MPLAB PICkit4 In-Circuit Debugger User's Guide

MPLAB PICkit 4 In-Circuit Debugger Quick Start Guide

You may have noticed that MATLAB Mobile now sports a different UI. For this post, I’d like to welcome Geeta Sonigra, our User Experience designer to talk about what’s changed. ... read more >>

Due to the global COVID-19 pandemic, engineers and scientists are finding themselves suddenly working from home or other remote locations. We’d like to help you continue to use MATLAB and Simulink productively. We hope this brief collection of resources will help you access MATLAB, collaborate and connect with others, and... read more >>

The Philippines’ Department of Health (DOH), with support from ADB, has set up a new laboratory in Pampanga province, north of the capital Manila. It will significantly increase the government’s testing capacity for COVID-19...

MPLAB XC Compiler Functional Safety Manual

SST and SK hynix system ic Partner to Expand Availability of Embedded SuperFlash Technology

MPLAB Connect Configurator V2.3.9

MPLAB XC8-AVR v2.20 GCC Source

MPLAB XC8 ReadMe

MPLAB XC8 ReadMe for AVR

AN3401 - Using Microchip I2C EERAMs with MPLAB X and MPLAB Code Configurator

Stamford, CT – May 5, 2020–JBL is now offering its first portable Bluetooth speaker made of recyclable plastic and packaging with the new Flip 5 - Eco edition. The popular Bluetooth speaker is back with the same superb sound and cool tech as before -...

AUTO CHINA 2014, BEIJING -- Harman International Industries, Inc. (NYSE:HAR), the premium global audio and infotainment group, announced today it has entered into an agreement with China’s Tsinghua University to establish a new joint research laboratory focused on creating disruptive innovations for future vehicles.

CES 2015, LAS VEGAS – HARMAN, the premium global audio, visual, infotainment and enterprise automation group (NYSE:HAR), announced today that its Clari-Fi™ music restoration technology has been ported to the Cirrus Logic Smart Codec platform.

GENEVA MOTOR SHOW 2015 – HARMAN, the premium global audio, visual, infotainment and enterprise automation group (NYSE:HAR), will demo its expanded scalable embedded infotainment platform at the Geneva International Motor Show. The offering addresses the full spectrum of vehicle segments, including entry- to mid-level cars, with a feature-rich, automotive-grade platform that leverages the latest smartphone integration technologies such as Apple CarPlay, Android Auto™ and MirrorLink for best-in-class connectivity for the world’s automakers.

Former British Prime Minister Tony Blair argued that the two major UK parties, Conservative and Labour, are 'peddling fantasies' ahead of the upcoming election.

STAMFORD, Conn. –  SEPTEMBER 26, 2019 – HARMAN International, a wholly-owned subsidiary of Samsung Electronics Co., Ltd., focused on connected technologies for automotive, consumer and enterprise markets, today announced a new automotive partnership with...

CES 2020 – LAS VEGAS, Nev. – January 6, 2020 – HARMAN, a wholly-owned subsidiary of Samsung Electronics Co. Ltd., focused on connected technologies for automotive, consumer and enterprise markets, today launched the HARMAN Ignite Marketplace, an...

Forget fake steaks, the first cultured meat we're likely to eat will be shrimp. How will it compare to the real thing? Will it be better for the environment? And will people eat it?

Title: Lab Mice Stressed Out By Men, But Not Women, Study Finds
Category: Health News
Created: 4/28/2014 2:35:00 PM
Last Editorial Review: 4/29/2014 12:00:00 AM

Title: Induced Labor May Lower Risk for C-Section, Study Finds
Category: Health News
Created: 4/28/2014 12:35:00 PM
Last Editorial Review: 4/29/2014 12:00:00 AM

Title: FDA Puts Tough Warning Label on Ambien, Lunesta, Other Sleep Aids
Category: Health News
Created: 4/30/2019 12:00:00 AM
Last Editorial Review: 5/1/2019 12:00:00 AM

Title: How to Understand New Food Labels
Category: Health News
Created: 3/11/2020 12:00:00 AM
Last Editorial Review: 3/12/2020 12:00:00 AM

JATS-Con is a conference for users of the Journal Article Tag Suite, that is, users of any of the "NLM DTDs" or NISO Z39.96. JATS-Con will take place on the NIH campus in Bethesda, Maryland on October 22 and 23, 2013.

