KBP-7072 is a novel third-generation tetracycline (aminomethylcycline) antibacterial that overcomes common efflux and ribosomal protection resistance mechanisms that cause resistance in older-generation tetracyclines. KBP-7072 completed phase 1 clinical development studies for safety, tolerability, and pharmacokinetics (ClinicalTrials.gov identifier NCT02454361) and multiple ascending doses in healthy subjects (ClinicalTrials.gov identifier NCT02654626) in December 2015. Both oral and intravenous formulations of KBP-7072 are being developed. In this study, we evaluated the in vitro activities of KBP-7072 and comparator agents by CLSI document M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-A. calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum-β-lactamase (ESBL)- and metallo-β-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC_50/90, 0.25/1 mg/liter) was comparable in activity to colistin (92.8%/92.8% susceptible [S] [CLSI/EUCAST]) against A. baumannii isolates, inhibiting 99.2% of isolates at ≤2 mg/liter and 97.6% of isolates at ≤1 mg/liter. KBP-7072 was equally active against A. baumannii isolates, including carbapenem-resistant, colistin-resistant, and tetracycline-resistant isolates, regardless of geographic location, and maintained activity against ESBL- and MBL-producing isolates. KBP-7072 outperformed comparator agents, including ceftazidime (40.3% S [CLSI]), gentamicin (48.2%/48.2% S [CLSI/EUCAST]), levofloxacin (39.5%/37.9% S [CLSI/EUCAST]), meropenem (42.0%/42.0% S [CLSI/EUCAST]), piperacillin-tazobactam (33.3% S [CLSI]), and all tetracycline-class comparator agents, which include doxycycline (67.3% S [CLSI]), minocycline (73.8% S [CLSI]), tetracycline (37.2% S [CLSI]), and tigecycline (79.5% inhibited by ≤2 mg/liter). The potent in vitro activity of KBP-7072 against recent geographically diverse, molecularly characterized, and drug-resistant A. baumannii isolates supports continued clinical development for the treatment of serious infections, including those caused by A. baumannii.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition, causing progressive decline in lung function leading to premature death. Acute exacerbations in COPD patients are predominantly associated with respiratory viruses. Ribavirin is a generic broad-spectrum antiviral agent that could be used for treatment of viral respiratory infections in COPD. Using the Particle Replication In Nonwetting Templates (PRINT) technology, which produces dry-powder particles of uniform shape and size, two new inhaled formulations of ribavirin (ribavirin-PRINT-CFI and ribavirin-PRINT-IP) were developed for efficient delivery to the lung and to minimize bystander exposure. Ribavirin-PRINT-CFI was well tolerated in healthy participants after single dosing and ribavirin-PRINT-IP was well tolerated in healthy and COPD participants after single and repeat dosing. Ribavirin-PRINT-CFI was replaced with ribavirin-PRINT-IP since the latter formulation was found to have improved physicochemical properties and it had a higher ratio of active drug to excipient per unit dose. Ribavirin concentrations were measured in lung epithelial lining fluid in both healthy and COPD participants and achieved target concentrations. Both formulations were rapidly absorbed with approximately dose proportional pharmacokinetics in plasma. Exposure to bystanders was negligible based on both the plasma and airborne ribavirin concentrations with the ribavirin-PRINT-IP formulation. Thus, ribavirin-PRINT-IP allowed for an efficient and convenient delivery of ribavirin to the lungs while minimizing systemic exposure. Further clinical investigations would be required to demonstrate ribavirin-PRINT-IP antiviral characteristics and impact on COPD viral-induced exacerbations. (The clinical trials discussed in this study have been registered at ClinicalTrials.gov under identifiers NCT03243760 and NCT03235726.)

