In children with congenital toxoplasmosis, ocular lesions can be detected and may relapse after birth despite pre- and postnatal treatment. Long-term ocular outcome beyond puberty and associated prognostic factors are unknown due to limited follow-up.

Our study in 477 patients with treated congenital toxoplasmosis who were followed up to 22 years indicated that new ocular lesions can be detected well into adolescence (with a cumulative probability at 18 years of almost 50%), but they rarely cause severe visual impairment. (Read the full article)

Adolescent males from low-income communities are a group at increased risk of obesity and related health concerns. Obesity prevention interventions targeting adolescents have so far had mixed success. Targeted interventions, tailored for specific groups, may be more appealing and efficacious.

A multicomponent school-based intervention using smartphone technology can improve muscular fitness, movement skills, and key weight-related behaviors among low-income adolescent boys. (Read the full article)

Little is known about the impact of tobacco smoke exposure on preterm children with bronchopulmonary dysplasia. It is essential to understand how environmental exposures, such as tobacco smoke, influence respiratory morbidities in this vulnerable population.

Chronic tobacco smoke exposure is common in children with bronchopulmonary dysplasia. In children who required home respiratory support, hair nicotine levels were a better predictor of hospitalization and activity limitation than caregiver self-report. (Read the full article)

Clinical trials of the quadrivalent human papillomavirus vaccine show it to be highly efficacious in preventing vaccine-type–specific cervical dysplasia and anogenital warts, but few studies have assessed its effects in the real world and none have done so at the program/population level.

This study provides strong evidence of the early benefits of quadrivalent human papillomavirus vaccination on reductions in cervical dysplasia and possible reductions in anogenital warts among girls aged 14 to 17 years, offering additional justification for not delaying vaccination until girls are older. (Read the full article)

The majority of youth are not meeting the recommended physical activity guidelines. Dance classes are popular for girls and have potential to provide physical activity for many youth. Little is known about how active youth are in different dance types.

Objectively measured physical activity in dance classes are low and generally provide less physical activity than youth sports. There is a public health imperative to engage the dance profession in efforts to improve the health impact of youth dance classes. (Read the full article)

Stevens-Johnson syndrome (SJS) is a rare and severe immunologic phenomenon characterized by rash and mucous membrane disease. SJS may be triggered by medications and, less commonly, by infections such as Mycoplasma pneumoniae (Mp). Outbreaks of SJS are exceedingly rare.

We describe the largest SJS outbreak reported in children, which was also Mp-associated. In the first case-control study of this disease, we identify predictors of Mp-associated SJS versus non–Mp-associated SJS, including fewer skin lesions, pneumonia, and elevated erythrocyte sedimentation rate. (Read the full article)

Hypoplastic left heart syndrome (HLHS) is a critical congenital heart defect with high mortality. With advances in surgical intervention in recent years, survival of infants with HLHS has improved, but information on long-term survival using population-based data is limited.

In this population-based study, survival to adolescence of children with HLHS has significantly improved in recent years. Among infant survivors, >90% survived up to 18 years. Gestational age, birth weight, and neighborhood poverty may affect survival. (Read the full article)

Children with life-threatening complex chronic conditions (LT-CCCs) experience high hospital use.

Hospital use in the last year of life for these children varies by type and number of LT-CCCs. Most children with ≥3 LT-CCCs are admitted to the hospital for more than 2 months in the last year of life. (Read the full article)

The impact of neonatal abstinence syndrome is of concern because the number of newborns showing symptoms of withdrawal after intrauterine drug exposure is increasing worldwide. Newborns developing neonatal abstinence syndrome require prolonged medical treatment and longer hospital admission after birth.

This first randomized controlled trial presents data on newborns with neonatal abstinence syndrome treated with laser acupuncture. The findings suggest that adjuvant laser acupuncture has the potential to reduce duration of morphine therapy and length of hospital stay. (Read the full article)

After more than six years and 800 blog posts, I am wrapping up my contributions to Education Week. Before I go, a look at innovation vs. improvement and how we can all support creating a future that works for everyone.

If I've learned anything after hanging out at a think tank for close to two decades, it's that dreaming up education innovations is easy. Number 12 in our countdown is my take on the goofy contests that talkers seem to be so fond of.

The Atari 2600's library is incredibly diverse; let's explore hidden gems from the golden age of console gaming.

The Dallas String Quartet will deliver its passionate fusion of classical and contemporary music to the Community Arts Center at 7:30 p.m. Thursday, March 19.

A majority of states have at least one policy that limits the number of students that may be in a general education classroom, according to the Education Commission of the States. Among states that have changed their class-size policies since 2008, all have opted to relax those constraints.

As I attended the annual Storage Visions conference a couple of weeks ago, I was struck again by just how much flash is being used in enterprise systems, and what the potential is for future uses going forward.

We analyse how Latvia secured a point against Germany at UEFA EURO 2004.

Integrating technology requires a significant investment of time and money, but the resources are well-spent if the focus is improving instruction, writes educational consultant Matthew Lynch.

About two dozen teachers from across the country spent a week wrestling with questions about how to remember the Confederacy.

Indonesia was rattled by more than 11 500 earthquakes last year, almost double the annual average of the past decade, according to the nation’s meteorological agency.

La imagen de Camerún como una isla de paz en medio de una región tumultuosa terminó en 2013, cuando la violencia de Boko Haram cruzó la frontera nigeriana. Este grupo está afiliado al llamado Estado Islámico o Daesh, e incluso se rebautizó como Estado Islámico de África Occidental a principios de este año. Pero la forma brutal de yihadismo africano que representa difícilmente se explica por el auge del Estado Islámico en Irak y Siria. De hecho, es en parte una consecuencia del cambiante panorama religioso africano, que afecta y no poco a Camerún.

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

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

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

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

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.

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.

Antibiotic resistance is a global concern; however, data on antibiotic-resistant Ureaplasma spp. and Mycoplasma hominis are limited in comparison to similar data on other microbes. A total of 492 Ureaplasma spp. and 13 M. hominis strains obtained in Hangzhou, China, in 2018, were subjected to antimicrobial susceptibility testing for levofloxacin, moxifloxacin, erythromycin, clindamycin, and doxycycline using the broth microdilution method. The mechanisms underlying quinolone and macrolide resistance were determined. Meanwhile, a model of the topoisomerase IV complex bound to levofloxacin in wild-type Ureaplasma spp. was built to study the quinolone resistance mutations. For Ureaplasma spp., the levofloxacin, moxifloxacin and erythromycin resistance rates were 84.69%, 51.44% and 3.59% in U. parvum and 82.43%, 62.16% and 5.40% in U. urealyticum, respectively. Of the 13 M. hominis strains, 11 were resistant to both levofloxacin and moxifloxacin, and five strains showed clindamycin resistance. ParC S83L was the most prevalent mutation in levofloxacin-resistant Ureaplasma strains, followed by ParE R448K. The two mutations GyrA S153L and ParC S91I were commonly identified in quinolone-resistant M. hominis. A molecular dynamics-refined structure revealed that quinolone resistance-associated mutations inhibited the interaction and reduced affinity with gyrase or topoisomerase IV and quinolones. The novel mutations S21A in the L4 protein and G2654T and T2245C in 23S rRNA and ermB gene were identified in erythromycin-resistant Ureaplasma spp. Fluoroquinolone resistance in Ureaplasma spp. and Mycoplasma hominis remains high in China, the rational use of antibiotics needs to be further enhanced.

The rapid evolution of resistance in the malaria parasite to every single drug developed against it calls for the urgent identification of new molecular targets. Using a stain specific for the detection of intracellular amyloid deposits in live cells we have detected the presence of abundant protein aggregates in Plasmodium falciparum blood stages and female gametes cultured in vitro, in the blood stages of mice infected by Plasmodium yoelii, and in the mosquito stages of the murine malaria species Plasmodium berghei. Aggregated proteins could not be detected in early rings, the parasite form that starts the intraerythrocytic cycle. A proteomics approach was followed to pinpoint actual aggregating polypeptides in functional P. falciparum blood stages, which resulted in the identification of 369 proteins, with roles particularly enriched in nuclear import-related processes. Five aggregation-prone short peptides selected from this protein pool exhibited different aggregation propensity according to Thioflavin-T fluorescence measurements, and were observed to form amorphous aggregates and amyloid fibrils in transmission electron microscope images. The results presented suggest that generalized protein aggregation might have a functional role in malaria parasites. Future antimalarial strategies based on the upsetting of the pathogen's proteostasis and therefore affecting multiple gene products could represent the entry to new therapeutic approaches.

Despite the worldwide re-emergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. We here aim to identify the target of a novel class of CHIKV inhibitors i.e. CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 50% effective concentrations in the low micromolar range. A CHVB-resistant variant (CHVB^res) was selected that carried two mutations in the gene encoding nsP1 (responsible for viral RNA capping), one mutation in nsP2 and one mutation in nsP3. Reverse genetics studies demonstrated that both nsP1 mutations were necessary and sufficient to achieve ~18-fold resistance, suggesting that CHVB targets viral mRNA capping. Interestingly, CHVB^res was cross-resistant to the previously described CHIKV capping inhibitors from the MADTP series, suggesting they share a similar mechanism of action. In enzymatic assays, CHVB inhibited the methyltransferase and guanylyltransferase activities of alphavirus nsP1 proteins. To conclude, we identified a class of CHIKV inhibitors that targets the viral capping machinery. The potent anti-CHIKV activity makes this chemical scaffold a potential candidate for CHIKV drug development.

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.

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.

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

Background

Optimal concentrations of unbound antimicrobials are essential for maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model.

Methods

Design

Prospective, three phase intervention observational study.

Subjects

Healthy Merino sheep.

Interventions

Eight sheep were subject to three experimental phases; normoalbuminemia, hypoalbuminemia using plasmapheresis and albumin replacement using a 25% albumin solution. In each phase, ceftriaxone 40 mg/kg and ertapenem 15 mg/kg were given intravenously. Blood samples were collected at pre-defined intervals and analyzed using an ultra-high-performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters such as area under the curve (AUC_0-24), plasma clearance (CL) and apparent volume of distribution in the terminal phase (V_d) were estimated and compared between the phases.

Results

The protein and albumin concentrations were significantly different between phases. Hypoalbuminemia resulted in a significantly lower AUC_0-24 and higher CL of total and unbound concentrations of ceftriaxone compared to the other phases. Whereas albumin replacement led to higher AUC_0-24 and lower CL compared to other phases for both drugs. The V_d for total drug concentrations for both drugs were significantly lower with albumin replacement.

Conclusions

For highly protein-bound drugs such as ceftriaxone and ertapenem, both hypoalbuminemia and albumin replacement may affect unbound drug exposure.

In number 10 in our countdown, I tried to offer a few thoughts to funders as they embraced new agendas and looked to avoid repeating yesterday's missteps.

Penn State Health has enrolled its first COVID-19 patient into an experimental treatment program called convalescent plasma therapy.

Many teachers scrapped their lesson plans on Monday and gave their students space to talk about Kobe Bryant.

Penn State Campus Recreation is now offering a library of more than 50 workouts online through YouTube as well as live classes that are held every business day on the Penn State Campus Recreation Instagram. Group fitness instructor Alexis "Lexi" Neimeyer talked about her experience on the transition to virtual fitness classes.

A new high-res audio player looks like a wooden flask and has a tie-up with Tidal.

You don't have to fork over a bunch of cash to get a bunch of storage. PNY flash drives, SD cards, and portable drives are on sale at Amazon, with prices starting as low as $5.84.

RANGERS vice-chairman John Bennett last night dismissed a claim that Ibrox chairman Douglas Park had threatened SPFL chief executive Neil Doncaster as “unfounded”.

Forty-nine Penn State Berks students received recognition for the University Scholastic awards on April 2, through personalized emails. The awards presented included the Evan Pugh Scholars Award,

Already home to a thriving ecosystem of private school choice, the state’s lawmakers want vouchers for thousands of new students.

Richard A. Ehrenkranz
Dec 1, 2005; 116:1353-1360
ARTICLES

G. J. Schwartz
Aug 1, 1976; 58:259-263
ARTICLES

Another dozen school districts have landed federal Teacher Incentive Fund grants, including one that will focus on paying principals and assistant principals for their performance.

History teacher Bill Tolley offers tips on adapting to learning environments that combine face-to-face instruction with self-directed online experiences.

"With unparalleled technology support, digital and curriculum innovation, a flexible structure including our Commonwealth and University Park campuses, effective outreach programming, and a wide array of top-ranked academic programs, Penn State is uniquely prepared for the arrival of the Class of 2024," wrote President Eric J. Barron in a message inviting accepted students to attend a four-part virtual series titled "Welcome to the Penn State Community."

Media literacy belongs in science class, insists Media Literacy Now’s Andy Zucker. Here’s how to bring it there.

A multi-disciplinary collaborative relationship, developed between Penn State EMS Energy Institute researchers and a Pittsburgh-based start-up company, may hold the answer to reducing global greenhouse gas (GHG) emissions while also paving the way to disrupt the chemical and material industries.