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Abstract Background Eligibility criteria for clinical trials are crucial for maintaining safety and study integrity. However, overly restrictive criteria can result in unrepresentative trial populations, leading to gaps in understanding real‐world treatment efficacy. Addressing potentially modifiable exclusions (PMEs) could enhance trial accessibility and participation without compromising safety. Methods The authors retrospectively analyzed screen‐failed patients with biliary tract cancer or pancreatic cancer between August 2019 and November 2024 at The University of Texas MD Anderson Cancer Center. Screen‐failed patients were those who provided informed consent but did not participate for any reason. Clinical data were obtained from screening logs and electronic health records. PMEs were identified and validated by two independent medical oncologists. Results Of 585 screen‐failed patients from 18 trials, 509 were analyzed (367 with pancreatic cancer and 142 with biliary tract cancer) after excluding 76 because of incomplete data. Leading causes of screen failure were declined participation (19%), comorbidities (12%), suboptimal organ function (11%), absence of a biomarker (10%), and insufficient biospecimens (7%). Reasons for declining included preference for standard care (23%), travel (22%), and competing trials (5%). The authors identified 69 patients (13.6%) who had PMEs (primarily borderline laboratory abnormalities), including liver function (23%), kidney function (20%), platelet count (12%), hemoglobin (7%), and white blood cell count (6%) abnormalities. Other PMEs included previous or concurrent malignancies (9%) and viral hepatitis (4%). PMEs were evenly distributed across trials. Conclusions Rigid eligibility criteria exclude stable patients who might benefit from investigational treatments. Easing criteria related to incidental or asymptomatic laboratory abnormalities could broaden trial accessibility and improve enrollment in populations that are more representative of real‐world use.

37 cases of Mycoplasma pneumoniae pneumonia were diagnosed in children in North Dakota, over 3.5 months (35 by PCR); 44% harbored macrolide-resistance. Children with macrolide-resistant M. pneumoniae had a longer period of coughing prior to diagnosis (+ 3.9 days, p=0.048), a longer duration of illness (+ 5.4 days, p=0.011) and earlier resolution of fever after initiation of doxycycline (- 0.92 days, p=0.025) compared to those without macrolide resistant M. pneumoniae.

Background: Phages are being assessed for treatment of periprosthetic joint infection (PJI). Staphylococci are the most common cause of PJI. Phages are traditionally considered to be strain-specific and restricted to specific species. We aimed to assess the in vitro activity of a collection of staphylococcal phages against a selection of clinical Staphylococcus isolates recovered from PJI over a 20-year period. Methods: The activity of 37 staphylococcal phages was evaluated against 204 staphylococcal isolates, including 102 Staphylococcus aureus, 81 Staphylococcus epidermidis , and 21 Staphylococcus lugdunensis , using a tetrazolium dye–based metabolic assay. Standardized inocula of bacteria and phage were incubated over 48 hours. Growth inhibition ≥8 hours was considered indicative of phage activity. Results: A total of 7,548 phage-isolate pairs were assessed. Overall, 31 of 37 phages had activity against at least 1 isolate. The most broadly active phage showed activity against 50 of 195 isolates (26%) tested. Twenty-three phages showed cross-species activity, with 11 phages active against all 3 Staphylococcus species, and 12 phages active against 2 species. Of all S. aureus isolates tested, 61% were susceptible to at least 1 phage, while 31% and 76% of S. epidermidis and S. lugdunensis isolates were susceptible to at least 1 phage, respectively. Conclusions: This is the largest library of phages evaluated against staphylococci from PJI. Results show that staphylococcal phages can have cross-species activity, suggesting that phage libraries may offer cross-species coverage of clinically encountered staphylococcal isolates from PJI. Level of Evidence: Level V . Mechanism-based reasoning. See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND Among antiretroviral therapy–suppressed (ART-suppressed) people with HIV (PWH), women have higher levels of some inflammatory markers than men, but the effect of sex on the inflammatory proteome, and whether age modifies these differences, remain unclear. METHODS Plasma inflammatory protein levels were assessed in ART-suppressed PWH from the Center for AIDS Research Network of Integrated Clinical Systems. The relationship between sex and plasma proteins — including 22 interferon-α response pathway proteins — was assessed, adjusting for confounders and assessing interactions by age. RESULTS Of 922 participants, 162 (18%) were female. The median age was 47, above which the majority of women had undetectable plasma anti-Müllerian hormone levels, a biomarker of ovarian reserve. Age modified the influence of sex on the inflammatory proteome. Older age (>47) was associated with greater increases among women than men in 194 proteins. Interferon-α response proteins were higher in men in those ≤ 47 but higher in women in those > 47 (interaction P < 0.001). Among the 131 proteins associated with mortality risk ( q < 0.05), only 5 differed by sex among those ≤ 47, while 79 differed by sex in those > 47, with nearly all being higher in women. Women had decreased mortality than men ≤ 47 ( P < 0.001) but had similar mortality > 47 ( P = 0.84). CONCLUSION The menopausal transition appears to increase systemic type I interferon responses and inflammation in women with HIV, which may contribute to a loss of female advantage in mortality. FUNDING NIH National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute of Allergy and Infectious Diseases.

