The Clinical Pharmacogenetics Implementation Consortium (CPIC) TPMT/NUDT15 Pharmacogene Curation Expert Panel (PCEP) conducted a comprehensive review of clinical, laboratory, and computational evidence to determine the clinical function assignments for TPMT and NUDT15 star alleles. These genes are critical for the metabolism of thiopurines, which are widely used in the treatment of cancer and autoimmune disorders. Standardized allele function assignment is essential for predicting metabolizer phenotypes and pharmacogenetics-guided thiopurine dosing. The work presented here includes the first designation of decreased function alleles for both TPMT and NUDT15, reflecting new clinical data that demonstrate partial loss of enzymatic activity and reduced dose tolerance. The panel also reclassified several alleles previously assigned uncertain or unknown function. The functional assignments were informed by a standardized framework incorporating clinical data, such as thiopurine tolerance and toxicity, as well as in vitro protein activity, ex vivo enzymatic measurements, and in silico variant effect prediction tools. These updates enhance the precision of genotype-to-phenotype mapping and support more personalized thiopurine therapy across diverse patient populations.
Background:Escherichia coli is a leading cause of neonatal sepsis. This study's objective was to investigate the clinical characteristics of newborns with E. coli bacteremia, and recent antibiotic resistance trends and molecular epidemiologic features of these invasive strains. Methods:Clinical data and blood E. coli isolates collected from 54 neonates with bacteremia were studied. E. coli antibiotic susceptibility trends over time, and whole-genome sequencing data relevant to the genomic relatedness and capsule genotype of the isolates were analyzed. Results:Thirty percent of bacteremic newborns were preterm. Mortality was 19% in preterm versus 5% in term infants. Cerebrospinal fluid was collected in 43 (80%); meningitis was diagnosed in 28%. Necrotizing enterocolitis occurred in 2 neonates, both born preterm. Fifty-four percent of isolates were nonsusceptible to ampicillin and 7% to ceftriaxone. Nonsusceptibility to cefazolin increased over time; non-susceptibility rates for gentamicin and tobramycin were 11% for each antibiotic. Whole-genome sequencing showed multiple sequence types (STs), of which ST95 (17%) was the most prevalent, followed by ST69 (11%), ST131 (7%), and ST12 (7%). K1 (43%) and K5 (20%) capsule genes were most prevalent. Conclusions:Mortality from E. coli sepsis remains high, especially in preterm newborns. Resistance to β-lactams and aminoglycosides, the most common empiric treatments for E. coli sepsis, is worsening. Treatment regimens against neonatal E. coli sepsis need to be tailored according to evolving antibiotic resistance trends. Neonatal sepsis isolates are characterized by specific genomic traits indicative of virulent phenotypes that need continued surveillance.
STUDY QUESTION:What updates of the International Glossary on Infertility and Fertility Care are required, to reflect contemporary scientific knowledge, social needs, and inclusive definitions, while harmonizing international communication across clinical, research, policy, and public domains? SUMMARY ANSWER:This 4th edition presents 348 consensus-based terms and definitions, including numerous revisions from the previous edition and 79 newly introduced definitions reflecting advances in reproductive science, technology, and evolving social contexts. WHAT IS KNOWN ALREADY:Previous glossary editions (2006, 2009, 2017) established internationally recognized definitions related to clinical practice, research, and policy. The 2017 edition comprised 283 terms and, among many others, expanded the concept of infertility to include not only its recognition as a disease, but also as an impairment of function generating disability. The glossary has been extensively used worldwide and has contributed to international standardization of data collection, appropriate comparison of outcome measures, and provided a reference for all stakeholders including policy makers. STUDY DESIGN, SIZE, DURATION:Under guidance of the organizing committee, 21 professionals from across the world, and representing expertise in different sub-specialties, formed five working groups: clinical definitions; outcome measures; embryology laboratory; clinical and laboratory andrology; and epidemiology, public health and gender related definitions. The definitions from the previous glossary were evaluated and new terms identified. All definitions were then reviewed by an international advisory panel of nine experts that evaluated the glossary from scientific, ethical, cultural, and policy perspectives. PARTICIPANTS/MATERIALS, SETTING, METHODS:Between November 2024 and October 2025, periodical virtual meetings were held within and between working groups and the organizing committee. Following circulation of the first consensually agreed draft, a one-day in-person meeting with representatives of all working groups and members of the international advisory panel was held at ESHRE, June 2025. Most terms and definitions were discussed and agreed. In the absence of agreement, further discussions were held between the organizing committee, working group chairs and members of the advisory panel. It had been determined at the outset that final disagreement would be resolved via a two-third majority vote. All terms and definitions were, however, reached by consensus and adopted following a final round of review and approval by all authors. MAIN RESULTS AND THE ROLE OF CHANCE:The glossary now includes 348 terms. Compared to the previous edition, 14 terms were deleted, numerous terms modified and 79 new terms were added. Modifications reflect current scientific knowledge, technological advancements, and inclusivity related to gender and family structures. Chance does not play a role, as all definitions are consensus-based. LIMITATIONS, REASONS FOR CAUTION:Some terms may require future refinement as scientific knowledge evolves and societal contexts change. The glossary reflects consensus rather than empirical testing of all definitions. WIDER IMPLICATIONS OF THE FINDINGS:This glossary provides a global reference for standardized terminology, supporting clinical care, research, international comparisons, policy making, patient communication, and reproductive health literacy. STUDY FUNDING/COMPETING INTEREST(S):Neither ICMART, responsible for conducting this project, nor any of the participants received specific financial support for their activities in this project. Ferring provided ICMART with a fixed amount to cover venue costs and a one-day hotel accommodation for participants attending the in-person meeting held prior to the ESHRE Congress in June 2025. Disclosures were provided by all authors, and none reported any conflict of interest related to this manuscript. TRIAL REGISTRATION NUMBER:N/A.
