Childhood inflammatory mediators are associated with adult obesity, but the stimuli that initiate and perpetuate chronic inflammation start in early life are largely unknown.

Childhood infection-related hospitalization was independently associated with adverse adult metabolic variables, which suggests that infections and/or their treatment in childhood may contribute to causal pathways leading to adult cardiometabolic diseases. (Read the full article)

Infants born very prematurely or with a very low birth weight are known to have an increased risk of attention-deficit/hyperactivity disorder (ADHD). Results concerning late preterm children are controversial and studies examining fetal growth represented by weight for gestational age are scarce.

We demonstrate that each declining week of gestation increases the risk of ADHD. Also, late preterm infants have an increased risk. Furthermore, as weight for gestational age becomes smaller than 1 SD below the mean, the risk of ADHD increases. (Read the full article)

Urologic outcomes of prenatal myelomeningocele closure have previously been reported. This study, however, represents a large, prospectively followed cohort of these patients and presents detailed findings of urologic outcomes. To our knowledge, this is the largest study of this type.

Our study is the only trial to compare urologic outcomes in children with myelomeningocele having undergone prenatal closure with those who had postnatal repair in a prospective and systematic manner. We report our findings at 12 and 30 months. (Read the full article)

Source: www.mirror.co.uk - Saturday, May 09, 2020
At least the garish crystal cheetah clutches aren't as saucy as the hamper sent to Kim Kardashian from cheeky Khloé as the family shower each other with odd gifts

Canon is lifting the lid on the tech inside its upcoming EOS-1D X Mark III SLR. It's a fully pro, and fully loaded camera, with 20fps Raw imaging and 5.5K Raw video capture.

United States President Donald Trump told CBS’s 60 Minutes that he would added pressure on Saudi Arabia, vowing "severe punishment" should the kingdom’s leaders be linked to the disappearance of Washington Post columnist Jamal Khashoggi.

An op-ed in Saudi-owned Al Arabiya news has warned of repercussions should the US impose sanctions on Saudi Arabia over the disappearance of journalist Jamal Khashoggi.

Dans de nombreux pays, le pétrole suscite des débats controversés sur son rôle de moteur de changements économiques, sociaux et géopolitiques. Depuis quelques années, les réflexions sur la question du pétrole ont démontré une corrélation négative entre son exploitation, le développement socioéconomique, la gouvernance et le regain des conflits dans les pays producteurs.

Objectives. The aim of this study was to assess the safety of early oral switch (EOS) prior to 14 days for low-risk Staphylococcus aureus bacteremia (LR-SAB), which is the primary treatment strategy employed at our institution. Usually recommended therapy is 14 days of intravenous (IV) antibiotics.

Methods. All patients with SAB at our hospital were identified between 1 January 2014 and 31 December 2018. Those meeting low-risk criteria (healthcare-associated, no evidence of deep infection or demonstrated involvement of prosthetic material, and no further positive blood cultures after 72-hours) were included in the study. The primary outcome was occurrence of a SAB-related complication within 90 days.

Results. There were 469 SAB episodes during the study period, 100 (21%) of whom met inclusion criteria. EOS was performed in 84 patients. In this group, line infection was the source in 79%, methicillin-susceptible S. aureus caused 95% of SABs and 74% of patients received IV flucloxacillin. The median duration of IV and oral antibiotics in the EOS group was 5 (IQR 4-6) and 10 days (IQR 9-14), respectively. Seventy-one percent of patients received flucloxacillin as their EOS agent. Overall, 86% of oral step-down therapy was with beta-lactams. One patient (1%) undergoing EOS had SAB relapse within 90 days. No deaths attributable to SAB occurred within 90 days.

Conclusions. In this low MRSA prevalence LR-SAB cohort, EOS was associated with a low incidence of SAB-related complications. This was achieved with oral beta-lactam therapy in most patients. Larger prospective studies are needed to confirm these findings.

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.

β-lactam resistance in Staphylococcus aureus limits treatment options. Stp1 and Stk1, a serine-threonine phosphatase and kinase respectively, mediate serine-threonine kinase (STK) signaling. Loss of function point mutations in stp1 were detected among laboratory passaged, β-lactam resistant S. aureus strains lacking mecA and blaZ, the major determinants of β-lactam resistance in the bacteria. Loss of Stp1 function facilitates β-lactam resistance of the bacteria.

