One of the reasons for the lengthy tuberculosis (TB) treatment is the difficult to treat non-multiplying mycobacterial subpopulation. In order to assess the ability of (new) TB drugs to target this subpopulation, we need to incorporate dormancy models in our pre-clinical drug development pipeline. In most available dormancy models it takes a long time to create a dormant state and it is difficult to identify and quantify this non-multiplying condition.

The Mycobacterium tuberculosis 18b strain might overcome some of these problems, because it is dependent on streptomycin for growth and becomes non-multiplying after 10 days of streptomycin starvation, but still can be cultured on streptomycin-supplemented culture plates. We developed our 18b dormancy time-kill kinetic model to assess the difference in the activity of isoniazid, rifampicin, moxifloxacin and bedaquiline against log-phase growth compared to the non-multiplying M. tuberculosis subpopulation by CFU counting including a novel AUC-based approach as well as time-to-positivity (TTP) measurements.

We observed that isoniazid and moxifloxacin were relatively more potent against replicating bacteria, while rifampicin and high dose bedaquiline were equally effective against both subpopulations. Moreover, the TTP data suggest that including a liquid culture-based method could be of additional value as it identifies a specific mycobacterial subpopulation that is non-culturable on solid media.

In conclusion, the results of our study underline that the time-kill kinetics 18b dormancy model in its current form is a useful tool to assess TB drug potency and thus has its place in the TB drug development pipeline.

A case of M. leprae rifampicin resistance after irregular anti-leprosy treatments since 1971 is reported. Whole-genome sequencing from four longitudinal samples indicated relapse due to acquired rifampicin resistance and not to reinfection with another strain. A putative compensatory mutation in rpoC was also detected. Clinical improvement was achieved using an alternative therapy.

Many transferable quinolone-resistance mechanisms have been already identified in Gram-negative bacteria. The plasmid-encoded 65 amino-acid long ciprofloxacin-modifying enzyme, namely CrpP, was recently identified in Pseudomonas aeruginosa. We analyzed a collection of 100 clonally-unrelated and multidrug-resistant P. aeruginosa clinical isolates among which 46 (46%) were found positive for crpP-like genes, encoding five CrpP variants conferring variable levels of reduced susceptibility to fluoroquinolones. Those crpP-like genes were chromosomally located, as part of PAGI-like pathogenicity genomic islands.

Introduction: This study was performed to evaluate the impacts of vanA-positivity of Enterococcus faecium (EFM) exhibiting diverse susceptibility phenotypes to glycopeptides on clinical outcomes in patients with a bloodstream infection (BSI) through a prospective, multicenter, observational study.

Methods: A total of 509 patients with an EFM BSI from eight sentinel hospitals in South Korea during a two-year period were enrolled in this study. Risk factors of the hosts and causative EFM isolates were assessed to determine associations with the 30-day mortality of EFM BSI patients via multivariable logistic regression analyses.

Results: The vanA gene was detected in 35.2% (179/509) of EFM isolates; 131 EFM isolates exhibited typical VanA phenotypes (group vanA-VanA), while the remaining 48 EFM isolates exhibited atypical phenotypes (group vanA-Atypical), including VanD (n = 43) and vancomycin-variable phenotypes (n = 5). A multivariable logistic regression indicated that vanA-positivity of causative pathogens was independently associated with the increased 30-day mortality rate in the patients with an EFM BSI; however, there was no significant difference in the survival rates between the patients of the vanA-VanA and vanA-Atypical groups (log-rank test, P = 0.904).

Conclusions: A high 30-day mortality rate was observed in patients with vanA-positive EFM BSIs, and vanA-positivity of causative EFM was an independent risk factor for early mortality irrespective of the susceptibility phenotypes to glycopeptides; thus, intensified antimicrobial stewardship is needed to improve clinical outcome of patients with vanA-positive EFM BSI.

