Working with a higher performance CAD environment is the major criterion these days in the design community within SOLIDWORKS. Now we have a new option for opening the drawing within seconds and make changes in drawings to communicate with our

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It’s always interesting to know about some cool tricks that you can use when it comes to modelling within SOLIDWORKS. Well, within this blog we just happen to have one of those tricks for you. They always say a magician never

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Pursuant to Clearing Advisory 20-152 that was published on April 8th, the clearing house will switch the options pricing and valuation model to Bachelier to accommodate negative prices in the underlying futures and allow for listing of option contracts with negative strikes for the set of products specified in the link below. The switch will be effective for the margin cycle run at the end of trading tomorrow April 22, 2020 and will remain in place until further notice.

Click here for the full text of the advisory

20-170

Amendments to the Price Increments of the 3-Year U.S. Treasury Note Futures Contract

Click here for the full text of the advisory

20-188

One major goal of integrative and comparative biology is to understand and explain the interaction between the performance and behavior of animals in their natural environment. The Caviomorph, Octodon degu, is a native rodent species from Chile, and represents a unique model to study physiological and behavioral traits, including cognitive and sensory abilities. Degus live in colonies and have a well-structured social organization, with a mostly diurnal–crepuscular circadian activity pattern. More notable is the fact that in captivity, they reproduce and live between 5 and 7 yr and show hallmarks of neurodegenerative diseases (including Alzheimer's disease), diabetes, and cancer.

Forty-five women from around the world begin their trek on 9 April to Mt. Everest Base Camp and summit of Kala Patthar Peak in Nepal.

CNA Staff, May 4, 2020 / 11:45 am (CNA).- Modern society is formulating an “anti-Christian creed” and punishing those who resist it with “social excommunication,” Benedict XVI has said in a new biography, published in Germany May 4.

In a wide-ranging interview at the end of the 1,184-page book, written by German author Peter Seewald, the pope emeritus said the greatest threat facing the Church was a “worldwide dictatorship of seemingly humanistic ideologies.”

Benedict XVI, who resigned as pope in 2013, made the comment in response to a question about what he had meant at his 2005 inauguration, when he urged Catholics to pray for him “that I may not flee for fear of the wolves.”

He told Seewald that he was not referring to internal Church matters, such as the "Vatileaks" scandal, which led to the conviction of his personal butler, Paolo Gabriele, for stealing confidential Vatican documents. 

In an advanced copy of “Benedikt XVI - Ein Leben” (A Life), seen by CNA, the pope emeritus said: “Of course, issues such as ‘Vatileaks’ are exasperating and, above all, incomprehensible and highly disturbing to people in the world at large.”

“But the real threat to the Church and thus to the ministry of St. Peter consists not in these things, but in the worldwide dictatorship of seemingly humanistic ideologies, and to contradict them constitutes exclusion from the basic social consensus.”

He continued: “A hundred years ago, everyone would have thought it absurd to speak of homosexual marriage. Today whoever opposes it is socially excommunicated. The same applies to abortion and the production of human beings in the laboratory.”

“Modern society is in the process of formulating an ‘anti-Christian creed,’ and resisting it is punishable by social excommunication. The fear of this spiritual power of the Antichrist is therefore only too natural, and it truly takes the prayers of a whole diocese and the universal Church to resist it.”

The biography, issued by Munich-based publisher Droemer Knaur, is available only in German. An English translation, “Benedict XVI, The Biography: Volume One,” will be published in the U.S. on Nov. 17.

In the interview, the 93-year-old former pope confirmed that he had written a spiritual testament, which could be published after his death, as did Pope St. John Paul II.

Benedict said that he had fast-tracked the cause of John Paul II because of “the obvious desire of the faithful” as well as the example of the Polish pope, with whom he had worked closely for more than two decades in Rome.

He insisted that his resignation had “absolutely nothing” to do with the episode involving Paolo Gabriele, and explained that his 2010 visit to the tomb of Celestine V, the last pope to resign before Benedict XVI, was “rather coincidental.” He also defended the title “emeritus” for a retired pope.