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.

Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1->3)-β-D-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with anti-mould triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in an additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well established persistently neutropenic NZW rabbit model of experimental IPA. Treatment groups included untreated rabbits (UC) and rabbits receiving ibrexafungerp at 2.5(SCY2.5) and 7.5(SCY7.5) mg/kg/day, isavuconazole at 40(ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced in vitro synergistic interaction. There was significant in vivo reduction of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40-treatment groups vs that of SCY2.5-treated, SCY7.5-treated and UC (p<0.01). Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of SCY2.5-, SCY7.5-, ISA40-treated or UC (p<0.05). Serum GMI and (1->3)-β-D-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those treated with SCY7.5 or ISA40 (p<0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, lower GMI and (1->3)-β-D-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an anti-mould triazole for treatment of IPA.

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.

Highly conserved PenI-type class A β-lactamase in pathogenic members of Burkholderia can evolve to extended-spectrum β-lactamase (ESBL), which exhibits hydrolytic activity towards third-generation cephalosporins, while losing its activity towards the original penicillin substrates. We describe three single-amino-acid-substitution mutations in the ArgS arginine-tRNA synthetase that confer extra antibiotic tolerance protection to ESBL-producing Burkholderia thailandensis. This pathway can be exploited to evade antibiotic tolerance induction in developing therapeutic measures against Burkholderia species, targeting their essential aminoacyl-tRNA synthetases.

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.

The Cpx stress response is widespread among Enterobacteriaceae. We have previously reported a mutation in cpxA in a multidrug resistant strain of Klebsiella aerogenes isolated from a patient treated with imipenem. This mutation yields to a single amino acid substitution (Y144N) located in the periplasmic sensor domain of CpxA. In this work, we sought to characterize this mutation in Escherichia coli by using genetic and biochemical approaches. Here, we show that cpxA^Y144N is an activated allele that confers resistance to β-lactams and aminoglycosides in a CpxR-dependent manner, by regulating the expression of the OmpF porin and the AcrD efflux pump, respectively. We also demonstrate the intimate interconnection between Cpx system and peptidoglycan integrity on the expression of an exogenous AmpC β-lactamase by using imipenem as a cell wall active antibiotic or inactivation of penicillin-binding proteins. Moreover, our data indicate that the Y144N substitution abrogates the interaction between CpxA and CpxP and increase phosphotransfer activity on CpxR. Because the addition of a strong AmpC inducer such as imipenem is known to causes abnormal accumulation of muropeptides (disaccharide-pentapeptide, N-acetylglucosamyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamy-meso-diaminopimelic-acid-d-alanyl-d-alanine) in the periplasmic space, we propose these molecules activate the Cpx system by displacing CpxP from the sensor domain of CpxA. Altogether, these data could explain why large perturbations to peptidoglycan caused by imipenem lead to mutational activation of the Cpx system and bacterial adaptation through multidrug resistance. These results also validate the Cpx system, in particular the interaction between CpxA and CpxP, as a promising therapeutic target.

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.

Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae are classified as critical priority pathogens, with extended-spectrum β-lactamases (ESBLs) as principal resistance determinants. Enmetazobactam (formerly AAI101) is a novel ESBL inhibitor developed in combination with cefepime for empiric treatment of serious Gram-negative infections in settings where ESBLs are prevalent. Cefepime-enmetazobactam has been investigated in a phase 3 trial in patients with complicated urinary tract infections or acute pyelonephritis. This study examined pharmacokinetic-pharmacodynamic (PK-PD) relationships of enmetazobactam, in combination with cefepime, for ESBL-producing isolates of Klebsiella pneumoniae in 26-hour murine neutropenic thigh infection models. Enmetazobactam dose fractionation identified time above a free threshold concentration (fT > C_T) as the PK-PD index predictive of efficacy. Nine ESBL-producing isolates of K. pneumoniae, resistant to cefepime and piperacillin-tazobactam, were included in enmetazobactam dose-ranging studies. The isolates encoded CTX-M-type, SHV-12, DHA-1 and OXA-48 β-lactamases and covered a cefepime-enmetazobactam MIC range from 0.06 to 2 μg/ml. Enmetazobactam restored the efficacy of cefepime against all isolates tested. Sigmoid curve fitting across the combined set of isolates identified enmetazobactam PK-PD targets for stasis and for a 1-log₁₀ bioburden reduction of 8% and 44% fT > 2 μg/ml, respectively, with a concomitant cefepime PK-PD target of 40 – 60% fT > cefepime-enmetazobactam MIC. These findings support clinical dose selection and breakpoint setting for cefepime-enmetazobactam.