As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in south East Asia, there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other malaria endemic regions. Artemisinin reduced susceptibility in South East Asia (SEA) has been primarily linked to mutations in P. falciparum Kelch-13, which is currently widely recognised as a molecular marker of artemisinin resistance. However, 2 mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with artemisinin reduced susceptibility in a rodent model of malaria and some cases of UBP-1 mutation variants associating with artemisinin treatment failure have been reported in Africa and SEA. In this study, we have employed CRISPR-Cas9 genome editing and pre-emptive drug pressures to test these artemisinin susceptibility associated mutations in UBP-1 in P. berghei sensitive lines in vivo. Using these approaches, we have shown that the V2721F UBP-1 mutation results in reduced artemisinin susceptibility, while the V2752F mutation results in resistance to chloroquine and moderately impacts tolerance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines while simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. Our work has provided independent experimental evidence on the role of UBP-1 in modulating parasite responses to artemisinin and chloroquine under in vivo conditions.

Florfenicol belongs to a class of phenicol antimicrobials widely used as feed additives and for the treatment of respiratory infections. In recent years, increasing resistance to florfenicol has been reported in Campylobacter spp., the leading foodborne enteric pathogen causing diarrheal diseases worldwide. Here, we reported the identification of fexA, a novel mobile florfenicol resistance gene in Campylobacter. Of the 100 Campylobacter jejuni strains isolated from poultry in Zhejiang, China, nine of them were shown to be fexA positive, and their whole genome sequences were further determined by integration of Illumina short-read and MinION long-read sequencing. The fexA gene was found in the plasmid of one strain and chromosomes of eight strains, and its location was verified by S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and Southern blotting. Based on comparative analysis, the fexA gene was located within a region with the tet(L)-fexA-catA-tet(O) gene arrangement, demonstrated to be successfully transferrable among C. jejuni strains. Functional cloning indicated that acquisition of the single fexA gene significantly increased resistance to florfenicol, whereas its inactivation resulted in increased susceptibility to florfenicol in Campylobacter. Taken together, these results indicated that the emerging fexA resistance is horizontally transferable, which might greatly facilitate the adaptation of Campylobacter in food producing environments where florfenicols are frequently used.

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.

Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOmutS (MIC_{ciprofloxacin} 0.25 mg/L, MIC_meropenem 2 mg/L) and CW44 (MIC_{ciprofloxacin} 0.5 mg/L, MIC_meropenem 4 mg/L), were investigated for 120h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin 0.4g every 8h as 1h-infusions (80% ELF penetration), meropenem 6 g/day as continuous infusion (CI; 30% and 60% ELF penetration) and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by UHPLC-PDA. For both strains, all monotherapies failed with substantial regrowth and resistance of planktonic (≥8log₁₀ CFU/mL) and biofilm (>8log₁₀ CFU/cm²) bacteria at 120h (MIC_{ciprofloxacin} up to 8 mg/L, MIC_meropenem up to 64 mg/L). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ~48h onwards and suppressed regrowth to ≤4log₁₀ CFU/mL and ≤6log₁₀ CFU/cm² at 120h. Overall, both combination treatments suppressed amplification of resistance of planktonic bacteria for both strains, and biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed amplification of resistance of biofilm bacteria for PAOmutS. Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains.

CYP450 enzymes are involved in biotransformation of chloroquine (CQ), but the role of the different metabolism profiles of this drug has not been properly investigated in relation to P. vivax recurrences. To investigate the influence of CYPs genotypes associated with CQ-metabolism on early recurrence rates of P. vivax, a case-control study was carried out. Cases included patients presenting an early recurrence (CQ-recurrent), defined as recurrence during the first 28 days after initial infection, plasma concentrations of CQ plus desethylchloroquine (DCQ, the major CQ metabolite) higher than 100 ng/mL. A control (CQ-responsive) with no parasite recurrence over the follow-up was also included. CQ and DCQ plasma levels were measured on Day 28. CQ CYPs (CYP2C8, CYP3A4 and CYP3A5) genotypes were determined by real-time PCR. An ex vivo study was conducted to verify CQ and DCQ efficacy in P. vivax isolates. The frequency of alleles associated with normal and slow metabolism was similar between the cases and controls for CYP2C8 (OR=1.45, 95% CI=0.51-4.14, p=0.570), CYP3A4 (OR=2.38, 95% CI=0.92-6.19, p=0.105) and CYP3A5 (OR=4.17, 95% CI=0.79-22.04, p=1.038) genes. DCQ levels were higher than CQ, regardless of the genotype. Regarding the DCQ/CQ rate, there was no difference between groups or between those patients who had a normal or mutant genotype. DCQ and CQ showed similar efficacy ex vivo. CYPs genotypes had no influence on early recurrence rates. Similar efficacy of CQ and DCQ ex vivo could explain the absence of therapeutic failure, despite presence of alleles associated with slow metabolism.