Balamuthia mandrillaris is an under-reported, pathogenic free-living amoeba that causes Balamuthia amoebic encephalitis (BAE) and cutaneous skin infections. Although cutaneous infections are not typically lethal, BAE with or without cutaneous involvement is usually fatal. This is due to the lack of drugs that are both efficacious and can cross the blood-brain barrier. We aimed to discover new leads for drug discovery by screening the open-source Medicines for Malaria Venture (MMV) Malaria Box and MMV Pathogen Box, with 800 compounds total. From an initial single point screen at 1 and 10 μM, we identified 54 hits that significantly inhibited the growth of B. mandrillaris in vitro. Hits were reconfirmed in quantitative dose-response assays and 23 compounds (42.6%) were confirmed with activity greater than miltefosine, the current standard of care.

Nacubactam is a novel β-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine β-lactamases (classes A and C and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae. The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single- and multiple-ascending-dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam of 50 to 8,000 mg, multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for up to 7 days, or nacubactam of 2,000 mg plus meropenem of 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild to moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Coadministration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential β-lactam partner for nacubactam. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].)

Plasmodium vivax relapse is one of the major causes of sustained global malaria transmission. Primaquine (PQ) is the only commercial drug available to prevent relapses, and its efficacy is dependent on metabolic activation by cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 function, caused by allelic polymorphisms, leads to the therapeutic failure of PQ as a radical cure for P. vivax malaria. Here, we hypothesized that the host immune response to malaria parasites modulates susceptibility to P. vivax recurrences in association with CYP2D6 activity. We performed a 10-year retrospective study by genotyping CYP2D6 polymorphisms in 261 malaria-exposed individuals from the Brazilian Amazon. The immune responses against a panel of P. vivax blood-stage antigens were evaluated by serological assays. We confirmed our previous findings, which indicated an association between impaired CYP2D6 activity and a higher risk of multiple episodes of P. vivax recurrence (risk ratio, 1.75; 95% confidence interval [CI], 1.2 to 2.6; P = 0.0035). An important finding was a reduction of 3% in the risk of recurrence (risk ratio, 0.97; 95% CI, 0.96 to 0.98; P < 0.0001) per year of malaria exposure, which was observed for individuals with both reduced and normal CYP2D6 activity. Accordingly, subjects with long-term malaria exposure and persistent antibody responses to various antigens showed fewer episodes of malaria recurrence. Our findings have direct implications for malaria control, since it was shown that nonimmune individuals who do not respond adequately to treatment due to reduced CYP2D6 activity may present a significant challenge for sustainable progress toward P. vivax malaria elimination.

The new complexes Zn(ITZ)₂Cl₂ (1) and Zn(ITZ)₂(OH)₂ (2) were synthetized by a reaction of itraconazole with their respective zinc salts under reflux. These Zn-ITZ complexes were characterized by elemental analyses, molar conductivity, mass spectrometry, ¹H and ¹³C{¹H} nuclear magnetic resonance, and UV-vis and infrared spectroscopies. The antiparasitic and antifungal activity of Zn-ITZ complexes was evaluated against three protozoans of medical importance, namely, Leishmania amazonensis, Trypanosoma cruzi, and Toxoplasma gondii, and two fungi, namely, Sporothrix brasiliensis and Sporothrix schenckii. The Zn-ITZ complexes exhibited a broad spectrum of action, with antiparasitic and antifungal activity in low concentrations. The strategy of combining zinc with ITZ was efficient to enhance ITZ activity since Zn-ITZ-complexes were more active than the azole alone. This study opens perspectives for future applications of these Zn-ITZ complexes in the treatment of parasitic diseases and sporotrichosis.