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.

Chromosomal and plasmid-borne AmpC cephalosporinases are a major resistance mechanism to β-lactams in Enterobacteriaceae and Pseudomonas aeruginosa. The new β-lactamase inhibitor avibactam effectively inhibits class C enzymes and can fully restore ceftazidime susceptibility. The conserved amino acid residue Asn³⁴⁶ of AmpC cephalosporinases directly interacts with the avibactam sulfonate. Disruption of this interaction caused by the N³⁴⁶Y amino acid substitution in Citrobacter freundii AmpC was previously shown to confer resistance to the ceftazidime-avibactam combination (CAZ-AVI). The aim of this study was to phenotypically and biochemically characterize the consequences of the N³⁴⁶Y substitution in various AmpC backgrounds. Introduction of N³⁴⁶Y into Enterobacter cloacae AmpC (AmpC_cloacae), plasmid-mediated DHA-1, and P. aeruginosa PDC-5, led to 270-, 12,000-, and 79-fold decreases in the inhibitory efficacy (k₂/K_i) of avibactam, respectively. The kinetic parameters of AmpC_cloacaeand DHA-1 for ceftazidime hydrolysis were moderately affected by the substitution. Accordingly, AmpC_cloacaeand DHA-1 harboring N³⁴⁶Y conferred CAZ-AVI resistance (MIC of ceftazidime of 16 µg/ml in the presence of 4 µg/ml of avibactam). In contrast, production of PDC-5 N³⁴⁶Y was associated with a lower MIC (4 µg/ml) since this β-lactamase retained a higher inactivation efficacy by avibactam in comparison to AmpC_cloacaeN³⁴⁶Y. For FOX-3, the I³⁴⁶Y substitution did not reduce the inactivation efficacy of avibactam and the substitution was highly deleterious for β-lactam hydrolysis, including ceftazidime, preventing CAZ-AVI resistance. Since AmpC_cloacaeand DHA-1 display substantial sequence diversity, our results suggest that loss of hydrogen interaction between Asn³⁴⁶ and avibactam could be a common mechanism of acquisition of CAZ-AVI resistance.

Durlobactam (DUR, also known as ETX2514) is a novel β-lactamase inhibitor with broad activity against Ambler class A, C, and D β-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii. The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem/cilastatin (IMI/CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In Part A, subjects including an elderly cohort (DUR 1 g) received single ascending doses of DUR 0.25-8 g. In Part B, multiple ascending dose of DUR 0.25-2 g were administered every 6 hours (q6h) for 29 doses. In Parts C and D, the drug-drug interaction (DDI) potential, including safety, of DUR (1 g) with SUL (1 g) and/or IMI/CIL (0.5/0.5 g) was investigated after single and multiple doses. Plasma and urine concentrations of DUR, SUL, and IMI/CIL were determined. Among 124 subjects, DUR was generally safe and well tolerated either alone or in combination with SUL and/or IMI/CIL. After single and multiple doses, DUR demonstrated linear dose proportional exposure across the studied dose ranges. Renal excretion was a predominant clearance mechanism. No drug:drug interaction potential was identified between DUR and SUL and/or IMI/CIL. SUL-DUR, 1 g (of each component) administered q6h with a 3 hour IV infusion, is under development for the treatment of serious infections due to A. baumannii.