Abstract Introduction : Current standard of care for smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), is observation until progression to active MM. Increasing evidence suggests that patients (pts) with SMM at high risk for progression to active MM may benefit from early treatment (tx). In AQUILA, a phase 3 study in pts with high-risk SMM (NCT03301220), daratumumab (Dara) monotherapy significantly reduced risk of progression to active MM or death with a trend of extending overall survival (OS) vs active monitoring (ActMon), with no new safety concerns. Given the evolution in SMM risk stratification, a post hoc analysis was performed to assess outcomes using the IMWG 2020 and IMWG 2020 plus cytogenetic risk models to assess which AQUILA pts benefited most from Dara monotherapy. Safety and efficacy analysis by age and stem cell collection outcomes were also assessed. Methods: Eligible pts with a confirmed diagnosis (≤5 y) of high-risk SMM per IMWG 2014 criteria, defined as clonal bone marrow plasma cells (BMPC) ≥10% and ≥1 risk factor (IgA SMM, serum protein ≥30 g/dL, serum involved:uninvolved free light chain [I/U FLC] ratio ≥8 and &lt;100, immunoparesis with reduction of 2 uninvolved Ig isotypes, and/or clonal BMPC &gt;50% to &lt;60%) at study entry, were randomized 1:1 to receive subcutaneous Dara or ActMon for 39 cycles, 36 months, or until confirmed disease progression (PD), whichever came first. Primary endpoint was progression-free survival (PFS) assessed by independent review committee, defined as progression to active MM (based on IMWG SLiM-CRAB diagnostic criteria) or death. Secondary endpoints included time to first-line (1L) MM tx and OS. For this post hoc analysis, we assessed outcomes by age, IMWG 2020 high-risk SMM criteria (BMPC &gt;20%, monoclonal spike &gt;2 g/dL, serum FLC ratio &gt;20; ≥2 factors=high risk; also known as the Mayo 2018 or the 20-2-20 criteria), and the IMWG 2020 plus cytogenetic criteria (IMWG 2020 criteria + presence of ≥1 high-risk cytogenetic abnormalities [t(4;14), t(14;16), +1q and/or del13q]; ≥3 factors=high risk). Results : Dara tx showed a PFS benefit across all IMWG 2020 risk subgroups (low: hazard ratio [HR], 0.59; intermediate: HR, 0.70), with the largest benefit in the high-risk subgroup, where the PD/death rate in the ActMon arm was ~1.6-fold that in the Dara arm (62.8% vs 37.5%; HR, 0.36). This benefit of Dara vs ActMon was preserved over time, with 5-year PFS rates of 78.2% vs 71.6%, 56.2% vs 42.9%, and 60.4% vs 23.6% in IMWG 2020 low-, intermediate-, and high-risk groups, respectively. There was a positive trend favoring Dara for time to 1L MM treatment across all IMWG 2020 risk groups (low-risk HR, 0.63; 95% CI, 0.22–1.80; intermediate-risk HR, 0.57; 95% CI, 0.35–0.92; high-risk HR, 0.39; 95% CI, 0.25–0.62). IMWG 2020 plus cytogenetic risk classification results will be available at the time of presentation. When comparing the younger (&lt;65y HR, 0.51; 95% CI, 0.32–0.79) vs the older (≥65y, HR, 0.50; 95% CI, 0.32–0.77) pt population, a PFS benefit was observed regardless of age. Similarity was also observed in TEAE incidence rate when looking into &lt;65, 65 to &lt;75, and ≥75 y subgroups (82.7%, 81.1%, and 87.5% with ActMon; 96.2%, 98.5%, and 95.2% with Dara); however, serious TEAEs were more frequently observed in older ActMon pts (12.2%, 18.9%, and 50.0% with ActMon; 24.8%, 35.8%, and 28.6% with Dara). Across all pts treated/monitored in AQUILA, 23 (11.9%) and 41 (20.9%) pts in the Dara and ActMon arms, respectively, received autologous stem cell transplant as part of their first tx after progressing to active MM, with very limited plerixafor use (Dara, 3 [1.6%] vs ActMon, 9 [4.6%]). Median (range) CD34+ cell yield was 5.0 (2–20)×106 cells/kg body weight among 22 pts in the Dara arm and 5.1 (2–21)×106 cells/kg body weight among 39 pts in the ActMon arm. Conclusions : In this analysis, pts with high-risk SMM from the phase 3 AQUILA study treated with Dara monotherapy experienced long-term PFS benefit across IMWG 2020 subgroups, with the most pronounced benefit in the high-risk subgroup. No notable differences in PFS or safety were observed across age subgroups. Early Dara tx for high-risk SMM did not have a detrimental impact on stem cell yield. Although mature OS analyses are forthcoming, overall, these results further support early intervention with Dara monotherapy vs ActMon among pts with high-risk SMM, regardless of risk stratification criteria used.