Benedict XVI lamented the reaction to his various public comments since his resignation, citing criticism of his tribute read at the funeral of Cardinal Joachim Meisner in 2017, in which he said that God would prevent the ship of the Church from capsizing. He explained that his words were “taken almost literally from the sermons of St. Gregory the Great.”

Seewald asked the pope emeritus to comment on the “dubia” submitted by four cardinals, including Cardinal Meisner, to Pope Francis in 2016 regarding the interpretation of his apostolic exhortation Amoris laetitia.

Benedict said that he did not want to comment directly, but referred to his last general audience, on Feb. 27, 2013.

Summing up his message that day, he  said: “In the Church, amid all the toils of humanity and the confusing power of the evil spirit, one will always be able to discern the subtle power of God's goodness.”

“But the darkness of successive historical periods will never allow the unadulterated joy of being a Christian ... There are always moments in the Church and in the life of the individual Christian in which one feels profoundly that the Lord loves us, and this love is joy, is ‘happiness’.”

Benedict said that he treasured the memory of his first meeting with the newly elected Pope Francis at Castel Gandolfo and that his personal friendship with his successor has continued to grow.

Author Peter Seewald has conducted four book-length interviews with Benedict XVI. The first, “Salt of the Earth,” was published in 1997, when the future pope was prefect of the Vatican Congregation for the Doctrine of the Faith. It was followed by “God and the World” in 2002, and “Light of the World” in 2010.

In 2016, Seewald published “Last Testament,” in which Benedict XVI reflected on his decision to step down as pope.

Publisher Droemer Knaur said that Seewald had spent many hours talking to Benedict for the new book, as well as speaking to his brother, Msgr. Georg Ratzinger and his personal secretary, Archbishop Georg Gänswein.

In an interview with Die Tagespost April 30, Seewald said that he had shown the Pope Emeritus a few chapters of the book before publication. Benedict XVI, he added, had praised the chapter on Pope Pius XI’s 1937 encyclical Mit brennender Sorge.
 

 

GREAT news. I think. Glasgow is a great place in which to be looking for love, with 44 per cent of the city single, according to an online dating company.Why does this matter? Flash back to Valentine’s Day. There I was, lying in a pool of poetical blood, having been shot in the heart with the killer question no single man over a certain age wants to hear: “How many Valentine’s cards did you get?” asked a friend.

One of the loveliest towns in Italy is the walled city of San Gimignano, an hour’s drive from Florence. When I first visited it was bleak midwinter and all but a few shops and cafes were shuttered against the sleet. Its claim to fame is a profusion of medieval towers, hence its hyperbolic label as the Manhattan of Tuscany. When I arrived these fortresses soared overhead, making shadowy streets even darker.

GLUMNESS settles on a large part of the nation whenever the subject of comedy comes up now. The lockdown has led to a more frenetic search for entertainment, and the current state of humour hasn’t wanted for critics. This week, Royle Family star Ricky Tomlinson, 80, said it was dire, and listed several comedians, adding: “They should be done under the Trade Description Act.”

40 groups will band together to push principles for "modernizing and elevating" teaching, but many of the groups have contrasting agendas.

Two UK models predict the risk of mortality in very preterm Western infants (1) alive at onset of labor and (2) admitted for neonatal intensive care. Prognostic models need temporal and geographic validation to evaluate their performance.

The 2 models showed very good performance in a recent large cohort of very preterm infants born in another Western country. The accurate performance of both models suggests application in clinical practice (Read the full article)

Delayed umbilical cord clamping in premature infants has been associated with decreased rates of intraventricular hemorrhage; however, the mechanisms that explain this finding have not been described.

Premature infants with delayed umbilical cord clamping have improved superior vena cava blood flow over the first days of life. This may provide one of the mechanism(s) by which this technique reduces the incidence in intraventricular hemorrhage in this at-risk population. (Read the full article)

Neglect cases in Child Protective Services often receive home-based interventions, but their success in preventing maltreatment recidivism has been elusive. Structured, behavioral skills models, such as SafeCare, are promising but have not been tested in full-scale implementation trials.