Currently, the expansion of the novel human respiratory coronavirus (known as SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2], COVID-2019 [coronavirus disease 2019], or 2019-nCoV [2019 novel coronavirus]) has stressed the need for therapeutic alternatives to alleviate and stop this new epidemic. The previous epidemics of infections by high-morbidity human coronaviruses, such as SARS-CoV in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, prompted the characterization of compounds that could be potentially active against the currently emerging novel coronavirus, SARS-CoV-2. The most promising compound is remdesivir (GS-5734), a nucleotide analog prodrug currently in clinical trials for treating Ebola virus infections. Remdesivir inhibited the replication of SARS-CoV and MERS-CoV in tissue cultures, and it displayed efficacy in nonhuman animal models. In addition, a combination of the human immunodeficiency virus type 1 (HIV-1) protease inhibitors lopinavir/ritonavir and interferon beta (LPV/RTV–IFN-β) was shown to be effective in patients infected with SARS-CoV. LPV/RTV–IFN-β also improved clinical parameters in marmosets and mice infected with MERS-CoV. Remarkably, the therapeutic efficacy of remdesivir appeared to be superior to that of LPV/RTV–IFN-β against MERS-CoV in a transgenic humanized mouse model. The relatively high mortality rates associated with these three novel human coronavirus infections, SARS-CoV, MERS-CoV, and SARS-CoV-2, have suggested that proinflammatory responses might play a role in the pathogenesis. It remains unknown whether the generated inflammatory state should be targeted. Therapeutics that target the coronavirus alone might not be able to reverse highly pathogenic infections. This minireview aims to provide a summary of therapeutic compounds that have shown potential in fighting SARS-CoV-2 infections.

Chromosomal resistance islands containing the methicillin resistance gene mecD (McRI_mecD) have been reported in Macrococcus caseolyticus. Here, we identified novel macrolide resistance genes in Macrococcus canis on similar elements, called McRI_msr. These elements were also integrated into the 3' end of the 30S ribosomal protein S9 gene (rpsI), delimited by characteristic attachment (att) sites, and carried a related site-specific integrase gene (int) at the 5' end. They carried novel macrolide resistance genes belonging to the msr family of ABC subfamily F (ABC-F)-type ribosomal protection protein [msr(F) and msr(H)] and the macrolide efflux mef family [mef(D)]. Highly related mef(D)-msr(F) fragments were found on diverse McRI_msr elements in M. canis, M. caseolyticus, and Staphylococcus aureus. Another McRI_msr-like element identified in an M. canis strain lacked the classical att site at the 3' end and carried the msr(H) gene but no neighboring mef gene. The expression of the novel resistance genes in S. aureus resulted in a low-to-moderate increase in the MIC of erythromycin but not streptogramin B. In the mef(D)-msr(F) operon, the msr(F) gene was shown to be the crucial determinant for macrolide resistance. The detection of circular forms of McRI_msr and the mef(D)-msr(F) fragment suggested mobility of both the island and the resistance gene subunit. The discovery of McRI_msr in different Macrococcus species and S. aureus indicates that these islands have a potential for dissemination of antibiotic resistance within the Staphylococcaceae family.

Fluoroquinolones are reported to possess immunomodulatory activity; hence, a novel benzoquinolizine fluoroquinolone, levonadifloxacin, was evaluated in lipopolysaccharide-stimulated human whole-blood (HWB) and mouse acute lung injury (ALI) models. Levonadifloxacin significantly mitigated the inflammatory responses in an HWB assay through inhibition of proinflammatory cytokines and in the ALI model by lowering lung total white blood cell count, myeloperoxidase, and cytokine levels. The immunomodulatory effect of levonadifloxacin, along with promising antibacterial activity, is expected to provide clinical benefits in the treatment of infections.

The MaMTH-DS assay detected inhibitors of mutant EGFR in non–small cell lung cancer cells.

Background:

Early diagnosis can significantly reduce colorectal cancer deaths. We sought to identify serum PIWI-interacting RNAs (piRNAs) that could serve as sensitive and specific noninvasive biomarkers for early colorectal cancer detection.

Methods:

We screened the piRNA expression profile in sera from 7 patients with colorectal cancer and 7 normal controls using small RNA sequencing. Differentially expressed piRNAs were measured in a training cohort of 140 patients with colorectal cancer and 140 normal controls using reverse transcription quantitative PCR. The identified piRNAs were evaluated in two independent validation cohorts of 180 patients with colorectal cancer and 180 normal controls. Finally, the diagnostic value of the identified piRNAs for colorectal adenoma (CRA) was assessed, and their expression was measured in 50 patients with lung cancer, 50 with breast cancer, and 50 with gastric cancer.