The full program is now available, as are proceedings from previous years.

There is no charge for the conference; however, space is limited so registration is required.

You may also sign up for a pre-conference tutorial on October 21, 2013. Details are on the Tutorial Registration page.

PMC is happy to announce the addition of a citation exporter feature. This feature makes it easy to retrieve either styled citations that you can copy/paste into your manuscripts, or to download them into a format compatible with your bibliographic reference manager software.

When viewing an Entrez search results page, each result summary will now include a "Citation" link. When, clicked, this will open a pop-up window that you can use to easily copy/paste citations formatted in one of three popular styles: AMA (American Medical Association), MLA (Modern Language Association), or APA (American Psychological Association). In addition, the box has links at the bottom that can be used to download the citation information in one of three machine-readable formats, which most bibliographic reference management software can import.

The same citation box can also be invoked from an individual article, either in classic view (with the "Citation" link among the list of formats) or the PubReader view, by clicking on the citation information just below the article title in the banner.

These human-readable styled citations, and machine-readable formats, will be available through a public API, and we will be providing more details about that in another announcement, on the pmc-utils-announce mailing list. Please subscribe to that list if you are interested.

In order to facilitate text and data mining for articles in the Open Access Subset, we are now providing plain text files for those articles on our FTP site. These files contain the full text of the article, extracted either from the XML source files, or (for those articles that don't have XML) the PDF files. Users are directly and solely responsible for compliance with copyright restrictions and are expected to adhere to the terms and conditions defined by the copyright holder (see the PMC Copyright Notice).

These text files are bundled in gzipped archives. Note that these files are quite large (each greater than one gigabyte). They are available for download as:

• ftp://ftp.ncbi.nlm.nih.gov/pub/pmc/articles.txt.0-9A-B.tar.gz
• ftp://ftp.ncbi.nlm.nih.gov/pub/pmc/articles.txt.C-H.tar.gz
• ftp://ftp.ncbi.nlm.nih.gov/pub/pmc/articles.txt.I-N.tar.gz
• ftp://ftp.ncbi.nlm.nih.gov/pub/pmc/articles.txt.O-Z.tar.gz

These files are updated every week, on Saturday.

For more information, see the Bulk Packages of OA Articles section of our FTP Service page.

PMC includes some journals published by US government agencies that make their articles available under a Creative Commons CC0 (public domain) license. Some other journals also apply a CC0 license to selected articles in PMC. All these articles may be used and reproduced without special permission. However, anyone using the material is requested to properly cite and acknowledge the source.

You may now search for CC0 articles by using special filters in both PMC (cc0 license[filter]) and PubMed (pmc cc0 license[filter]). These filters are based on license information that is provided to PMC by publishers and encoded as machine-readable identifiers in the source XML of each article. For more information, see the Open Access Subset page.

Please bear in mind that these articles, although made available under a CC0 license, may still contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

NIH-supported scientists have made over 300,000 author manuscripts available in PMC. Now NIH is making these papers accessible to the public in a format that will allow robust text analyses.

You can download the PMC collection of NIH-supported author manuscripts as a package in either XML or plain-text format at ftp://ftp.ncbi.nlm.nih.gov/pub/pmc/manuscript/. The collection encompasses all NIH manuscripts posted to PMC that were published in July 2008 or later. While the public can access the manuscripts’ full text and accompanying figures, tables, and multimedia via the PMC website, the newly available XML and plain-text files include full text only. In addition to text mining, the files may be used consistent with the principles of fair use under copyright law.

Please note that these author manuscript files are not part of the PMC Open Access Subset.

The NIH Office of Extramural Research developed this resource to increase the impact of NIH funding. Through this collection, scientists will be able to analyze these manuscripts, further apply NIH research findings, and generate new discoveries.

For more information, please visit the PMC author manuscript collection webpage.

Peer review documents, including review reports and editor decision letters, are increasingly being published along with the articles they review. This practice is intended to make the publishing process more transparent. To support these efforts, PMC’s Tagging Guidelines have been updated to include the tagging of peer review documents. NLM encourages PMC-participating publishers, journals, and data providers to review this guidance. Please contact us at pubmedcentral@ncbi.nlm.nih.gov if you have any questions.