The SHV β-lactamases (BLs) have undergone strong allele diversification that changed their substrate specificities. Based on 147 NCBI entries for SHV alleles, in silico mathematical models predicted five positions as relevant for the β-lactamase inhibitor (BLI) resistant (2br) phenotype, 12 as relevant for the extended-spectrum BL (ESBL) (2be) phenotype, and two positions were related to solely the narrow spectrum (2b) phenotype. These positions and additional 6 positions described in other studies (including one promoter mutation), were systematically substituted and investigated for their substrate specificities in a BL-free E. coli background, representing, to our knowledge, the most comprehensive substrate and substitution analysis for SHV alleles to date. An in vitro analysis confirmed the essentiality of the positions 238 and 179 for the 2be phenotype and 69 for the 2br phenotype. The substitutions E240K and E240R, which do not occur alone in known 2br SHV variants, led to a 2br phenotype, indicating a latent BLI-resistance potential of these substitutions. The substitutions M129V, A234G, S271I and R292Q conferred latent resistance to cefotaxime. In addition, 7 positions that were found to be not always associated with the ESBL phenotype resulted in increased resistance to ceftaroline. We also observed that coupling of a strong promoter (IS26) to a A146V mutant with the 2b phenotype resulted in a highly increased resistance to BLIs, cefepime and ceftaroline but not to 3^rd generation cephalosporins, indicating that SHV enzymes represent an underestimated risk for empirical therapies that use piperacillin/tazobactam or cefepime to treat different infectious diseases caused by gram-negatives.

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.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, β-lactam antibiotics have emerged as a potential option for combination therapy with VAN/DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available β-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with β-lactams have been the subject of many recent investigations due to in vitro findings such as the "see-saw effect", where β-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy.

Background: MRSA pose significant therapeutic challenges, related to their: frequency in clinical infections; innate virulence properties; and propensity for multi-antibiotic resistance. MRSA are among the most common causes of endovascular infections, including infective endocarditis (IE).

Objective: To employ transthoracic echocardiography (TTE) to evaluate the effect of exebacase, a novel direct lytic agent, in experimental aortic valve MRSA IE.

Study Design: TTE was utilized to evaluate the in vivo effect of exebacase on MRSA-infected vegetation progression when combined with daptomycin (vs daptomycin alone). Primary intravegetation outcomes were: maximum size; weights at sacrifice; and MRSA counts at infection baseline vs after 4 days of daptomycin treatment (alone or in addition to exebacase administered once on treatment Day 1).

Results: A single dose of exebacase in addition to daptomycin cleared significantly more intravegetation MRSA than daptomycin alone. This was associated with a statistical trend toward reduced maximum vegetation size in the exebacase + daptomycin vs the daptomycin-alone therapy groups (p = 0.07). Also, mean vegetation weights in the exebacase-treated group were significantly lower vs daptomycin-alone (p < 0.0001). Maximum vegetation size by TTE correlated with vegetation weight (p = 0.005). In addition, intravegetation MRSA counts in the combination group were significantly lower vs untreated controls (p<0.0001) and the daptomycin-alone group (p<0.0001).

Conclusion: This study suggests that exebacase has a salutary impact on MRSA-infected vegetation progression when combined with daptomycin, especially in terms of vegetation MRSA burden, size and weight. Moreover, TTE appears to be an efficient non-invasive tool to assess therapeutic efficacies in experimental MRSA IE.

Methicillin-resistant Staphylococcus aureus (MRSA) has grown to become a major burden on healthcare systems. The cumulation of limited therapeutic options and worsened patient outcomes with persistent MRSA bacteremia has driven research in optimizing its initial management. The guidelines published by the Infectious Disease of America currently recommend combination therapy for refractory MRSA bacteremia, but the utility of combining antibiotics from the start of therapy is under investigation. The alternative strategy of early use of a β-lactam antibiotics in combination with vancomycin upon initial MRSA bacteremia detection has shown promise. While this concept has gained international attention, providers should give this strategy serious consideration prior to implementation. The objective of this review is to examine retrospective and prospective evidence for early combination with vancomycin and β-lactam antibiotics, as well as explore potential consequences of combination therapy.

BACKGROUND:

The association of dietary fat distribution with markers of subclinical atherosclerosis during early life is unknown. We examined whether success in achieving the main target of an infancy-onset dietary intervention based on the distribution of dietary fat was associated with aortic and carotid intima-media thickness (IMT) and distensibility from childhood to young adulthood.

Payments Association of South Africa has warned consumers to be cautious when sharing personal information which can be used by fraudsters to make unauthorised debit orders.

CONTEXT:

Several antiemetics have been used in children with acute gastroenteritis. However, there is still controversy over their use.

If you love Metal Gear Solid, have some money to burn, and live in Japan, Sony has something special for you.

Graham A. Colditz
Jul 1, 1995; 96:29-35
ARTICLES

Retail stores, corporate offices, and contact centers in China are closed through February 9 as the coronavirus spreads globally. Apple's online store will remain open, though.

