Two KaiABC systems control circadian oscillations in one cyanobacterium.

The circadian clock of cyanobacteria, which predicts daily environmental changes, typically includes a standard oscillator consisting of proteins KaiA, KaiB, and KaiC. However, several cyanobacteria have diverse Kai protein homologs of unclear function. In particular, Synechocystis sp. PCC 6803 harbours, in addition to a canonical kaiABC gene cluster (named kaiAB1C1), two further kaiB and kaiC homologs (kaiB2, kaiB3, kaiC2, kaiC3). Here, we identify a chimeric KaiA homolog, named KaiA3, encoded by a gene located upstream of kaiB3. At the N-terminus, KaiA3 is similar to response-regulator receiver domains, whereas its C-terminal domain resembles that of KaiA. Homology analysis shows that a KaiA3-KaiB3-KaiC3 system exists in several cyanobacteria and other bacteria. Using the Synechocystis sp. PCC 6803 homologs, we observe circadian oscillations in KaiC3 phosphorylation in vitro in the presence of KaiA3 and KaiB3. Mutations of kaiA3 affect KaiC3 phosphorylation, leading to growth defects under both mixotrophic and chemoheterotrophic conditions. KaiC1 and KaiC3 exhibit phase-locked free-running phosphorylation rhythms. Deletion of either system (∆kaiAB1C1 or ∆kaiA3B3C3) alters the period of the cellular backscattering rhythm. Furthermore, both oscillators are required to maintain high-amplitude, self-sustained backscatter oscillations with a period of approximately 24 h, indicating their interconnected nature.

Single-cell spatial transcriptomics reveals distinct patterns of dysregulation in non-neuronal and neuronal cells induced by the Trem2R47H Alzheimer's risk gene mutation.

The R47H missense mutation of the TREM2 gene is a known risk factor for development of Alzheimer's Disease. In this study, we analyze the impact of the Trem2R47H mutation on specific cell types in multiple cortical and subcortical brain regions in the context of wild-type and 5xFAD mouse background. We profile 19 mouse brain sections consisting of wild-type, Trem2R47H, 5xFAD and Trem2R47H; 5xFAD genotypes using MERFISH spatial transcriptomics, a technique that enables subcellular profiling of spatial gene expression. Spatial transcriptomics and neuropathology data are analyzed using our custom pipeline to identify plaque and Trem2R47H-induced transcriptomic dysregulation. We initially analyze cell type-specific transcriptomic alterations induced by plaque proximity. Next, we analyze spatial distributions of disease associated microglia and astrocytes, and how they vary between 5xFAD and Trem2R47H; 5xFAD mouse models. Finally, we analyze the impact of the Trem2R47H mutation on neuronal transcriptomes. The Trem2R47H mutation induces consistent upregulation of Bdnf and Ntrk2 across many cortical excitatory neuron types, independent of amyloid pathology. Spatial investigation of genotype enriched subclusters identified spatially localized neuronal subpopulations reduced in 5xFAD and Trem2R47H; 5xFAD mice. Overall, our MERFISH spatial transcriptomics analysis identifies glial and neuronal transcriptomic alterations induced independently by 5xFAD and Trem2R47H mutations, impacting inflammatory responses in microglia and astrocytes, and activity and BDNF signaling in neurons.

Prostate-specific antigen and health-related quality of life in individuals with advanced prostate cancer treated with apalutamide: a plain language summary of the SPARTAN and TITAN studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper that describes the results of the SPARTAN and TITAN studies, which looked at whether a treatment called apalutamide can help treat individuals with advanced prostate cancer.The SPARTAN study included 1207 participants with nonmetastatic castration-resistant prostate cancer (or nmCRPC). The TITAN study included 1052 participants with metastatic castration-sensitive prostate cancer (or mCSPC). Treatment with apalutamide was compared with treatment with placebo. In both studies, all participants were also given androgen deprivation therapy (or ADT), which has been used for many years for the treatment of prostate cancer.The results showed that treatment with apalutamide plus ADT increased participants' survival time while their health-related quality of life stayed the same, compared with placebo plus ADT. Also, apalutamide plus ADT increased the length of time that the cancer did not spread to other parts of the body (metastasize) or did not continue to grow. In both studies, treatment with apalutamide plus ADT was associated with a deep decline in blood prostate-specific antigen (or PSA) levels (called a deep PSA decline). This additional analysis of the SPARTAN and TITAN studies was performed to understand whether the deep PSA decline in participants who received apalutamide plus ADT was linked to their overall health-related quality of life. WHAT WERE THE RESULTS OF THE ADDITIONAL ANALYSIS?: In participants who received apalutamide plus ADT, those who achieved a deep PSA decline after the start of treatment had a greater chance that their health-related quality of life would remain stable. When participants achieved a deep PSA decline at 3 months after the start of treatment, the benefit to their health-related quality of life, including physical wellbeing, was even greater. WHAT DO THESE RESULTS MEAN FOR INDIVIDUALS WITH ADVANCED PROSTATE CANCER?: For individuals with advanced prostate cancer, it is important to monitor both PSA decline and any impacts on health-related quality of life. These results will help doctors and other healthcare professionals have a better understanding of patients' cancer experience and the impact of their treatment.Clinical Trial Registration: NCT01946204 (SPARTAN) and, NCT02489318 (TITAN) (ClinicalTrials.gov).