This cluster trial experiment demonstrates significant maltreatment recidivism reduction due to implementing the SafeCare model in a fully scaled-up statewide system. The findings support adopting the SafeCare model for these types of services. (Read the full article)

Febrile infants in the first 90 days may have life-threatening serious bacterial infection. Well-appearing febrile infants with serious bacterial infections cannot be distinguished from those without by examination alone. Variation in care resulting in both undertreatment and overtreatment is common.

The systemwide implementation of an evidence-based care process model for the care of febrile infants in Intermountain Healthcare was associated with increased delivery of evidence-based care, improved infant outcomes, and lower costs. This model adopted nationally can improve value. (Read the full article)

Moderately preterm-born children (32–35^6/7 weeks’ gestation) are at risk for both neonatal morbidities after birth and developmental delays in early childhood. It is unknown whether neonatal morbidities contribute to the developmental delays of this particular group.

Of all neonatal morbidities commonly seen in moderately preterm-born children, only hypoglycemia increased the risk of developmental delay after moderately preterm birth. A concerted effort to prevent hypoglycemia after birth might enhance developmental outcome in this group. (Read the full article)

Adolescents living in lower-poverty neighborhoods have better mental health than youth in high-poverty contexts, but it is unclear if associations are causal. Furthermore, it is unknown why some youth benefit more than others from moving to more advantaged neighborhoods.

Using an experimental study that randomly assigned families to receive vouchers to move to lower-poverty neighborhoods, we found that recent violent crime victimization adversely modified the mental health effects of moving to better neighborhoods. (Read the full article)

First drink before age 15 greatly increases the likelihood for later alcohol abuse or dependence. Separate investigations have linked many variables to alcohol initiation, but few have attempted to identify the optimal combination of predictors for age of alcohol initiation.

This article supports the screening questions selected in the joint National Institute on Alcohol Abuse and Alcoholism and the American Academy of Pediatrics initiative to identify and initiate intervention in youth at risk for early use of alcohol. (Read the full article)

Children have been shown to imitate behaviors they see on screen.

Modifying what children watch can improve their observed behavior. (Read the full article)

Early detection for children with autism leads to better outcomes; early screening is critical. The Modified Checklist for Autism in Toddlers (M-CHAT) is a widely used instrument for early autism screening and is recommended by the American Academy of Pediatrics.

This large study provides empirical support for population screening for autism spectrum disorders and the use of the M-CHAT in primary care settings. This study provides updated results to facilitate use and scoring of the M-CHAT by clinical providers. (Read the full article)

Global health is of increasing interest and relevance to North American pediatric trainees. Opportunities for resident global health training and exposure are most often limited to electives or trainees in dedicated global health tracks.

A series of short, structured, participatory global child health modules improved knowledge and were well received and integrated within academic programs. Such modules enable global health learning for all residents, including those who never intend to practice overseas. (Read the full article)

Screening for autism spectrum disorders (ASDs) using the Modified Checklist for Autism in Toddlers (M-CHAT) improves early detection and long-term prognosis of ASD. Reducing the false-positive rate may increase implementation of screening for ASDs.

The Modified Checklist for Autism in Toddlers, Revised with Follow-up (M-CHAT-R/F), simplifies wording of the original M-CHAT. The current validation study indicates that the M-CHAT-R/F improves the ability to detect autism spectrum disorders in toddlers screened during well-child care visits. (Read the full article)

The American Academy of Pediatrics (AAP) and other organizations have recommended critical congenital heart disease (CCHD) pulse oximetry screening. Small studies have revealed lower saturations at higher altitude, but this effect on CCHD screening is unknown. The AAP requested additional studies at altitude to help clarify the dilemma.