On March 13, 2020, the National Science and Technology Advisors from a dozen countries, including the United States, called on publishers to voluntarily agree to make their COVID-19 and coronavirus-related publications and associated data immediately accessible in PubMed Central (PMC) and other appropriate public repositories to support the ongoing public health emergency response efforts.

For more information on which publishers have responded to this call and how to discover COVID-19 and coronavirus-related publications in PMC, see the main COVID-19 Initiative page.

A FAQ is also available. If you have questions not addressed in the FAQ, please contact pmc-phe@ncbi.nlm.nih.gov.

You can learn more about how this initiative fits into the wider NLM response to the current public health emergency in Dr. Patti Brennan's post, "How Does a Library Respond to a Global Crisis?"

Title: Don't Use Pricey New HIV PrEP Drug When Generics Available: Study
Category: Health News
Created: 3/9/2020 12:00:00 AM
Last Editorial Review: 3/10/2020 12:00:00 AM

Title: When Booze Labels Carry Health Warnings, Drinking Declines: Study
Category: Health News
Created: 5/4/2020 12:00:00 AM
Last Editorial Review: 5/4/2020 12:00:00 AM

Gastrointestinal stromal tumor (GIST), the most common sarcoma, is characterized by KIT protein overexpression, and tumors are frequently driven by oncogenic KIT mutations. Targeted inhibition of KIT revolutionized GIST therapy and ushered in the era of precision medicine for the treatment of solid malignancies. Here, we present the first use of a KIT-specific DNA aptamer for targeted labeling of GIST. We found that an anti-KIT DNA aptamer bound cells in a KIT-dependent manner and was highly specific for GIST cell labeling in vitro. Functionally, the KIT aptamer bound extracellular KIT in a manner similar to KIT mAb staining, and was trafficked intracellularly in vitro. The KIT aptamer bound dissociated primary human GIST cells in a mutation agnostic manner such that tumors with KIT and PDGFRA mutations were labeled. In addition, the KIT aptamer specifically labeled intact human GIST tissue ex vivo, as well as peritoneal xenografts in mice with high sensitivity. These results represent the first use of an aptamer-based method for targeted detection of GIST in vitro and in vivo.

Dental students’ ability to critique team performance in dental school team clinics is a key component of dental education. The aim of this study was to determine if students’ perceptions of their team leaders’ openness of communication, cooperative decision making, and well-defined goals were positively related to the students’ improvement-oriented voice behavior and willingness to raise concerns in the clinical environment. This study used a voluntary 12-question survey, distributed via email to all 311 students at the University of Nevada, Las Vegas School of Dental Medicine after completion of the spring 2017 semester. Eighty-seven students responded, for a response rate of 28%. Responses were stratified by team, class year, and gender, and the quantitative distribution of answers to each question was correlated with each other. Team leader collaborative qualities, which included openness for communication, cooperative decision making, and well-defined goals, were found to have a significant positive relationship with students’ willingness to both raise concerns and make suggestions. Additionally, when measured by class year and gender, team differences in voice behavior assessment by students across the teams were found to be independent of class year, and no significant differences were found by gender. These results suggested that, to maintain high levels of communication, proper reporting of concerns, and a high standard of care, dental schools should encourage team leaders to enhance their capacity to present active collaborative behaviors in the school’s clinic. The study also highlighted potential opportunities for further study of faculty traits and development in the dental school team model.

ABSTRACT

Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; however, the contributions of disease modifiers remain underappreciated. We exploited the Collaborative Cross (CC) mouse genetic-reference population to map genetic modifiers that affect the severity of Pseudomonas aeruginosa lung infection. Screening for P. aeruginosa respiratory infection in a cohort of 39 CC lines exhibits distinct disease phenotypes ranging from complete resistance to lethal disease. Based on major changes in the survival times, a quantitative-trait locus (QTL) was mapped on murine chromosome 3 to the genomic interval of Mb 110.4 to 120.5. Within this locus, composed of 31 protein-coding genes, two candidate genes, namely, dihydropyrimidine dehydrogenase (Dpyd) and sphingosine-1-phosphate receptor 1 (S1pr1), were identified according to the level of genome-wide significance and disease gene prioritization. Functional validation of the S1pr1 gene by pharmacological targeting in C57BL/6NCrl mice confirmed its relevance in P. aeruginosa pathophysiology. However, in a cohort of Canadian patients with cystic fibrosis (CF) disease, regional genetic-association analysis of the syntenic human locus on chromosome 1 (Mb 97.0 to 105.0) identified two single-nucleotide polymorphisms (rs10875080 and rs11582736) annotated to the Dpyd gene that were significantly associated with age at first P. aeruginosa infection. Thus, there is evidence that both genes might be implicated in this disease. Our results demonstrate that the discovery of murine modifier loci may generate information that is relevant to human disease progression.