The Culture, Tourism, Europe and External Affairs Committee will on Thursday (5 March) question the Secretary of State for Scotland regarding the Withdrawal Agreement and the future relationship between the European Union and the UK.

Casemiro and Isco scored for Real Madrid as the European champions beat Manchester United 2-1 in Skopje to win the UEFA Super Cup for the third time in the last four years.

In India and China, indigenous drug manufacturers market arbitrarily combined parenteral β-lactam and β-lactamase inhibitors (BL-BLIs). In these fixed-dose combinations, sulbactam or tazobactam is indiscriminately combined with parenteral cephalosporins, with BLI doses kept in ratios similar to those for the approved BL-BLIs. Such combinations have been introduced into clinical practice without mandatory drug development studies involving pharmacokinetic/pharmacodynamic, safety, and efficacy assessments being undertaken. Such unorthodox combinations compromise clinical outcomes and also potentially contribute to resistance development.

The Netherlands beat Italy for the second final running to become the first four-time Under-17 EURO champions.

Successful intervention for inborn errors of metabolism (IEMs) is a triumph of modern medicine. For many of these conditions, medical foods are the cornerstone of therapy and the only effective interventions preventing disability or death. Medical foods are designed for patients with limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foods or nutrients, whereby dietary management cannot be achieved by modification of the normal diet alone. In the United States today, access to medical foods is not ensured for many individuals who are affected despite their proven efficacy in the treatment of IEMs, their universal use as the mainstay of IEM management, the endorsement of their use by professional medical organizations, and the obvious desire of families for effective care. Medical foods are not sufficiently covered by many health insurance plans in the United States and, without insurance coverage, many families cannot afford their high cost. In this review, we outline the history of medical foods, define their medical necessity, discuss the barriers to access and reimbursement resulting from the regulatory status of medical foods, and summarize previous efforts to improve access. The Advisory Committee on Heritable Disorders in Newborns and Children asserts that it is time to provide stable and affordable access to the effective management required for optimal outcomes through the life span of patients affected with IEMs. Medical foods as defined by the US Food and Drug Administration should be covered as required medical benefits for persons of all ages diagnosed with an IEM.

All the results and highights from Switzerland as Spain won the Women's U19 title for the second year in a row.

Washington D.C., Mar 22, 2020 / 04:00 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.

Seta Kale, a Syrian with a Syriac and Armenian descent, was born and raised in Qamishli and fled to Sweden at the age of 16. Today, as a 23-year-old, she’s studying business and economics at Jönköping International Business School, while working part-time as a cashier at a supermarket called Coop, and as a saleswoman at Rituals Cosmetics. Kale likes to sing to cope with her stress, and she likes to read poetry.

In partnership with the Philos Project, CNA sat down with Seta Kale:

When and how did you flee to Sweden?

I moved to Sweden seven years ago in December 2012, a couple of days before Christmas. We flew from Syria to Armenia, and from there we came to Sweden as tourists. We are some of the lucky ones as there were not many who could flee safely. But it was not as easy as it sounds. My family and I had to split up and travel on different dates in order to avoid the suspicion that we were refugees. We had no idea how we were going to be treated upon our arrival in Sweden, and therefore did not want to take any risks by travelling together.

We have seven people in our family. My mom, two of my brothers and I went first. After six months my older sister and third brother came, and a year later my dad arrived. My dad had to take the most difficult route, one that was filled with risks. He couldn’t get a tourist visa, so he had to travel between countries (Turkey, Italy, Greece and France) to be able to come to Sweden. At one point, he had to cross the sea in a small boat together with 30 other people and walk through a forest for several days. Some days he was unreachable, and I’ve never felt that kind of fear ever before. It was a kind that I will never forget.

When did you start feeling the war?

As I mentioned before, I lived in Qamishli. It is a city in northeast Syria, and it was one of the cities that was least affected by war in the beginning unlike, for example, Aleppo and Raqqa. There still were bombs and shootings. The violence started when our bread factory was bombed. It then escalated to hospitals, schools and many public places. Everything became more expensive and there was no access to electricity and clean water 24/7. People were afraid to go to work and children were afraid to go to school. Qamishli felt like a haunted city.

It was when my school was bombed only minutes after my sister and I had left that my dad decided that we had to flee Syria. I will never forget the memory of that day. The ground was shaking under our feet as my mom and aunt ran towards us. After that, people became desperate to flee the war. Houses and apartments were quickly emptied. The feelings and stories that Syria has carried together with her people since 2011 is indescribable.