The off-label use of third generation cephalosporin (3GC) during in ovo vaccination or vaccination of newly hatched chicks, was a common practice worldwide. CMY-2-producing Escherichia coli have been disseminated among broiler production. The objectives of this study were to determine the epidemiological linkage of bla_CMY-2-positive plasmids among broilers both within and outside Japan because grandparent stock and parent stock were imported in Japan. We examined the whole genome sequences of 132 3GC-resistant E. coli isolates collected from healthy broilers during 2002-2014. The predominant 3GC-resistance gene was bla_CMY-2, which was detected in the plasmids of 87 (65.9%) isolates. The main plasmid replicon types were IncI1-I (n=21; 24.1%), IncI (n=12; 13.8%), IncB/O/K/Z (n=28; 32.2%), and IncC (n=22; 25.3%). Those plasmids were subjected to gene clustering and network analyses and plasmid multi-locus sequence typing (pMLST). The chromosomal DNA of isolates was subjected to MLST and single nucleotide variant (SNV)-based phylogenetic analysis.

MLST and SNV-based phylogenetic analysis revealed high diversity of E. coli isolates. ST429 harboring bla_CMY-2-positive IncB/O/K/Z was closely related to isolates from broiler in Germany harboring bla_CMY-2-positive IncB/O/K/Z. pST55-IncI and pST12-IncI1-I and pST3-IncC were prevalent in western Japan. pST12-IncI1-I and pST3-IncC were closely related to those detected in E. coli isolates from chicken in American continent, whereas 26 IncB/O/K/Z were related to those in Europe. These data will be useful to reveal the whole picture of transmission of CMY-2-producing bacteria in and out of Japan.

Google has made it easier to join the company's Advanced Protection Program, which is designed to stop the most sophisticated hackers from breaking into your Gmail account. Before you needed two security keys to enroll. Now you just need a smartphone.

Oil headed for its first back-to-back weekly gain since February as output cuts from the biggest producers and a nascent recovery in demand began to rebalance a market awash with crude.

BACKGROUND:

The ability of the decades-old Boston and Philadelphia criteria to accurately identify infants at low risk for serious bacterial infections has not been recently reevaluated.

A first-leg comeback has put Manchester City in the driving seat as Real Madrid travel to north-west England facing a 2-1 deficit.

The Penn State Center for Structural Oncology is shifting some of its focus from fighting cancer to fighting COVID-19, with three projects.

Spain ended Germany's two-year reign as champions to claim their fourth title.

Germany pipped the Netherlands on penalties to make it seven titles in the 12 #WU17EURO seasons.

Are you sure you know what the "insurance speak" in your policy means?

Money Smart Week SA, a financial literacy campaign aimed at motivating and empowering South Africans to become more educated about their finances, is taking place from March 23 to 28, 2020.

Fin24 asked financial experts how they would grow R10 000 in the new year. Here's what they said.

Metropolitan is sponsoring a financial literacy short course hosted on FunDza, an online literacy portal dedicated to helping South Africans better their skills.

Ebonie Slade, a senior majoring in biobehavioral health at Penn State Greater Allegheny, is the recipient of the 2020 Jackson Lethbridge Tolerance Award.

France beat Croatia to earn a final tournament debut, as they joined Serbia, Romania and Poland in qualifying for UEFA Futsal EURO 2018 via the play-offs.

Portugal are UEFA Futsal EURO winners for the first time while Ricardinho dominated the individual honours in a record-breaking personal tournament: the full story.

Having student board members with voting clout on school boards poses a number of logistical challenges, readers say in response to a recent Education Week feature.

Alongside a new protected area of storage, OneDrive and Office 365 storage options are changing for the better.

The world's largest education research group said it will work to convert much of the annual meeting into a virtual experience for attendees and presenters.

David Gozal
Sep 1, 1998; 102:616-620
ARTICLES

John Penders
Aug 1, 2006; 118:511-521
ARTICLES

Spain beat holders Portugal to claim their eighth U19 title, five more than anyone else.

"While policy-system enthusiasm for the idea is building, the research-and-evaluation jury is still out on educator performance pay," say James W. Guthrie and Patrick J. Schuermann.