Three previously uncharacterized bacterial species, designated strains BD586 T , BD613 T and BD626 T , isolated from human clinical specimens, were identified at Mayo Clinic, Rochester, Minnesota, USA. Initial identification efforts using matrix-assisted laser desorption ionization-time-of-flight MS and partial 16S rRNA gene sequencing proved inconclusive. Comprehensive analysis involving phenotypic characterization, biochemical assays and whole-genome sequencing was undertaken. The isolates were Gram-negative, motile, facultatively anaerobic rods, occurring singly, in pairs and in short chains; BD613 T additionally formed small aggregates. The isolates tested positive for catalase and negative for oxidase. Their colonies appeared smooth, white, opaque and non-haemolytic. Growth was observed at 35 °C under aerobic, anaerobic and CO₂-enriched conditions, as well as in media with NaCl concentrations up to 10% and at pH 7-9. Phylogenetic relationships were inferred from core gene alignments, average nucleotide identity and digital DNA–DNA hybridization comparisons. Results confirmed the placement of BD586 T , BD613 T and BD626 T within the recently established Dryocola genus, while also indicating their novelty as distinct species. The major cellular fatty acids were C 16:0 and C 17:0 cyclo. Based on these findings, a formal description of three new species, Dryocola mayonis sp. nov. (type strain BD586 T =TSD 474 T , =NCTC 15089 T , =DSM 119465 T ), Dryocola sharpae sp. nov. (type strain BD613 T =TSD 475 T , =NCTC 15090 T , =DSM 119466 T ) and Dryocola baronae sp. nov. (type strain BD626 T =TSD 476 T , =NCTC 15091 T , =DSM 119479 T ), is proposed, and the genus description of Dryocola is emended to refine its genomic, morphological and chemotaxonomic boundaries.

Abstract Objectives The primary objective of this research is to assess the content coverage of nursing data within a publicly available common data model (CDM), focusing on how nursing data, documented in flowsheets, are represented within the model. Materials and Methods This mapping study was informed by previous evaluation studies and serves as a framework for evaluating information resources, including to guide development and implementation. The overall research process consists of 4 steps: (1) identify a CDM; (2) define evaluation criteria; (3) map nursing flowsheet data; and (4) apply evaluation criteria. Results Overall, 65.5% (n = 1170) of the flowsheet concepts were mapped to Systematized Nomenclature of Medicine—Clinical Terms (SNOMED CT) and Logical Observation Identifiers Names and Codes (LOINC) target codes and 56.0% (n = 1831) of the flowsheet values were mapped to SNOMED CT and LOINC target codes. The flowsheet concepts had a higher average mapping time per concept/reviewer (1.19 min) as compared to the average mapping time per value/reviewer (0.64 min). Discussion This mapping study demonstrated the progress and ongoing challenges of mapping nursing data to a national common data model. However, the ability to use nursing data at scale in a national CDM remains limited until more comprehensive mapping is completed. Conclusion This mapping study identifies a significant gap in integrating nursing data into a national common data model, highlighting an opportunity to enhance patient care through improved real-time insights and evidence-based nursing practices. Addressing this gap can help shape policies that prioritize the inclusion of nursing data. Additionally, aligning nursing data at scale can advance research, increase efficiency, and optimize nurse-sensitive patient outcomes.

Abstract Description During the humoral immune response, B cells undergo rapid metabolic reprogramming with a high demand for nutrients, which are vital to sustain the formation of the germinal centers (GCs). Rag-GTPases sense amino acid availability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway and suppress transcription factor EB (TFEB) and transcription factor enhancer 3 (TFE3). However, how Rag-GTPases coordinate amino acid sensing, mTORC1 activation, and TFEB/TFE3 activity in humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and generate plasmablasts in both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer’s patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish Rag-GTPase-TFEB/TFE3 pathway as an mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells. Funding Sources National Institute of Allergy and Infectious Diseases (NIAID) - AI162678 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) - AR077518 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

ABSTRACT The genomic sequences of seven phages isolated from municipal sewage in Rochester, Minnesota, USA, using Klebsiella pneumoniae strains ( bla KPC carriers) as hosts are reported. These phages are lytic and belong to the Ackermannviridae, Drexlerviridae , and Zobellviridae families. No known antimicrobial resistance or virulence genes were found within their genomes.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .