Los conflictos en los países pequeños suelen agravarse debido a la indiferencia internacional. Sin embargo, en el caso de la República Centroafricana (RCA), el problema es ligeramente distinto. Hay una importante presencia internacional en este Estado, pero los actores principales han decidido mantenerse al margen y esperar en vez de intervenir activamente en la crisis.

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.

Continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance markers is needed to follow treatment effectiveness and further update control strategies. Here, we genotyped Plasmodium falciparum resistance gene markers associated with sulfadoxine-pyrimethamine (SP) and artemisinin-based combination therapy (ACT) in isolates from pregnant women in Ghana. The prevalence of the septuple IRNI-A/FGKGS/T pfdhfr/pfdhps haplotypes including the pfdhps A581G and A613S/T mutations was high at delivery among post-SP treatment isolates (18.2%) compared to those of first-antenatal care (before initiation of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP); 6.1%; p = 0.03). Regarding the pfk13 marker gene, two non-synonymous mutations (N458D and A481C) were detected at positions previously related to artemisinin resistance in isolates from Southeast-Asia. These mutations were predicted in silico to alter the stability of the pfk13 propeller-encoding domain. Overall, these findings highlight the need for intensified monitoring and surveillance on additional mutations associated with increased SP resistance as well as emergence of resistance against artemesinin derivatives.

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.

Bacteria of the genus Campylobacter are major foodborne pathogens which have become increasingly resistant to clinically important antimicrobial agents (1)....

KBP-7072 is a semi-synthetic aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative pathogens including multidrug resistant bacterial strains. The pharmacokinetics (PK) of KBP-7072 after oral and intravenous (IV) administration of single and multiple doses were investigated in animal models including during fed and fasted states and also evaluated the protein binding and excretion characteristics. In Sprague-Dawley (SD) rats, Beagle dogs, and CD-1 mice, KBP-7072 demonstrated a linear PK profile after administration of single oral and IV and multiple oral doses. Oral bioavailability ranged from 12% to 32%. Mean T_max ranged from 0.5 to 4 hours, and mean half-life ranged from approximately 6 to 11 hours. Administration of oral doses in the fed state resulted in a marked reduction in C_max and AUC compared with dosing in fasted animals. The mean bound fractions of KBP-7072 were 77.5%, 69.8%, 64.5%, 69.3%, and 69.2% in mouse, rat, dog, monkey, and human plasma, respectively. Following a single 22.5 mg/kg oral dose of KBP-7072 in SD rats, cumulative excretion in feces was 64% and in urine was 2.5% of the administered dose. The PK results in animal models are consistent with single and multiple ascending dose studies in healthy volunteers and confirm the suitability of KBP-7072 for once daily oral and IV administration in clinical studies.

The human diseases caused by the fungal pathogens Cryptococcus neoformans and C. gattii are associated with high indices of mortality, and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anti-cryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anti-cryptococcal benzimidazole. Fenbendazole was inhibitory against 17 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anti-cryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anti-cryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mice model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis.

Gepotidacin, a triazaacenaphthylene bacterial type II topoisomerase inhibitor, is in development for treatment of uncomplicated urinary tract infection (uUTI). This Phase 2a study in female participants with uUTI evaluated the pharmacokinetics (primary objective), safety, and exploratory efficacy of gepotidacin. Eligible participants (N = 22) were confined to the clinic at baseline, received oral gepotidacin 1,500 mg twice daily for 5 days (on-therapy; Days 1 to 5), and returned to the clinic for test-of-cure (Days 10 to 13) and follow-up (Day 28±3). Pharmacokinetic, safety, clinical, and microbiological assessments were performed. Maximum plasma concentrations were observed approximately 1.5 to 2 hours postdose. Steady state was attained by Day 3. Urinary exposure over the dosing interval increased from 3,742 μg.h/ml (Day 1) to 5,973 μg.h/ml (Day 4), with trough concentrations of 322 to 352 μg/ml from Day 3 onward. Gepotidacin had an acceptable safety-risk profile with no treatment-limiting adverse events and no clinically relevant safety trends. Clinical success was achieved in 19 (86%) and 18 (82%) of 22 participants at test-of-cure and follow-up, respectively. Eight participants had a qualifying baseline uropathogen (growth; ≥10⁵ CFU/ml). A therapeutic (combined clinical and microbiological [no growth; <10³ CFU/ml]) successful response was achieved in 6 (75%) and 5 (63%) of 8 participants at test-of-cure and follow-up, respectively. Plasma area under the free-drug concentration-time curve over 24 hours at steady state divided by the MIC (fAUC_0-24/MIC) and urine AUC_0-24/MIC ranged from 6.99 to 90.5 and 1,292 to 121,698, respectively. Further evaluation of gepotidacin in uUTI is warranted. (NCT03568942)

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.

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

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.

Exploring different ways of minimising linezolid toxicity without compromising efficacy is a major quest in the treatment of drug resistant tuberculosis (TB)....

We thank Kim and colleagues for their interest in our study....

The hackers have been using files and emails that warn about a new coronavirus strain to trick users into opening them. Doing so can secretly deliver malware to the victim's machine.

Malware on an air-gapped computer can transmit data like Morse code by changing screen brightness in a way that's invisible to the naked eye but easily recorded with a camera.

BACKGROUND:

Pediatricians are less frequently sued than other physicians. When suits are successful, however, the average payout is higher. Little is known about changes in the risk of litigation over time. We sought to characterize malpractice lawsuit trends for pediatricians over time.

Student Sandisiwe Msomi saved R23 400 in small change over a year, which she will now use to pay for the registration fees of her second academic year.