“How about defining student and teacher performance based on what parents and citizens actually want for their children—all of the goals, not just one,” suggests Donald B. Gratz.

A survey by the American Association of School Administrators finds fewer than half interested in such compensation plans.

Iowa appears to be poised to consider a pay-for-performance compensation plan for teachers, following the lead of a handful of districts and schools that have embraced the controversial policy.

Teacher performance pay may soon be coming to the Cornhusker State.

Catherine Awsumb Nelson and Richard Wertheimer offer Pittsburgh’s City High as a case study of basing pay decisions on the quality of classroom teaching, rather than standardized-test scores.

Amid bad feelings between the union and district administrators, Cincinnati teachers overwhelmingly rejected a groundbreaking plan that would have based their pay on performance.

The end of the year is a propitious time to take a closer look at the proposal that teachers should be paid like workers in business because it's when bonuses are handed out. In this regard, no group is more fitting to examine than executives, whose pay is ostensibly based on company performance. Bu

Corporate reformers speak with forked tongue about performance pay for teachers.

The Penn State Board of Trustees Committee on Finance, Business and Capital Planning today (May 7) advanced a plan to adjust tuition schedules for the summer 2020 semester due to the ongoing financial challenges many students and families are experiencing as a result of COVID-19 disruptions. The measure will go to the full board for a final vote on Friday, May 8.

CNA Staff, Mar 31, 2020 / 06:01 pm (CNA).- Local media in Nicaragua are reporting that despite the nation’s bishops’ conference suspending Mass and prohibiting large gatherings, the mayor of Granada is going ahead with an annual pilgrimage that the bishops had canceled.

For more than 150 years, Catholics in Nicaragua have venerated an image of Jesus del Rescate (Jesus of the Rescue) in Popoyuapa, near the city of Rivas. The image represents the crowning of thorns and the flogging of Christ.

Normally there is an annual pilgrimage to the image, which pilgrims make by wagon and on foot, during the "Week of Sorrows" that marks "the final stretch" of the time of Lent, according to ACI Prensa, CNA’s Spanish language news partner.

However, the bishops have said that this year it will not be possible to carry it out in the traditional way, given the coronavirus (COVID-19) pandemic.

Nevertheless, Julia Mena, mayor of Granada, has organized and funded a group of pilgrims to do the pilgrimage, providing them with food and personal hygiene supplies, according to the Nicaraguan news website Confidencial. The priest at the shrine told Confidencial that he has “no plans to receive the pilgrimage.”

The Nicaraguan Episcopal Conference has not commented publicly on the matter.

Nicaragua has five confirmed cases of COVID-19. The government has not yet decreed any kind of alert or emergency regarding the pandemic, nor has it ordered a suspension of classes, Confidencial reports.

The country’s Ministry of Health has maintained that the internal movements of travelers arriving from countries with outbreaks of coronavirus would not be restricted, La Prensa reports.

President Daniel Ortega has been president of Nicaragua since 2007, and oversaw the abolition of presidential term limits in 2014.

The Church had suggested that elections, which are not scheduled until 2021, be held this year, but Ortega has ruled this out.

Ortega was a leader in the Sandinista National Liberation Front, which had ousted the Somoza dictatorship in 1979 and fought US-backed right-wing counterrevolutionaries during the 1980s. Ortega was also leader of Nicaragua from 1979 to 1990.

Denver Newsroom, Apr 28, 2020 / 05:17 pm (CNA).- Archbishop Michael Miller of Vancouver has announced that he is donating to the University of British Columbia’s research toward a COVID-19 vaccine.

“May the search for COVID-19 solutions also be a moment of solidarity, of collaboration, and of growing together as a visible sign to the world of the healing and reconciliation so needed right now,” Archbishop Miller said April 27 as reported by the B.C. Catholic.

Ryan Thomas, a special advisor to the archdiocese, told CNA that Archbishop Miller wanted to express, through his donation, the Catholic Church’s support for science and medicine that contribute to the common good.

“The Church— as Pope Francis has said from the beginning of his pontificate— is called to go out, we're called to engage, not called to retreat,” Thomas told CNA.

“From a scientific standpoint, that means identifying the research that is worthy of our investment, that meets the high standards that we have to protect life,” he said.

Thomas declined to specify the amount of the donation, but said that it was in the thousands of dollars.

