of our roads using checkpoints and patrols. The […]

(Dover, Del.) October 28, 2019 – The Delaware Office of Highway Safety (OHS) coordinated DUI checkpoints in all three counties on Saturday, October, 26th, from 10 p.m. until Sunday, October 27th, at 2 a.m. the following morning. Working together with the Delaware State Police and local law enforcement, OHS supported three DUI checkpoints across the state. OHS is pleased to […]

In a relief to Sunil Bhari-led Bharti Airtel, the Delhi High Court has allowed the telco to rectify its GST returns for July 2017 to September 2017 and thus claim refund of Rs 923 crore, which was denied earlier by the tax department.

Stick to asset allocation matrix, take regular profits and go for bottom fishing in select stocks/ MF schemes in these turbulent times

The objective of a good asset allocation plan is to develop an investment portfolio that helps you reach your financial goals with the degree of risk you find comfortable

Multi-asset funds of mutual funds can be a good option for asset allocation mix even as gold is a good diversifIer. Also, do keep emergency funds in debt funds & fixed deposits

Dearness Allowance (DA) Hike Latest News: The April salary, which is due to be paid in a week’s time, was supposed to be based on revised DA, along with arrears for three months (January-March).

Debt schemes of mutual funds for long have been seen as low risk, but shuttering six schemes and leaving investors in a lurch will impact investor sentiment.

The order issued by the state finance department will impact over 16 lakh state employees and officers, approximately three lakh teachers and 12 lakh pensioners.

The EPFO has already extended to May 15 the due date for depositing statutory contributions for the wage month of March, due by April 15.

The year 2020 is not going to be a year to forget. Understanding the nuances and re-learning the basics is a good thing to do.

Dr. Datuk Noor Zari Secretary-General Tourism Ministry Malaysia stated that the tourists from India and China were among the top contributors to the tourism sector in the country.Focus on Two NationsAlso, the number of arrivals from India and China is…

DNERR’s Tree Swallows and Bluebirds Need YOU Spring is here, and the St. Jones and Blackbird Creek Reserves have sprouted a number of mysterious, wooden boxes affixed to PVC poles. Where did these boxes come from? And why? With such questions in mind, this writer approached Christina Whiteman, DNERR’s Environmental Scientist and Stewardship Coordinator, and […]

The post DNERR’s Tree Swallows and Bluebirds Need YOU appeared first on DNERR Blog - State of Delaware.

GSTN added that a taxpayer can now transfer the amount available in an electronic cash ledger from one major head to another major head, keeping the minor head the same.

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

It also passed a string of directions on safe passage for the bodies of the victims, their proper burial/cremation, adequate number of helplines and help desks, besides rehabilitation of those affected.