Results:

The piRNAs piR-020619 and piR-020450 were consistently elevated in sera of patients with colorectal cancer as compared with controls. A predicative panel based on the two piRNAs was established that displayed high diagnostic accuracy for colorectal cancer detection. The two-piRNA panel could detect small-size and early-stage colorectal cancer with an area under the ROC curve of 0.863 and 0.839, respectively. Combined use of the two piRNAs could effectively distinguish CRA from controls. Aberrant elevation of the two piRNAs was not observed in sera of patients with lung, breast, and gastric cancer.

Conclusions:

Serum piR-020619 and piR-020450 show a strong potential as colorectal cancer-specific early detection biomarkers.

Impact:

The field of circulating piRNAs could allow for novel tumor biomarker development.

Scientists demonstrate a completely new way of treating snakebites. The team have shown that the repurposing of an existing medicine, commonly used to treat mercury poisoning, is an effective oral therapy for the treatment of certain hemotoxic snakebites.

Though COVID-19 likely makes recovered patients immune, experts aren't sure how long protection lasts

The author of The Miniaturist on the beguiling blend of tradition and modernity (and pancakes) in a city that provided the inspiration for her 17th-century-set debut novel and Waterstones Book of the Year 2014

• Top 10 free things to do in Amsterdam
  
• A new Amsterdam – and a new Rijksmuseum

Amsterdam is classically romantic but is also funky, forward-thinking and citizen-friendly. In the old centre, around the southern canal belt, there are these beautiful 17th-century merchants’ houses that 21st-century Amsterdammers still live in. I’ve always thought it wears its historical cloak quite casually and doesn’t just dwell in the past.

The Rijksmuseum is stunning and I love it as a fascinating, cool, accessible museum, as well as for the part it played in inspiring The Miniaturist. I came across Petronella Oortman’s doll’s house there by chance. It’s an exact scale replica of her real home, and Oortman spent a fortune having it created. I thought at the time it was an interesting story, but I didn’t think I was going to write a novel about it. I’m in its debt, really.

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Elena Ferrante’s Naples, Umberto Eco’s medieval mysteries, EM Forster’s Tuscany … Italy comes alive through these great books
• 10 of the best novels about France

Long before Covid-19, there were always bad things in the press about Italy: corruption, mafia, bureaucracy. But, whenever I went, life seemed to work out even so. People may be poor but they still sit in the sun, drink and chat; music and culture are a birthright; the right seems in the ascendant but on the ground it feels blessed with far-seeing idealists – it has almost four times as much land under organic cultivation as the UK, for example. For now, my remedy to the withdrawal symptoms I feel is to visit via the written word. Many writers have set books in Italy – I was sorry to leave out Martin Amis’s The Pregnant Widow (Calabria), and Ali Smith’s How to be Both (Ferrara) – but here are my top 10 romanze italiane.

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By Allan Eastman The photographs of water bombers fighting the horrendous Ft. McMurray conflagration of 2016 invoked a sudden wash of memories having to do with two of the great Canadian cultural institutions that I had the good fortune to be involved with and a bizarre set of circumstances that led from a burned out […]

New clip gives viewers a sense of what the much-anticipated series will be like

'I thought at the time it was a work of fiction,' author says

Emma Glass's book set in an isolation ward is both terrific and timely. She talks to Katie Law

When truth is stranger than fiction

The new Twilight novel, told from Edward's perspective, will be released on August 1

The new Twilight novel, told from Edward's perspective, will be released on August 4

Some of the top creative minds at Mexican broadcaster Televisa are puzzling over an unexpected challenge: crafting their signature soap operas without a single love scene or even a tender kiss.

Coming-of-age drama Normal People, based on Irish author Sally Rooney's bestselling novel and touted as one of the best book-to-series adaptations in recent years, is set to debut in Canada on CBC Gem.

Although rare, health authorities advise any children presenting with Kawasaki-like symptoms be taken immediately to a specialist in pediatric infectious disease, rheumatology, or critical care.
Medscape Medical News

(MedPage Today) -- Calcium-channel blocker nasal spray etripamil flopped for rapid conversion of paroxysmal supraventricular tachycardia (PSVT) in its pivotal phase III trial, but the story may not be over for the novel agent. The novel agent...