IMPORTANCE Respiratory infection caused by P. aeruginosa is one of the most critical health burdens worldwide. People affected by P. aeruginosa infection include patients with a weakened immune system, such as those with cystic fibrosis (CF) genetic disease or non-CF bronchiectasis. Disease outcomes range from fatal pneumonia to chronic life-threatening infection and inflammation leading to the progressive deterioration of pulmonary function. The development of these respiratory infections is mediated by multiple causes. However, the genetic factors underlying infection susceptibility are poorly known and difficult to predict. Our study employed novel approaches and improved mouse disease models to identify genetic modifiers that affect the severity of P. aeruginosa lung infection. We identified candidate genes to enhance our understanding of P. aeruginosa infection in humans and provide a proof of concept that could be exploited for other human pathologies mediated by bacterial infection.

The past 20 years have seen major advances in the understanding and treatment of pulmonary arterial hypertension (PAH; group 1 of the pulmonary hypertension (PH) clinical classification) [1]. A strong basis of knowledge has been acquired in: 1) large randomised clinical trials for drug development; 2) national registries for epidemiology and outcome; and 3) smaller studies on the pathophysiological mechanisms of the disease. This knowledge has been reviewed at World Symposia on Pulmonary Hypertension (the most recent in 2018 [2]) and summarised in European Respiratory Society (ERS)/European Society of Cardiology (ESC) clinical guidelines (the most recent in 2015 [3, 4]). We are, however, much less knowledgeable on specific aspects such as 1) the implementation of guidelines and access to therapies in different European countries; 2) the management of PH crises and progressive (acute on chronic) heart failure; and 3) other groups of PH, such as PH due to lung diseases. Therapeutic strategies also need to be optimised, in particular regarding the combination of drugs, the use of anticoagulants, the place for new medications targeting different pathophysiological pathways, etc.

Noemie Liesch and Friedrich Ladich

In vocal fish species, males possess larger sound-generating organs and signal acoustically with pronounced sex-specific differences. Sound production is known in two out of three species of croaking gouramis (Trichopsis vittata and T. schalleri). The present study investigates sex-specific differences in sonic organs, vocalizing behaviour and sounds emitted in the third species, the pygmy gourami T. pumila, in order to test the hypothesis that females are able to vocalize despite their less-developed sonic organs, and despite contradictory reports. Croaking gouramis stretch and pluck two enhanced (sonic) pectoral fin tendons during alternate fin beating, resulting in a series of double-pulsed bursts termed croaking sound. We measured the diameter of the first and second sonic tendon and showed that male tendons were twice as large as in same-sized females. We also determined the duration of dyadic contests, visual displays, number of sounds and buttings. Sexes differ in all sound characteristics but in no behavioural variable. Male sounds consisted of twice as many bursts, a higher percentage of double-pulsed bursts and a higher burst period. Additionally, male sounds had a lower dominant frequency and a higher sound level. In summary, female pygmy gouramis possessed sonic organs and vocalized in most dyadic contests. The sexual dimorphism in sonic tendons is clearly reflected in sex-specific differences in sound characteristics, but not in agonistic behaviour, supporting the hypothesis that females are vocal.