The AAP has endorsed higher-altitude studies of CCHD screening. This observational prospective study revealed a higher positive screen rate at moderate altitude than at sea level. These findings suggest that current national recommendations may result in increased screening failures at moderate altitude. (Read the full article)

Concussions in youth are a common injury evaluated in the emergency department (ED). Early recognition and active management of this mild traumatic brain injury are important to safe recovery. Tools to assess and manage concussion in the ED are lacking.

Acute Concussion Evaluation tools, modified for ED use, improved reported follow-up with primary care or concussion specialists and adherence to recommendations. Barriers to follow-up remain and the importance of ongoing outpatient management should be stressed. (Read the full article)

Children born late and moderately preterm are at increased risk of developmental problems compared with term-born peers. Screening for developmental problems in the early years may thus aid in the early identification of children at risk for adverse outcomes.

The Parent Report of Children’s Abilities-Revised has good concurrent validity and 90% sensitivity and 76% specificity for identifying moderate/severe cognitive developmental delay in infants born late and moderately preterm. This parent questionnaire may be used as a clinical screening tool. (Read the full article)

Several studies have revealed an association between cesarean section (CS) and childhood type 1 diabetes. Most of these studies lacked important information on indication for CS and induction of labor. It is unknown whether the reported associations are causal.

Using a cohort of 2.6 million children we found an association between elective CS and type 1 diabetes. The sibling analysis suggested the association is not causal. The findings are crucial evidence to advise women on mode of delivery choice. (Read the full article)

The incidence of cerebral palsy is dependent on the gestational age in very preterm infants and risk factors have been identified for term infants. The risk has also proved to be greater among late preterm births compared with term.

The incidence of cerebral palsy was 24-fold in moderately preterm and 6-fold in late preterm infants compared with full-term infants. The most prominent risk factors included asphyxia and intracranial hemorrhage. The incidence diminished over time and with increasing gestational age. (Read the full article)

Parental depression is associated with adverse child outcomes. It is important to understand possible mediators and moderators. Several studies suggest that the family environment or parenting style may be potential pathways for transmission of risk from parents to children.

Paternal depression appears to exert its influence on children’s outcomes through an effect on family functioning (couple conflict and maternal depression), whereas maternal postnatal depression appears to affect children through other mechanisms, potentially including direct mother-infant interaction and care. (Read the full article)

The number of nurse practitioner graduates in the United States has nearly doubled over the past 2 decades. However, the number of pediatric nurse practitioner (PNP) graduates has remained relatively flat, although the demand for PNPs is expected to increase.

This study estimates the best-case shortage of PNPs over the next 25 years. We propose possible policy interventions to address key areas of the PNP workforce system and we compute their impact on the forecasted PNP shortage. (Read the full article)

There is growing evidence reporting that moderately preterm, late preterm, and early term infants are at increased risk of developmental delay. The characteristics of this association are not well established in the literature.

In a sample of infants born between 32 and 41 weeks, there was an inverse and "dose response" relationship between gestational age and developmental delay risk using the ASQ at 8 and 18 months of corrected postnatal age. (Read the full article)

Concern of the risk of malignancy from ionizing radiation has prompted many to advocate for judicious use of computed tomography (CT) and as low as necessary radiation doses administered per scan. Recent analysis has shown a decline in CT utilization.

We identified decreases in CT utilization between 2004 and 2012 for the 10 most common diagnostic groups receiving CT. Decreases were typically associated with increases in alternate imaging modalities. We provide a possible reason for the decrease in CT utilization. (Read the full article)

Guidelines for postdischarge monitoring of hyperbilirubinemia for neonates of white descent are available from the American Academy of Pediatrics; however, such information for healthy term and late preterm Chinese neonates is lacking.