Tell me about your hometown in Syria.

In Qamishli, Syriacs, Armenians, Assyrians, Arabs, Kurds, Christians, Muslims all lived together. There were as many churches as there were mosques. People worked alongside one another. They were humble, loving, loyal and respectful towards each other. We felt secure because we knew that if we ever were in danger, the whole city would come and help. Religion and ethnicity did not matter to us, and this was the case in the whole country, not only in my hometown. We never thought “he’s Muslim” or “she’s Christian.”

The social life never stopped in Qamishli. There were things to do 24/7 with friends and family. Christians and Muslims celebrated Christmas, Eid al-fitr, Easter and Eid al-adha together.

When I came to Sweden, everyone thought I lived in a tent in the desert. But the more they got to know me, they were surprised by my knowledge and all the languages I could speak. Unfortunately, people tend to believe things about Syria that are not true. We had access to development, education, jobs and more. People say that nothing is perfect, but Syria was perfect in my eyes. We were very rich, but not in a materialistic way. We were rich in culture, religion, knowledge, history, tradition, peoples and so much more. Everything had a reason and I am the way I am today mostly because of what and who Syria is.

What are your best and worst memories from Qamishli?

Wow, I don’t know where to begin. I have so many good memories imprinted in my heart. I cannot choose one because there are so many; from silly things in school with friends, to mini trips with the family throughout Syria, to celebrations of Christmas and Easter.

The worst memory I have was a time when I was on my way from Qamishli to Aleppo while we were fleeing the war. It was a 9-hour drive by bus. Before, it used to be a beautiful ride with beautiful buildings, houses, people and restaurants on the road. But that day I saw a completely different scene. It was filled with sorrow, and the beautiful buildings were reduced to stones on the ground. There were no houses, no restaurants and no people. During the trip to Aleppo the bus had to stop more than five times at checkpoints. Some checkpoints belonged to the Syrian military and some were controlled by ISIS. Once, my sister and I had to hide under the seats so the ISIS soldiers wouldn’t take us. Another horrible memory is simply when I realized that this is it, I will never go back to my country. I cried the entire flight.

Have you lost any friends or family members during the war?

I was one of the lucky ones who didn’t lose any friends or family members. But in Qamishli, everyone knows everyone, and we heard a lot of incredibly sad stories about people who disappeared during bombings and shootings. I had family members and friends, both boys and girls, who were drafted to the military. It was during the worst time in the war and the military needed as many people as possible. When these people would return, they were very different. What they witnessed during their time in the military changed them. In that way, I’ve lost loved ones.

If you could go back, would you stay in Sweden or move back to Syria?

I would definitely go back. Besides the fact that I miss it, I want to help rebuild what the war has destroyed. I want to see my country back on its feet and stronger than ever. I want to start a family there and I want my children to grow up in the country that I grew up in.

If you could send a message to Christians in the West, what would you want them to know about Syria?

I want people not to only think of war when they hear “Syria,” because it’s so much more. I want them to know that the Syrian people are struggling and fighting for the country to remain. But most of all, I want them to continue to pray every day for the people there and know that any contribution is an enormous help for the Syrians.

 

 

By Sr. Joan L. Roccasalvo, C.S.J.

It’s a wonderful phenomenon—yeast.  It permeates lifeless flour and causes it to rise and expand.  The power of yeast effects the brewing of beer and the making of wine.   The yeast plant is a fungus that grows without limits to its borders.  Only if yeast is alive and active will it interact with the dough.

On her TV program, “Martha Bakes,” the talented Ms. Stewart cannot contain her delight when she makes yeast dough: “Look at the sheen—so soft and shiny! The aroma is “bee-you-tee-ful,” and the fragrance gratifies all the senses!” Follow these instructions: proof active yeast, blend it into the flour mixture, and let it rise to double the size.  From yeast dough come baked goods such as breads, sticky buns and sugar buns, and monkey bread.  “Soo pretty, soo delicious,” Ms. Stewart swoons over her culinary works of art.