Reactive oxygen and nitrogen species have been implicated in many biological processes and diseases, including immune responses, cardiovascular dysfunction, neurodegeneration, and cancer. These chemical species are short-lived in biological settings, and detecting them in these conditions and diseases requires the use of molecular probes that form stable, easily detectable, products. The chemical mechanisms and limitations of many of the currently used probes are not well-understood, hampering their effective applications. Boronates have emerged as a class of probes for the detection of nucleophilic two-electron oxidants. Here, we report the results of an oxygen-18–labeling MS study to identify the origin of oxygen atoms in the oxidation products of phenylboronate targeted to mitochondria. We demonstrate that boronate oxidation by hydrogen peroxide, peroxymonocarbonate, hypochlorite, or peroxynitrite involves the incorporation of oxygen atoms from these oxidants. We therefore conclude that boronates can be used as probes to track isotopically labeled oxidants. This suggests that the detection of specific products formed from these redox probes could enable precise identification of oxidants formed in biological systems. We discuss the implications of these results for understanding the mechanism of conversion of the boronate-based redox probes to oxidant-specific products.

The presence of antinuclear antibodies (ANAs) is a hallmark of a number of systemic autoimmune rheumatic diseases, and testing is usually performed as part of the initial diagnostic workup when suspicion of an underlying autoimmune disorder is high. The indirect immunofluorescence antibody (IFA) technique is the preferred method for detecting ANAs, as it demonstrates binding to specific intracellular structures within the cells, resulting in a number of staining patterns that are usually categorized based on the cellular components recognized and the degree of binding, as reflected by the fluorescence intensity or titer. As a screening tool, the ANA patterns can guide confirmatory testing useful in elucidating a specific clinical diagnosis or prognosis. However, routine use of ANA IFA testing as a global screening test is hampered by its labor-intensiveness, subjectivity, and limited diagnostic specificity, among other factors. This review focuses on current efforts to standardize the nomenclature of ANA patterns and on alternative methods for ANA determination, as well as on recent advances in image-based computer algorithms to automate IFA testing in clinical laboratories.

Current pneumococcal vaccines cover the 10 to 23 most common serotypes of the 92 presently described. However, with the increased usage of pneumococcal-serotype-based vaccines, the risk of serotype replacement and an increase in disease caused by nonvaccine serotypes remains. Serotype surveillance of pneumococcal infections relies heavily on culture techniques, which are known to be insensitive, particularly in cases of noninvasive disease. Pneumococcal-serotype-specific urine assays offer an alternative method of serotyping for both invasive and noninvasive disease. However, the assays described previously cover mainly conjugate vaccine serotypes, give little information about circulating nonvaccine serotypes, and are currently available only in one or two specialist laboratories. Our laboratory has developed a Luminex-based extended-range antigen capture assay to detect pneumococcal-serotype-specific antigens in urine samples. The assay targets 24 distinct serotypes/serogroups plus the cell wall polysaccharide (CWP) and some cross-reactive serotypes. We report that the assay is capable of detecting all the targeted serotypes and the CWP at 0.1 ng/ml, while some serotypes are detected at concentrations as low as 0.3 pg/ml. The analytical serotype specificity was determined to be 98.4% using a panel of polysaccharide-negative urine specimens spiked with nonpneumococcal bacterial antigens. We also report clinical sensitivities of 96.2% and specificities of 89.9% established using a panel of urine specimens from patients diagnosed with community-acquired pneumonia or pneumococcal disease. This assay can be extended for testing other clinical samples and has the potential to greatly improve serotype-specific surveillance in the many cases of pneumococcal disease in which a culture is never obtained.

Bovine tuberculosis (TB), caused by Mycobacterium bovis, remains an important zoonotic disease posing a serious threat to livestock and wildlife. The current TB tests relying on cell-mediated and humoral immune responses in cattle have performance limitations. To identify new serodiagnostic markers of bovine TB, we screened a panel of 101 recombinant proteins, including 10 polyepitope fusions, by a multiantigen print immunoassay (MAPIA) with well-characterized serum samples serially collected from cattle with experimental or naturally acquired M. bovis infection. A novel set of 12 seroreactive antigens was established. Evaluation of selected proteins in the dual-path platform (DPP) assay showed that the highest diagnostic accuracy (~95%) was achieved with a cocktail of five best-performing antigens, thus demonstrating the potential for development of an improved and more practical serodiagnostic test for bovine TB.