Early Prostate-Specific Antigen Response by 6 Months Is Predictive of Treatment Effect in Metastatic Hormone Sensitive Prostate Cancer: An Exploratory Analysis of TITAN Trial.

PURPOSE: Early PSA response has been found to be prognostic of outcomes in metastatic hormone sensitive prostate cancer. We performed a secondary analysis of the TITAN trial to determine if early PSA response was predictive of treatment efficacy in metastatic hormone sensitive prostate cancer patients. MATERIALS AND METHODS: Early PSA response was defined as achieving a PSA level of ≤ 0.2 ng/mL by 6 months of random assignment. A Cox proportional hazard model was constructed in a landmark population with an interaction term between the treatment and early PSA response to determine differential treatment effect on overall survival (OS). We applied multivariable Cox proportional hazard regression model with time to early PSA response fitted with restricted cubic spline to determine the association of time to early PSA response with OS. RESULTS: Approximately 24% (124/524) of patients in the androgen deprivation therapy (ADT) alone group and 61% (321/524) in the apalutamide group had PSA response ≤ 0.2 ng/mL by 6 months. Longer time to early PSA response was associated with significantly superior OS in the apalutamide group. There was a significant difference in treatment effect from apalutamide on OS (P = .03 for interaction) among 6-month PSA responders (HR: 0.66; 95% CI: 0.44-1.00) vs nonresponders (HR: 1.14; 95% CI: 0.89-1.46). This difference in treatment effect was not statistically significant at 3 months (P = .17 for interaction). Among 6-month PSA responders, 3-year confounder-adjusted OS was 84% (80%-88%) for the apalutamide group and 74% (66%-82%) for the ADT alone group. Among nonresponders, 3-year adjusted OS for the 2 treatment arms were 58% (52%-65%) and 56% (51%-60%), respectively. CONCLUSIONS: Early PSA response by 6 months was a predictor of treatment efficacy from ADT plus apalutamide on OS. Longer time to early PSA response was associated with superior OS in the apalutamide arm.

Exposure to Endocrine Disruptors in Early life and Neuroimaging Findings in Childhood and Adolescence: a Scoping Review.

PURPOSE OF REVIEW: Evidence suggests neurotoxicity of endocrine disrupting chemicals (EDCs) during sensitive periods of development. We present an overview of pediatric population neuroimaging studies that examined brain influences of EDC exposure during prenatal period and childhood. RECENT FINDINGS: We found 46 studies that used magnetic resonance imaging (MRI) to examine brain influences of EDCs. These studies showed associations of prenatal exposure to phthalates, organophosphate pesticides (OPs), polyaromatic hydrocarbons and persistent organic pollutants with global and regional brain structural alterations. Few studies suggested alteration in functional MRI associated with prenatal OP exposure. However, studies on other groups of EDCs, such as bisphenols, and those that examined childhood exposure were less conclusive. These findings underscore the potential profound and lasting effects of prenatal EDC exposure on brain development, emphasizing the need for better regulation and strategies to reduce exposure and mitigate impacts. More studies are needed to examine the influence of postnatal exposure to EDC on brain imaging.

Improving Sarcoma Outcomes: Target Trial Emulation to Compare the Impact of Unplanned and Planned Resections on the Outcome.