A classification model for predicting the risk of significant hyperbilirubinemia in Chinese neonates was developed that combines a transcutaneous bilirubin–based nomogram with clinical risk factors. It classified newborns into 6 risk groups, which can guide clinicians in planning appropriate follow-up strategies. (Read the full article)

Source: www.letfreedomringblog.com - Saturday, May 09, 2020
John Solomon has worked overtime and then some to rip Adam Schiff’s mask off. So have Catherine Herridge, Sara Carter, Lee Smith, Gregg Jarrett, Kim Strassel, Mollie Hemmingway and Byron York. Solomon’s article highlights how utterly dishonest Adam Schiff is. Ditto with the upper echelon of the FBI. Strap yourself in. This isn’t a short ride. The pursuit of the truth ended Thursday when the Justice Department formally asked a court to vacate Flynn’s conviction and end the criminal case, acknowledging the former general had indeed been cleared by FBI agents and that the bureau did not have a lawful purpose when it interviewed him in January 2017. Attorney General William Barr put it more bluntly in an interview Thursday : “They kept it open for the express purpose of trying to catch, to lay a perjury trap for General Flynn.” According to Solomon’s reporting, the FBI didn’t have a reason to investigate Gen. Flynn: 3. Case closed memo. FBI agents wrote a memo to close the investigation of Flynn on Jan. 4, 2017, writing they found “no derogatory” evidence that Flynn committed a crime or posed a national security threat. FBI management then ordered the closure to be rescinded and pivoted toward trying lure Flynn into an interview. https://justthenews.com/accountability/russia-and-ukraine-scandals/fbi-found-no-derogatory-russia-evidence-flynn-planned Corrupt FBI agent Peter Strzok allegedly ordered Crossfire Razor, the codename for th

Texas has become the first state to have its "alternate assessment aligned to modified academic-achievement standards" pass the U.S. Department of Education's peer-review process.

This article, published ahead of print on 28 July 2008, has been withdrawn by the authors. Although moderate synergy between P2-RANTES and C peptides can be observed with high statistical significance in cell fusion assays, this synergy was not able to be verified in HIV viral assays. The authors regret the overstatement of synergy and will revise the paper for publication at a later date.

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.

Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo β-lactamase (MBL) families. The recent introduction of SBL carbapenemase-inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n=234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ~30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modelling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor, capable of operating in a functional space not presently filled by any clinically approved compound.

Telacebec (Q203) is a new anti-tubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture-negative in 2 weeks. Combining Q203 with rifampin resulted in relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF+clarithromycin, the current standard of care, for 4 weeks.

The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2-10 mg/kg were culture-negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2 and 10 mg/kg were culture-negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics sub-study revealed that Q203 doses of 2-10 mg/kg in mice produce plasma concentrations similar to those produced by 100-300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations.

These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for cure to ≤ 1 week (or 5 doses of 2-10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.

Background. CLSI and EUCAST susceptibility breakpoints for voriconazole and C. albicans differ by one dilution (≤0.125 and ≤0.06 mg/l, respectively) whereas the epidemiological cutoff values (ECOFF/ECV) with both methodologies are the same (0.03 mg/L). We therefore determined the pharmacokinetic-pharmacodynamic (PK/PD) breakpoints of voriconazole against C. albicans for both methodologies with an in vitro PK/PD model, which was validated using existing animal PK/PD data.

Methods. Four clinical wild-type and non-wild-type C. albicans isolates (voriconazole MICs 0.008-0.125 mg/l) were tested in an in vitro PK/PD model. For validation purposes, mouse PK were simulated and in vitro PD were compared with in vivo outcome. Human PK were simulated and the exposure-effect relationship fAUC_0-24/MIC was described for EUCAST and CLSI24/48h methods. PK/PD breakpoints were determined using the fAUC_0-24/MIC associated with half-maximal activity (EI₅₀) and Monte Carlo simulation analysis.

Results. The in vitro 24h-PD EI₅₀ of voriconazole against C. albicans were 2.5-5 (1.5-17) fAUC/MIC. However, the 72h-PD were higher, 133 (51-347) fAUC/MIC for EUCAST and 94 (35-252) fAUC/MIC for CLSI. The mean (95% confidence interval) probability of target attainment (PTA) was 100(95-100)%, 97(72-100)%, 83(35-99)%, and 49(8-91)% and 100(97-100)%, 99(85-100)%, 91(52-100)% and 68(17-96)% for EUCAST and CLSI MICs 0.03, 0.06, 0.125, and 0.25 mg/L, respectively. Significantly, >95% PTAs were found for EUCAST/CLSI MICs ≤0.03 mg/ll. For MICs 0.06-0.125 mg/l trough levels 1-4 mg/ll would be required.