Yeast as a Metaphor

In the Matthean parable (13:33), the reign of God is like yeast that a woman took and kneaded into three measures of flour.  Eventually the entire mass of dough began to rise.  The image of yeast was a favorite in the Early Church.  Everyone understood the inner power of yeast with its limitless ability to make things grow, even in small beginnings with “three measures of flour.”  They grasped the comparison.  The yeast referred to the Church as an unlimited and growing reality, “destined ultimately to be present everywhere and to affect everything, though by no means to convert everything into itself” (Walter J. Ong, “Yeast: A Parable for Catholic Higher Education,” America Magazine, April 7, 1990).  The Church is catholic because it has always been expanding into new and shiny ‘dough’ without limit. Katholicos, from kata or kath and holos, means “through-the-whole or “throughout-the-whole.”

The Laity: Worldly and Yet Unworldly    

The laity are catholic, yeast in business and finance, entertainment, nursing and medicine, arts and science, law and law enforcement, politics, and sports.  They are the inner power with its limitless ability to make things grow, even in small ways. The laity find their holiness in the world with its financial concerns and family responsibilities.  Those who marry and have children become not just a family but also the Domestic Church.

In 1987, the Catholic Church held a World Synod on the Laity, one of many, beginning with Vatican II in the 1960s.  According to the synod’s final document, the laity are equal with clergy and consecrated religious in the life and mission of the Church.  

The call to holiness of the laity differs from the vocation of consecrated religious.  The laity are to be in the world in an unworldly way.  They approach life with wisdom that teaches the limited and relative value of material things. This would seem to be a contradiction in terms.  How to be worldly and unworldly at the same time?   It cannot be easy, for at times, the challenges seem insurmountable.  Yet, it remains for the lay vocation to find a theology of being present in the world. It is a practical spirituality of the family and the workplace.  For the laity, this is where holiness resides.*  

Holiness of the Laity

The holiness of the laity began with Jesus himself.  He was a rabbi and teacher, as were his disciples. Peter was a married man, and for all we know, so were the other apostles, the exception being John, the Beloved Disciple.  

St. Paul addresses and refers to those he evangelized as ‘saints,’ meaning that they were on their way to becoming saints.  In the Early Church, there were no consecrated institutes of men and women.  All Christians grasped the importance of living as disciples and ambassadors of the Lord.

As increasing numbers of Christians came to view the world as wicked, they flocked to the desert to live alone. When the desert grew so overcrowded with these solitaries, they came together and formed religious communities.  Thus, the start of monastic orders of men and women.

Prayer

Consecrated men and women, and especially those who live in cloisters, spend several hours a day in prayer.

This is not the way of the laity. Their days focus almost entirely on family and the means of supporting it.  Their prayer is measured not in hours but in minutes—two here, five there, perhaps a Holy Hour or Retreat Day on rare occasions.

The conciliar document on the sacred liturgy encourages Catholic families to pray portions of the Liturgy of the Hours (#102-111).  The Hours are not private or devotional prayer but the prayer of the entire Church, the Church at prayer.  Praying the psalms nourishes Catholic family life whose welfare is daily beset with conflicting external forces. If prayer is the underlying power of strong family life, then parents can find ways to incorporate parts of the Hours into their daily schedule. In prayer, married couples derive the strength of God’s grace to live their married vocation.  

As children mature, they too must learn to travel the road to discipleship in the Lord.  Small children can be taught to pray a psalm or two at bed time. If this is not feasible during the week, then prayer on weekend is an alternate possibility.  

A minimal and external Christianity will not fortify today’s Domestic Church but only a vibrant Christianity in which Christ is a living reality.  It takes a few minutes to pray short sections of the Hours, even on public transit.  It is a consoling thought to recall that “in him, we live and move and have our being” (Acts 17:28).  

At Pre-Cana instructions, couples can learn the practice of making the Hours an integral part of their married life.

Can Yeast Corrupt?

The image of yeast is not always positive.  In First Corinthians 5:6-8, St. Paul mentions what all Jews understood.  At the Paschal festival time, they were to destroy all yeasted products because leaven was a metaphor for the corruptive influence of evil, for puffing up the self, leaving no room for God.   

Proofing the yeast in warm water will yield bubbles around the surface, and the yeast will become puffed up if it does not interact with the flour dough.  The puffed up yeast will die.  In this sense, neither the laity, nor any minister in the Church, can afford to be puffed up with pride.