This study follows the Target Trial Emulation (TTE) framework to assess the impact of unplanned resections (UEs) and planned resections (PEs) of sarcomas on local recurrence-free survival (LRFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Sarcomas, malignant tumors with mesenchymal differentiation, present a significant clinical challenge due to their rarity, complexity, and the frequent occurrence of UEs, which complicates effective management. Our analysis utilized real-world-time data from the Swiss Sarcoma Network, encompassing 429 patients, to compare the impact of UEs and PEs, adjusting for known prognostic factors through a multivariable Cox regression model and propensity score weighting. Our findings reveal a significantly higher risk of local recurrence for UEs and a short-term follow-up period that showed no marked differences in MFS, CSS, and OS between the UE and PE groups, underlining the importance of optimal initial surgical management. Furthermore, tumor grade was validated as a critical prognostic factor, influencing outcomes irrespective of surgical strategy. This study illuminates the need for improved referral systems to specialized sarcoma networks to prevent UEs and advocates for the integration of TTE in sarcoma research to enhance clinical guidelines and decision-making in sarcoma care. Future research should focus on the prospective validations of these findings and the exploration of integrated care models to reduce the incidence of UEs and improve patient outcomes.

Correlation analyses of radiographic progression-free survival with clinical and health-related quality of life outcomes in metastatic castration-resistant prostate cancer: Analysis of the phase 3 VISION trial.

BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus protocol-permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression-free survival (rPFS) versus SOC in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health-related quality of life (HRQOL). METHODS: Post hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu-PSMA-617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy-Prostate [FACT-P] and 5-level EQ-5D [EQ-5D-5L]). Correlation analyses used an iterative multiple imputation copula-based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong). RESULTS: In the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT-P total score and emotional and physical well-being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time-to-worsening EQ-5D-5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms. CONCLUSIONS: In this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation.

Cystatin F attenuates neuroinflammation and demyelination following murine coronavirus infection of the central nervous system.

BACKGROUND: Cystatin F is a secreted lysosomal cysteine protease inhibitor that has been implicated in affecting the severity of demyelination and enhancing remyelination in pre-clinical models of immune-mediated demyelination. How cystatin F impacts neurologic disease severity following viral infection of the central nervous system (CNS) has not been well characterized and was the focus of this study. We used cystatin F null-mutant mice (Cst7-/-) with a well-established model of murine coronavirus-induced neurologic disease to evaluate the contributions of cystatin F in host defense, demyelination and remyelination. METHODS: Wildtype controls and Cst7-/- mice were intracranially (i.c.) infected with a sublethal dose of the neurotropic JHM strain of mouse hepatitis virus (JHMV), with disease progression and survival monitored daily. Viral plaque assays and qPCR were used to assess viral levels in CNS. Immune cell infiltration into the CNS and immune cell activation were determined by flow cytometry and 10X genomics chromium 3' single cell RNA sequencing (scRNA-seq). Spinal cord demyelination was determined by luxol fast blue (LFB) and Hematoxylin/Eosin (H&E) staining and axonal damage assessed by immunohistochemical staining for SMI-32. Remyelination was evaluated by electron microscopy (EM) and calculation of g-ratios. RESULTS: JHMV-infected Cst7-/- mice were able to control viral replication within the CNS, indicating that cystatin F is not essential for an effective Th1 anti-viral immune response. Infiltration of T cells into the spinal cords of JHMV-infected Cst7-/- mice was increased compared to infected controls, and this correlated with increased axonal damage and demyelination associated with impaired remyelination. Single-cell RNA-seq of CD45 + cells enriched from spinal cords of infected Cst7-/- and control mice revealed enhanced expression of transcripts encoding T cell chemoattractants, Cxcl9 and Cxcl10, combined with elevated expression of interferon-g (Ifng) and perforin (Prf1) transcripts in CD8 + T cells from Cst7-/- mice compared to controls. CONCLUSIONS: Cystatin F is not required for immune-mediated control of JHMV replication within the CNS. However, JHMV-infected Cst7-/- mice exhibited more severe clinical disease associated with increased demyelination and impaired remyelination. The increase in disease severity was associated with elevated expression of T cell chemoattractant chemokines, concurrent with increased neuroinflammation. These findings support the idea that cystatin F influences expression of proinflammatory gene expression impacting neuroinflammation, T cell activation and/or glia cell responses ultimately impacting neuroinflammation and neurologic disease.

The αC-ß4 loop controls the allosteric cooperativity between nucleotide and substrate in the catalytic subunit of protein kinase A.

Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic subunit of protein kinase A (PKA-C). This long-range synergistic action is involved in substrate recognition and fidelity, and it may also regulate PKA's association with regulatory subunits and other binding partners. To date, a complete understanding of this intramolecular mechanism is still lacking. Here, we integrated NMR(Nuclear Magnetic Resonance)-restrained molecular dynamics simulations and a Markov State Model to characterize the free energy landscape and conformational transitions of PKA-C. We found that the apoenzyme populates a broad free energy basin featuring a conformational ensemble of the active state of PKA-C (ground state) and other basins with lower populations (excited states). The first excited state corresponds to a previously characterized inactive state of PKA-C with the αC helix swinging outward. The second excited state displays a disrupted hydrophobic packing around the regulatory (R) spine, with a flipped configuration of the F100 and F102 residues at the αC-ß4 loop. We validated the second excited state by analyzing the F100A mutant of PKA-C, assessing its structural response to ATP and substrate binding. While PKA-CF100A preserves its catalytic efficiency with Kemptide, this mutation rearranges the αC-ß4 loop conformation, interrupting the coupling of the two lobes and abolishing the allosteric binding cooperativity. The highly conserved αC-ß4 loop emerges as a pivotal element to control the synergistic binding of nucleotide and substrate, explaining how mutations or insertions near or within this motif affect the function and drug sensitivity in homologous kinases.

APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology.

Background: Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects. Methods: We introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial transcriptomics and proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain's response to plaques and tau. Results: In 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Conclusions: These findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.

Concepts of lines of therapy in cancer treatment: findings from an expert interview-based study.

OBJECTIVE: The concept of lines of therapy (LOT) in cancer treatment is often considered for decision making in tumor boards and clinical management, but lacks a common definition across medical specialties. The complexity and heterogeneity of malignancies and treatment modalities contribute to an inconsistent understanding of LOT among physicians. This study assesses the heterogeneity of understandings of the LOT concept, its major dimensions, and criteria from the perspective of physicians of different specialties with an oncological focus in Germany. Semi-structured expert interviews with nine physicians were conducted and evaluated using qualitative content analysis. RESULTS: Most interviewees agreed that there is no single definition for LOT and found it difficult to explicate their understanding. A majority of experts stated that they had already encountered misunderstandings with colleagues regarding LOT and that they had problems with deciphering LOT from the medical records of their patients. Disagreement emerged about the roles of the following within the LOT concept: maintenance therapy, treatment intention, different therapy modalities, changing pharmaceutical agents, and therapy breaks. Respondents predominantly considered the same criteria as decisive for the definition of LOT as for a change in LOT (e.g., the occurrence of a progression event or tumor recurrence).

Selective targeting and modulation of plaque associated microglia via systemic hydroxyl dendrimer administration in an Alzheimer's disease mouse model.

BACKGROUND: In Alzheimer's disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue. METHODS: Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113). RESULTS: Treatment resulted in significant reductions in amyloid-beta (Aß) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice. CONCLUSIONS: This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.

Child and Adolescent Manganese Biomarkers and Adolescent Postural Balance in Marietta CARES Cohort Participants.

BACKGROUND: Manganese (Mn) plays a significant role in both human health and global industries. Epidemiological studies of exposed populations demonstrate a dose-dependent association between Mn and neuromotor effects ranging from subclinical effects to a clinically defined syndrome. However, little is known about the relationship between early life Mn biomarkers and adolescent postural balance. OBJECTIVES: This study investigated the associations between childhood and adolescent Mn biomarkers and adolescent postural balance in participants from the longitudinal Marietta Communities Actively Researching Exposures Study (CARES) cohort. METHODS: Participants were recruited into CARES when they were 7-9 y old, and reenrolled at 13-18 years of age. At both time points, participants provided samples of blood, hair, and toenails that were analyzed for blood Mn and lead (Pb), serum cotinine, hair Mn, and toenail Mn. In adolescence, participants completed a postural balance assessment. Greater sway indicates postural instability (harmful effect), whereas lesser sway indicates postural stability (beneficial effect). Multivariable linear regression models were conducted to investigate the associations between childhood and adolescent Mn biomarkers and adolescent postural balance adjusted for age, sex, height-weight ratio, parent/caregiver intelligence quotient, socioeconomic status, blood Pb, and serum cotinine. RESULTS: CARES participants who completed the adolescent postural balance assessment (n=123) were 98% White and 54% female and had a mean age of 16 y (range: 13-18 y). In both childhood and adolescence, higher Mn biomarker concentrations were significantly associated with greater adolescent sway measures. Supplemental analyses revealed sex-specific associations; higher childhood Mn biomarker concentrations were significantly associated with greater sway in females compared with males. DISCUSSION: This study found childhood and adolescent Mn biomarkers were associated with subclinical neuromotor effects in adolescence. This study demonstrates postural balance as a sensitive measure to assess the association between Mn biomarkers and neuromotor function. https://doi.org/10.1289/EHP13381.