The Z8H 8K LED vibrates the frame of the television to emit audio and give the impression that the sound is coming directly from the screen itself.

Philip M. Farrell
Jan 1, 2001; 107:1-13
ARTICLES

Terrie E. Inder
Feb 1, 2005; 115:286-294
ARTICLES

Andrew T. Shennan
Oct 1, 1988; 82:527-532
ARTICLES

UEFA's 'Women's football across the national associations 2017' report shows how the female game has evolved over the past five years, and offers a snapshot of the sport in each of UEFA's 55 member associations.

A recent school tour of three Bay Area schools with some blended learning experts helped provide answers to some of the common questions we hear about how to implement blended learning.

Türkiye devleti ile uluslararası alanda terör örgütü olarak kabul edilen PKK arasındaki çözüm sürecinin çökmesi, Temmuz 2015’te çatışmaların yeniden başlaması ve daha sonra derinleşen şiddet sarmalı, yeni bir çözüm sürecinin inşasını hiç olmadığı kadar gerekli kılıyor.

When scouting for a unit trust fund look for a decent track record.

An OM France couple works among trafficked women and fights for justice before government officials.

It no longer looks like a syringe, so parents can stop being suspicious their kid is doing drugs.

To view more press releases, please visit http://ir.wintrust.com/news.aspx?iid=1024452.

We've done the testing, and if you need to build an SMB-focused website, these are the best small business web hosting services for helping you get the job done.

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

The first program, focused on Small Business, will be held on May 13.

Here are five takeaways on the teaching profession from the newly released 2017-18 National Teacher and Principal Survey.

MPs have been told that some tax changes proposed by Finance Minister Pravin Gordhan in his February budget will hit small firms hard.

There is still no light at the end of the tunnel for small enterprises, according to the SMME Business Confidence Index for 2010.

Division of Small Business, Development & Tourism hosting listening sessions statewide WILMINGTON, Del. – Delaware received an A+ rating and ranked #2 out of 50 states in the 2017 Small Business Friendliness Survey released on Thursday by Thumbtack, a web and phone application for small businesses. Thumbtack awarded the state A+ ratings in 9 of […]

The two funds are designed to spur job growth in Delaware Community and business leaders came together today to celebrate the success of a small business initiative which began in Wilmington a few years ago and to announce a complimentary effort that will support small businesses and job growth throughout Delaware. Facilitated by West End […]

The Delaware Libraries Inspiration Space announces a new initiative to enable small business owners to expand their knowledge with the latest ideas from the business world’s thought leaders. A Book Club for Entrepreneurs will launch at the Lewes Public Library on Tuesday, January 9, 2018 at noon. Small business owners will have the opportunity to […]

A company working to make NASA spacesuits stronger and safer and another providing data to millions of drivers to help them avoid traffic jams are both growing in Delaware. Assistance from the state Division of Small Business, Development & Tourism is helping STF Technologies and TrafficCast take their businesses to the next level. “Growth in […]

Dover is unlocking the potential of its historic downtown with a new marketing campaign highlighting opportunities for small business owners ready to take their business dreams to the next level. State and local officials led by Gov. John Carney; Linda Parkowski, acting director of the Delaware Division of Small Business and Dover Mayor Robin Christiansen […]

The deadline to apply for Dover’s Unlock the Block program is fast approaching. July 9 is the final day to put in an application for the initiative, which seeks tenants for select vacant commercial properties on or adjacent to Loockerman Street in downtown Dover. Unlock the Block is looking for successful business owners, working from […]

For the fourth year in a row, the Delaware Department of State has received a State Trade and Export Promotion (STEP) award from the U.S. Small Business Administration (SBA.) This year’s award totals $268,096 and will be used to support the state’s efforts to assist small Delaware companies in entering and developing markets overseas.

DOVER, Del. (March 5, 2019) – Delaware small business owners in search of the right help at the right time will find it through the new Business Resource Connection on the website of the Delaware Division of Small Business, www.delbiz.com. The Business Resource Connection provides valuable information on approximately 300 programs from more than 80 […]

NEWARK, DE – Up-and-coming Delaware small businesses will now have a potential new source of capital to help them expand. As part of National Small Business Week (May 5 to May 11), the Division of Small Business on Monday launched a competitive, matching grant program to assist Delaware entrepreneurs who want to grow their small […]

WILMINGTON, DE – Ten Delaware small businesses were recognized Wednesday as the awardees of the first-ever EDGE Grants from the state Division of Small Business. Gov. John Carney and Division Director Damian DeStefano announced the companies at an event at the Carvel State Office Building in Wilmington. The grant recipients, located across the state, represent […]

The Delaware Department of State has received a State Trade and Export Promotion (STEP) award from the U.S. Small Business Administration (SBA.)

Deadline for Spring 2020 EDGE Grants is February 28, 2020 WILMINGTON, Del. – A bio-based materials company, a maker of wearable medical sensors, and a bakery-café were among the 10 Delaware small businesses recognized Thursday as awardees of the second round of EDGE Grants from the state Division of Small Business. Governor John Carney, Secretary […]

I am proud of what I do every day as the head of a nutrition company that works relentlessly to make an impact on people’s health by offering better formulations and nutritious products. India faces the double burden of over-nutrition and malnutrition, says Himanshu Bakshi.

OTT platforms are sexing up their original content library with bigger budgets, foreign locales and slick production values

Industry reports suggest that Italian cuisine is the second most popular international cuisine in India, after Chinese, due to the presence of several QSR chains. It isn’t, therefore, a surprise that companies like Del Monte want to ride this wave.