Neutralizing antibodies specific for respiratory syncytial virus (RSV) represent a major protective mechanism against RSV infection, as demonstrated by the efficacy of the immune-prophylactic monoclonal antibody palivizumab in preventing RSV-associated lower respiratory tract infections in premature infants. Accordingly, the RSV neutralization assay has become a key functional method to assess the neutralizing activity of serum antibodies in preclinical animal models, epidemiology studies, and clinical trials. In this study, we qualified a 24-h, fluorescent focus-based microneutralization (RSVA FFA-MN) method that requires no medium exchange or pre- or postinfection processing to detect green fluorescent protein-expressing RSV strain A2 (RSVA-GFP)-infected cells, using a high-content imaging system for automated image acquisition and focus enumeration. The RSVA FFA-MN method was shown to be sensitive, with a limit of detection (LOD) and limit of quantitation (LOQ) of 1:10, or 3.32 log₂; linear over a range of 4.27 to 9.65 log₂ 50% inhibitory concentration (IC₅₀); and precise, with intra- and interassay coefficients of variation of <21%. This precision allowed the choice of a statistically justified 3-fold-rise seroresponse cutoff criterion. The repeatability and robustness of this method were demonstrated by including a pooled human serum sample in every assay as a positive control (PC). Over 3 years of testing between two laboratories, this PC generated data falling within 2.5 standard deviations of the mean 98.7% of the time (n = 1,720). This high-throughput and reliable RSV microneutralization assay has proven useful for testing sera from preclinical vaccine candidate evaluation studies, epidemiology studies, and both pediatric and adult vaccine clinical trials.

The number of onsite clinical microbiology laboratories in hospitals is decreasing, likely related to the business model for laboratory consolidation and labor shortages, and this impacts a variety of clinical practices, including that of banking isolates for clinical or epidemiologic purposes. To determine the impact of these trends, infectious disease (ID) physicians were surveyed regarding their perceptions of offsite services. Clinical microbiology practices for retention of clinical isolates for future use were also determined. Surveys were sent to members of the Infectious Diseases Society of America’s (IDSA) Emerging Infections Network (EIN). The EIN is a sentinel network of ID physicians who care for adult and/or pediatric patients in North America and who are members of IDSA. The response rate was 763 (45%) of 1,680 potential respondents. Five hundred forty (81%) respondents reported interacting with the clinical microbiology laboratory. Eighty-six percent of respondents thought an onsite laboratory very important for timely diagnostic reporting and ongoing communication with the clinical microbiologist. Thirty-five percent practiced in institutions where the core microbiology laboratory has been moved offsite, and an additional 7% (n = 38) reported that movement of core laboratory functions offsite was being considered. The respondents reported that only 24% of laboratories banked all isolates, with the majority saving isolates for less than 30 days. Based on these results, the trend toward centralized core laboratories negatively impacts the practice of ID physicians, potentially delays effective implementation of prompt and targeted care for patients with serious infections, and similarly adversely impacts infection control epidemiologic investigations.

This minireview focuses on the microbiologic evaluation of patients with asymptomatic bacteriuria, as well as indications for antibiotic treatment. Asymptomatic bacteriuria is defined as two consecutive voided specimens (preferably within 2 weeks) with the same bacterial species, isolated in quantitative counts of ≥10⁵ CFU/ml in women, including pregnant women; a single voided urine specimen with one bacterial species isolated in a quantitative count ≥10⁵ CFU/ml in men; and a single catheterized urine specimen with one or more bacterial species isolated in a quantitative count of ≥10⁵ CFU/ml in either women or men (or ≥10² CFU/ml of a single bacterial species from a single catheterized urine specimen). Any urine specimen with ≥10⁴ CFU/ml group B Streptococcus is significant for asymptomatic bacteriuria in a pregnant woman. Asymptomatic bacteriuria occurs, irrespective of pyuria, in the absence of signs or symptoms of a urinary tract infection. The two groups with the best evidence of adverse outcomes in the setting of untreated asymptomatic bacteriuria include pregnant women and patients who undergo urologic procedures with risk of mucosal injury. Screening and treatment of asymptomatic bacteriuria is not recommended in the following patient populations: pediatric patients, healthy nonpregnant women, older patients in the inpatient or outpatient setting, diabetic patients, patients with an indwelling urethral catheter, patients with impaired voiding following spinal cord injury, patients undergoing nonurologic surgeries, and nonrenal solid-organ transplant recipients. Renal transplant recipients beyond 1 month posttransplant should not undergo screening and treatment for asymptomatic bacteriuria. There is insufficient evidence to recommend for or against screening of renal transplant recipients within 1 month, patients with high-risk neutropenia, or patients with indwelling catheters at the time of catheter removal. Unwarranted antibiotics place patients at increased risk of adverse effects (including Clostridioides difficile diarrhea) and contribute to antibiotic resistance. Methods to reduce unnecessary screening for and treatment of asymptomatic bacteriuria aid in antibiotic stewardship.