Abstract Background Respiratory viruses are a significant cause of pediatric illness and healthcare utilization. Diagnostic testing for respiratory viruses is generally performed using nasopharyngeal (NP) specimens obtained by trained medical staff, limiting testing to medical settings. Evaluating additional sampling methods in children, such as anterior nasal swab (NS) specimens may expand access to diagnostic testing and aid public health surveillance. Methods Eligible children hospitalized at Children’s Mercy Hospital in Kansas City who had a standard of care NP specimen collected for nucleic acid amplification testing for respiratory viruses were enrolled. Research NS specimens were obtained through self, caregiver, or staff collection. Specimens were tested on QIAstat-Dx-Analzyer using QIAstat-Dx Respiratory SARS-Cov-2 Panel and included: adenovirus, seasonal coronavirus (229E, HKU1, NL63, OC43), SARS-CoV-2, human metapneumovirus (hMPV) A+B, influenza A/A H1/A H3/A H1N1/pdm09, influenza B, parainfluenza virus 1/2/3/4, rhinovirus/enterovirus (RV/EV), and respiratory syncytial virus (RSV) A+B. Statistical analysis for sensitivity with 95% confidence intervals was calculated with NP as the gold standard. Further sub-analysis evaluating time to NS collection and test results (NP specimens as time zero and NS specimens grouped from 1-24 hours, 25-48 hours, and 49+ hours) was performed. Pairs with both NP and NS specimens having viruses detected or the same virus(es) detected were considered completely concordant. Specimens with multiple viruses detected on NP swab but only a single virus detected on NS swab, or vice versa, were considered partially concordant. Specimens with one virus detected on NS or NP and none detected on its pair were considered discordant. Results One hundred and forty-seven pairs, each including one NP and one NS specimen, were obtained. Of the 147 pairs, 114 (77.5%) had complete concordance – 86 (58.5%) had viruses detected and 28 (19%) had no viruses detected. Fourteen (9.5%) pairs were partially concordant, and 19 (13%) were discordant. Sensitivity of NS specimens collected within 48 hours of their NP pair was ≥80% for all viruses except seasonal coronavirus (sensitivity 42.9%) (Table 1). NS specimens for adenovirus, influenza, parainfluenza, RSV, and SARS-CoV-2 were 100% sensitive when collected within 24 hours of NP specimens. Conclusion Overall, NS are a potential alternative method for respiratory virus detection in the pediatric population. This less invasive collection method allows for broader use outside of medical settings, including respiratory virus surveillance in community settings. Future studies with closely time-matched NS and NP collection are needed to evaluate individual virus type detections.
Preeclampsia is a pregnancy disorder characterized by de novo maternal hypertension, end-organ damage, and fetal complications. It is also associated with increased long-term cardiovascular risk for both the mother and offspring. A general lack of understanding of this disease prevents effective treatment and prevention, with delivery of the fetoplacental unit being the current standard of care for severe cases. A hallmark characteristic of the maternal syndrome is endothelial dysfunction in both reproductive and nonreproductive vascular beds. As the uterine vascular bed serves as the interface between the maternal and fetal circulation, it is pivotal in the cardiovascular function of both mother and fetus. In this review, we highlight uterine artery endothelial maladaptation as a central feature of preeclampsia and discuss its anatomic, cellular, and circulating correlates.