Élisabeth Leseur (1866-1914) and Félix Leseur (1861-1950)

The story of Élisabeth Arrighi Leseur exemplifies the limitless power of marital love.  Élisabeth was born into a wealthy French Catholic family of Corsican descent.  As a child, she had contracted hepatitis, a disease from which she suffered all her life.  At twenty-one, she met Félix Leseur, a medical doctor, who also came from an affluent Catholic family.  Shortly before they were to be married, Élisabeth discovered that Félix was no longer a practicing Catholic.  Soon he became well known as the editor of an anti-clerical, atheistic newspaper.  

Despite the circumstances, the couple married, for Élisabeth was deeply in love with Félix.  They were unable to have children, a fact that made their marriage all the more difficult.  His attack on her religious devotion prompted an even more serious fidelity to the faith. She bore the brunt of his hatred of the Church with patient love.  At thirty-two years of age, Élisabeth experienced the grace to a deeper form of prayer.  She was convinced that her task now was to love her husband and pray for his conversion while remaining steadfast during his taunts against religion, and the Church in particular.

Homebound and Bed-Ridden

Élisabeth’s deteriorating health forced her to lead a sedentary life.  She received visitors and was able to conduct a vibrant apostolate from the confines of her home.  She became a devotee of St. Francis de Sales who wrote for the layperson in the seventeenth century. His Introduction to the Devout Life, perhaps the most famous spiritual guide of all time, is an offshoot of the Ignatian Exercises. During this period, Élisabeth kept a secret spiritual diary.  

When, at the age of forty-five, Élisabeth underwent surgery and radiation for the removal of a malignant tumor, she recovered and continued to receive visitors to her home. Three years later, she succumbed to cancer.  Her life has been recommended for sainthood. Why?  We turn the page to continue the narrative of her husband.

Dr. Félix Leseur

After Élisabeth’s death, Félix found a note addressed to him.  Not only did it predict his conversion, but he would also become a Dominican priest.  His hatred of the Church prompted him to expose her note as a fake, and he decided to do so at Lourdes, the famous Marian shrine in France.  There, something prevented him from carrying out his intended project—call it God’s intervening grace. As Élisabeth had predicted, he experienced a conversion and published her spiritual journal.  In 1919, Félix entered the Dominican Order, was ordained a priest four years later, and spent his remaining years speaking about his wife’s difficult yet remarkable life with him.  

In 1924, the future Archibishop Fulton J. Sheen made a retreat under Fr. Leseur’s direction.  It was at this time that he learned of Élisabeth’s life and her husband’s conversion.  In 1934, Fr. Leseur, O.P. worked to begin the cause for her canonization, and the Archbishop shared the story of this remarkable married couple in many presentations.  Élisabeth is currently a Servant of God, the first step in the cause for sainthood.

Élisabeth Leseur’s suffering was not wasted. On the contrary, her lifelong devotion to Félix was central to his conversion.  She became the yeast that permeated the lifeless soul of her husband.  It forever transformed his life so that he could affect change in the lives of others. Love begets love.

*The Ignatian “Prayer for Finding God in All Things” by Joan L. Roccasalvo, C.S.J. can help the busy person find God throughout the day.  Copies are available from the Institute of Jesuit Sources, Boston, MA.

A Neto double, including the extra-time winner 19 seconds from time, secured back-to-back FIFA Futsal World Cup triumphs for Brazil at the expense of regular rivals Spain.

The internal Windows 10 builds that leaked last week ended up revealing a brand new edition of the OS Microsoft is planning for power users.

At 2 p.m. on Saturday, May 9, Penn State will host its first virtual commencement. The ceremony will be livestreamed, and available internationally, at https://spring2020.commencement.psu.edu/.

Graduating members of Penn State Scranton’s Lambda Pi Eta Alpha Epsilon Pi chapter received their honor cords recently during a virtual celebration. Lambda Pi Eta is the official honor society of the National Communication Association and currently, the only academic honor society at Penn State Scranton.

Ajax have their backs to the wall against a Getafe side who are in a commanding position after a 2-0 first-leg win in Spain.

Conquerors of Ajax in the round of 32, Getafe's reward is another tie against esteemed European campaigners as they take on Italian giants Internazionale.

This phase IIb randomized controlled trial demonstrates greater efficacy of phenobarbital than levetiracetam in the treatment of neonatal seizures; more adverse events occurred with phenobarbital.

Investec's Value Fund has for the first time since 2000 ditched any exposure to big four banking stocks and major retail groups.