PF06821497 has been identified as an orally available small-molecule enhancer of zeste homolog 2 inhibitor. The objectives of the present study were to characterize pharmacokinetic-pharmacodynamic-disease relationships of PF06821497 in xenograft mouse models with diffuse large B-cell lymphoma (Karpas422). An indirect-response model reasonably fit dose-dependent pharmacodynamic responses [histone H3 on lysine 27 (H3K27) me3 inhibition] with an unbound EC₅₀ of 76 nM, whereas a signal-transduction model sufficiently fit dose-dependent disease responses (tumor growth inhibition) with an unbound tumor stasis concentration (T_sc) of 168 nM. Thus, effective concentration for 70% of maximal effect (EC₇₀) for H3K27me3 inhibition was roughly comparable to T_sc, suggesting that 70% H3K27me3 inhibition could be required for tumor stasis. Consistently, an integrated pharmacokinetic-pharmacodynamic-disease model adequately describing tumor growth inhibition also suggested that ~70% H3K27me3 inhibition was associated with tumor stasis. Based on these results, we would propose that an EC₇₀ estimate for H3K27me3 inhibition corresponding to tumor stasis could be considered a minimum target efficacious concentration of PF06821497 in cancer patients.

When we critically assess the reason for the current dominance of ⁶⁸Ga-labeled peptides and peptide-like ligands in radiopharmacy and nuclear medicine, we have to conclude that the major advantage of such radiopharmaceuticals is the apparent lack of suitable ¹⁸F-labeling technologies with proven clinical relevance. To prepare and to subsequently perform a clinical proof-of-concept study on the general suitability of silicon-fluoride-acceptor (SiFA)–conjugated radiopharmaceuticals, we developed inhibitors of the prostate-specific membrane antigen (PSMA) that are labeled by isotopic exchange (IE). To compensate for the pronounced lipophilicity of the SiFA unit, we used metal chelates, conjugated in close proximity to SiFA. Six different radiohybrid PSMA ligands (rhPSMA ligands) were evaluated and compared with the commonly used ¹⁸F-PSMA inhibitors ¹⁸F-DCFPyL and ¹⁸F-PSMA-1007. Methods: All inhibitors were synthesized by solid-phase peptide synthesis. Human serum albumin binding was measured by affinity high-performance liquid chromatography, whereas the lipophilicity of each tracer was determined by the n-octanol/buffer method. In vitro studies (IC₅₀, internalization) were performed on LNCaP cells. Biodistribution studies were conducted on LNCaP tumor–bearing male CB-17 SCID mice. Results: On the laboratory scale (starting activities, 0.2–9.0 GBq), labeling of ¹⁸F-rhPSMA-5 to -10 by IE was completed in < 20 min (radiochemical yields, 58% ± 9%; radiochemical purity, >97%) with molar activities of 12–60 GBq/μmol. All rhPSMAs showed low nanomolar affinity and high internalization by PSMA-expressing cells when compared with the reference radiopharmaceuticals, medium-to-low lipophilicity, and high human serum albumin binding. Biodistribution studies in LNCaP tumor–bearing mice revealed high tumor uptake, sufficiently fast clearance kinetics from blood, low hepatobiliary excretion, fast renal excretion, and very low uptake of ¹⁸F activity in bone. Conclusion: The novel ¹⁸F-rhPSMA radiopharmaceuticals developed under the radiohybrid concept show equal or better targeting characteristics than the established ¹⁸F-PSMA tracers ¹⁸F-DCFPyL and ¹⁸F-PSMA-1007. The unparalleled simplicity of production, the possibility to produce the identical ⁶⁸Ga-labeled ¹⁹F-⁶⁸Ga-rhPSMA tracers, and the possibility to extend this concept to true theranostic radiohybrid radiopharmaceuticals, such as F-Lu-rhPSMA, are unique features of these radiopharmaceuticals.