The author has been everywhere, in life and fiction. "A Children's Bible" passionately fuses the two: "You've gotta be Chicken Little sooner or later."

Amy Jo Burns' novel, "Shiner," illuminates an Appalachia whose men "pray for God to show Himself while our wives wash their husbands' underpants."

On location in Dublin with the stars of Normal People Paul Mescal and Daisy Edgar-Jones.

Tokyo’s Daiichi Sankyo has submitted a supplemental New Drug Application (sNDA) for trastuzumab deruxtecan…

In order to proceed with the first phase of their acquisition of certain patents and patent applications from Novell Inc., CPTN Holdings LLC and its owners have altered their original agreements to address the Justice Department’s antitrust concerns.

A manufacturer and exporter of wind turbines based in the People’s Republic of China, two employees of that manufacturer and a former employee of a subsidiary of AMSC, a United States-based company formerly known as American Superconductor Inc., were charged today with stealing trade secrets from AMSC causing an alleged loss of more than $800 million to the company.

Lewis Hamilton appears to be the first victim of the FIA's controversial helmet ban after being blocked from wearing a novelty lid in Malaysia

Her latest publication is every parent's dream come true -- an attempt to get teens to declutter.

The hog-nosed rat (Hyorhinomys stuempkei) possesses traits never seen by the scientific community before.

My title is disingenuous, because I didn't do any novel-writing in the Arctic. However, I thought and plotted and observed and learned with intensity, such that in the two months since my return, I've written an entire third of the new novel that was my primary Arctic project. This writing pace is unheard of for me. It's partly because I've had some clearheadedness lately, unrelated to the Arctic. But it's also largely because I got so much hands-on experience on the ship!

Since most of my work in the Arctic was happening in my head and my heart, it's not going to be possible to show the entire process in pictures. But I can share some of the experiences that helped me make progress.

My novel takes place partly on a tall ship, where my main character is learning a lot about the work the sailors are doing.

Therefore, it helped me to learn to haul lines, and to watch others do so. (On a ship, ropes are called lines. It takes 60-ish lines to operate the rigging on the Antigua!)

(The Antigua is a barquentine. That's a tall ship with three or more masts that has square sails on its foremast and fore-and-aft rigged sails [sails that stretch from front to back] on its other masts. This sail configuration gives it power and maneuverability, but also makes it possible to be operated by a small crew.)

On the occasions when we could turn the engine off and just sail... I was SO HAPPY. These were my favorite moments of the entire trip, which is saying an awful lot. It was silent, and graceful, and our movement felt so good in the water. It taught me a lot about my character and how she feels, too. 


The main character in my novel spends time lying inside a rowboat on deck, watching the sailors raise and lower the sails. So I did the same, curling up in one of the Zodiacs :o).

Photo by Dawn Jackson.

I did a lot of thinking and observing from that position. The masts swung back and forth above me as we moved through the waves and I got a lot of ideas! I also had the best views.




My main character also climbs the mast. So... in the picture below, our captain, Mario, gives me help and support as I make my first attempt.

John Hirsch took this picture, and the further-back one below, because I shoved my iPhone at him before I started :o)

Barbara Liles took this picture. As I climbed, the ship was moving through ice.

I'm on the right in this photo.

 Climbing was a thrill. Each time I tried it, I got up further. I knew it was safe, because I always wore a halter, but the ship was moving a lot and it was very, very cold up there, and sometimes slippery... and the places where your hands and feet went were not always intuitive... I learned a lot about my character's experience from that experience.

By the way, it's probably time for me to introduce our sailing crew -- our captain, Mario; first mate, Marijn, and second mate, Annet! I'll have more to say about them in future blog posts. They kept us safe, taught us so much, and were so patient whenever we "helped"!


That's it for today's Arctic chapter, but there's more to come. Hope you're all having a cozy December. :o)

A quick-thinking Helsinki bakery has saved itself from financial ruin due to the new coronavirus pandemic by creating a cake that looks like a toilet roll.