The global effort to develop a COVID-19 vaccine includes at least 50 other research teams, the university says, many of which in the U.S. and Canada have received government funding and are being conducted by large pharmaceutical companies.

Pro-life leaders have warned in recent months that among the many COVID-19 vaccines currently in development worldwide, in some cases researchers are using old cell lines derived from the cells of aborted babies.

It was important to Archbishop Miller, Thomas said, that the Church be seen to be promoting research into a vaccine that Catholics can support in good conscience.

A group of Evangelical Christians and Catholics in Vancouver began to rally around the idea of supporting a vaccine that corresponded to Christian ethical standards, and eventually presented the idea of supporting UBC’s research to Archbishop Miller.

Thomas said Miller made sure to inquire about whether UBC’s vaccine research makes use of aborted fetal cells, which it does not.

Dr. Wilf Jefferies, the project’s lead researcher, told CNA via email that his research team is currently in the process of validating the potency of vaccine candidates in preclinical trials, in order to assess their potential toxicity before trying them in human subjects.

The UBC lab is using immune-boosting components called adjuvants in its vaccine candidate, with the hopes of reducing the dosage of vaccine required for complete protection against the disease. In addition, Jefferies hopes that UBC’s vaccine will continue to provide protection against COVID-19 even if the virus mutates over time.

“I am heartened by the unity and kindness that is being demonstrated during this pandemic,” Jefferies told CNA.

“I think the response by the archdiocese is an affirmative and practical way to address the critical need in our society to develop a vaccine...I am sincerely humbled by the support we have received from the archdiocese and from other groups and individuals.”

So far, Jefferies’ lab has received grants from the government-funded Michael Smith Health Research Foundation and the Sullivan Urology Foundation affiliated with the University of British Columbia, as well as a number of private donations.

There are at least 1,000 clinical trials currently taking place around the world to test potential COVID-19 vaccines.

A group of pro-life leaders in a letter to the Trump administration earlier this month reiterated that development of a COVID-19 vaccine should avoid unethical links to abortion.

“No American should be forced to choose between being vaccinated against this potentially deadly virus and violating his or her conscience,” reads the April 17 letter to Dr. Stephen M. Hahn, commissioner of the U.S. Food and Drug Administration.

“Fortunately, there is no need to use ethically problematic cell lines to produce a COVID vaccine, or any vaccine, as other cell lines or processes that do not involve cells from abortions are available and are regularly being used to produce other vaccines,” it continued.

The letter’s signers include Archbishop Joseph Naumann of Kansas City in Kansas, chair of the U.S. Conference of Catholic Bishops’ Committee on Pro-Life Activities; the heads of three other bishops’ conference committees; and leaders of many other Catholic and non-Catholic groups.

The Pontifical Academy for Life has noted that Catholics have an obligation to use ethically-sourced vaccines when available, and have an obligation to speak up and request the development of new cell lines that are not derived from aborted fetuses.

The 2008 Vatican document Dignitatis personae strongly criticized aborted fetal tissue research. However, as regards common vaccines, such as those for chicken pox and measles, mumps, and rubella (MMR), that may be derived from cell lines of aborted babies, the Vatican said they could be used by parents for “grave reasons” such as danger to their children’s health.

In a 2017 document on vaccines, the academy noted a “moral obligation to guarantee the vaccination coverage necessary for the safety of others… especially the safety of more vulnerable subjects such as pregnant women and those affected by immunodeficiency who cannot be vaccinated against these diseases.”

 

Each spring, the Athletics department at Penn State Behrend honors the college’s best student-athletes for their performances on and off the field. This year, because of the transition to the remote-learning environment, the awards were announced on video by Senior Director of Athletics Brian Streeter.

The Brooklyn District Attorney released data to show the disparities in arrests. The NYPD released data to show the demographics of summonses.

Siena Salvaggio, who will graduate Saturday with a 4.0 GPA in finance and a minor in economics, has been named Smeal’s spring 2020 finance student marshal.

This isn't the first time states and schools have turned to projects, portfolios, exhibitions, and essays to measure students' learning. Here are lessons from the last go-around.

Here's a handy glossary on terms like project-based learning, competency-based learning, and standards-based grading.

AP has managed to dodge the partisan pitfalls that have felled other ambitious curricular efforts—so far, write Chester E. Finn Jr. and Andrew E. Scanlan.