Conclusion. A PK/PD breakpoint of C. albicans voriconazole at the ECOFF/ECV of 0.03 mg/L was determined for both EUCAST/CLSI methods, indicating the need for breakpoint harmonization for the reference methodologies.

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.

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

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.

There are limited treatment options for enterococcal urinary tract infections, especially vancomycin-resistant Enterococcus (VRE). Oral fosfomycin is a potential option, although limited data are available guiding dosing and susceptibility. We undertook pharmacodynamic profiling of fosfomycin against E. faecalis and E. faecium isolates using a dynamic in vitro bladder infection model. Eighty-four isolates underwent fosfomycin agar dilution susceptibility testing (E. faecalis MIC_50/90 32/64 μg/mL; E. faecium MIC_50/90 64/128 μg/mL). Sixteen isolates (including E. faecalis ATCC 29212 and E. faecium ATCC 35667) were chosen to reflect the MIC range and tested in the bladder infection model with synthetic human urine (SHU). Under drug-free conditions, E. faecium demonstrated greater growth restriction in SHU compared to E. faecalis (E. faecium maximal growth 5.8 ± 0.6 log₁₀ CFU/mL; E. faecalis 8.0 ± 1.0 log₁₀ CFU/mL). Isolates were exposed to high and low fosfomycin urinary concentrations after a single dose, and two-doses given daily with low urinary exposure. Simulated concentrations closely matched the target (bias 2.3%). E. faecalis isolates required greater fosfomycin exposure for 3 log₁₀ kill from the starting inoculum compared with E. faecium. The fAUC_0-72/MIC and f%T > MIC_0-72 for E. faecalis was 672 and 70%, compared to 216 and 51% for E. faecium, respectively. There was no rise in fosfomycin MIC post-exposure. Two doses of fosfomycin with low urinary concentrations resulted in equivalent growth inhibition to a single dose with high urinary concentrations. With this urinary exposure, fosfomycin was effective in promoting suppression of regrowth (>3 log₁₀ kill) in the majority of isolates.

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.

Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-hour dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five clinical H. influenzae isolates. These five isolates, which had MIC values of 1 or 2 mg/L, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log₁₀ colony forming units (CFU) from baseline at 24 hours and total-drug ELF AUC/MIC ratio for each isolate and the isolates pooled together were evaluated using Hill-type models and non-linear least squares regression. As evidenced by the high coefficient of determination (r²) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled together. The median total-drug ELF AUC/MIC ratio associated with net bacterial stasis and 1- and 2-log₁₀ CFU/mL reductions from baseline at 24 hours was 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.

Attention has been paid to H5N6 highly pathogenic avian influenza virus (HPAIV) because of its heavy burden on the poultry industry and human mortality. Since an influenza A virus carrying N6 neuraminidase (NA) has never spread in humans, the potential for H5N6 HPAIV to cause disease in humans and the efficacy of antiviral drugs against the virus need to be urgently assessed. We used non-human primates to elucidate the pathogenesis of H5N6 HPAIV as well as to determine the efficacy of antiviral drugs against the virus. H5N6 HPAIV infection led to high fever in cynomolgus macaques. The lung injury caused by the virus was severe with diffuse alveolar damage and neutrophil infiltration. In addition, an increase in IFN-α showed an inverse correlation with virus titers during the infection process. Oseltamivir was effective for reducing H5N6 HPAIV propagation, and continuous treatment with peramivir reduced virus propagation and severity of symptoms in the early stage. This study also showed the pathologically severe lung injury states in the cynomolgus macaques infected with H5N6 HPAIV, even in those that received early antiviral drug treatments, indicating the need for close monitoring and the need for further studies on the virus pathogenicity and new antiviral therapies.

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.

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

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

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

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

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