Composition effects of electrodeposited Cu-Ag nanostructured electrocatalysts for CO2 reduction.

The electrochemical carbon dioxide reduction (CO2RR) on Cu-based catalysts is a promising strategy to store renewable electricity and produce valuable C2+ chemicals. We investigate the CO2RR on Cu-Ag nanostructures that have been electrodeposited in a green choline chloride and urea deep eutectic solvent (DES). We determine the electrochemically active surface area (ECSA) using lead underpotential deposition (UPD) to investigate the CO2RR intrinsic activity and selectivity. We show that the addition of Ag on electrodeposited Cu primarily suppresses the production of hydrogen and methane. While the production of carbon monoxide slightly increases, the partial current of the total C2+ products does not considerably increase. Despite that the production rate of C2+ is similar on Cu and Cu-Ag, the addition of Ag enhances the formation of alcohols and oxygenates over ethylene. We highlight the potential of metal electrodeposition from DES as a sustainable strategy to develop bimetallic Cu-based nanocatalysts for CO2RR.

Sex-specific associations between AD genotype and the microbiome of human amyloid beta knock-in (hAß-KI) mice.

INTRODUCTION: Emerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome. METHODS: We used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAß-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD). RESULTS: Eighteen-month female (but not male) hAß-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAß-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups. DISCUSSION: These findings highlight a sex-dependent variation in the microbiomes of hAß-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD. HIGHLIGHTS: Microbial diversity and the abundance of several species differed in human amyloid beta knock-in (hAß-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAß-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome.

Stewardship Prompts to Improve Antibiotic Selection for Pneumonia: The INSPIRE Randomized Clinical Trial.

Importance: Pneumonia is the most common infection requiring hospitalization and is a major reason for overuse of extended-spectrum antibiotics. Despite low risk of multidrug-resistant organism (MDRO) infection, clinical uncertainty often drives initial antibiotic selection. Strategies to limit empiric antibiotic overuse for patients with pneumonia are needed. Objective: To evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO infection risk estimates could reduce empiric extended-spectrum antibiotics for non-critically ill patients admitted with pneumonia. Design, Setting, and Participants: Cluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time MDRO risk-based CPOE prompts; n = 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in non-critically ill adults (≥18 years) hospitalized with pneumonia. There was an 18-month baseline period from April 1, 2017, to September 30, 2018, and a 15-month intervention period from April 1, 2019, to June 30, 2020. Intervention: CPOE prompts recommending standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics during the empiric period who have low estimated absolute risk (<10%) of MDRO pneumonia, coupled with feedback and education. Main Outcomes and Measures: The primary outcome was empiric (first 3 days of hospitalization) extended-spectrum antibiotic days of therapy. Secondary outcomes included empiric vancomycin and antipseudomonal days of therapy and safety outcomes included days to intensive care unit (ICU) transfer and hospital length of stay. Outcomes compared differences between baseline and intervention periods across strategies. Results: Among 59 hospitals with 96 451 (51 671 in the baseline period and 44 780 in the intervention period) adult patients admitted with pneumonia, the mean (SD) age of patients was 68.1 (17.0) years, 48.1% were men, and the median (IQR) Elixhauser comorbidity count was 4 (2-6). Compared with routine stewardship, the group using CPOE prompts had a 28.4% reduction in empiric extended-spectrum days of therapy (rate ratio, 0.72 [95% CI, 0.66-0.78]; P < .001). Safety outcomes of mean days to ICU transfer (6.5 vs 7.1 days) and hospital length of stay (6.8 vs 7.1 days) did not differ significantly between the routine and CPOE intervention groups. Conclusions and Relevance: Empiric extended-spectrum antibiotic use was significantly lower among adults admitted with pneumonia to non-ICU settings in hospitals using education, feedback, and CPOE prompts recommending standard-spectrum antibiotics for patients at low risk of MDRO infection, compared with routine stewardship practices. Hospital length of stay and days to ICU transfer were unchanged. Trial Registration: ClinicalTrials.gov Identifier: NCT03697070.

Stewardship Prompts to Improve Antibiotic Selection for Urinary Tract Infection: The INSPIRE Randomized Clinical Trial.

Importance: Urinary tract infection (UTI) is the second most common infection leading to hospitalization and is often associated with gram-negative multidrug-resistant organisms (MDROs). Clinicians overuse extended-spectrum antibiotics although most patients are at low risk for MDRO infection. Safe strategies to limit overuse of empiric antibiotics are needed. Objective: To evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO risk estimates could reduce use of empiric extended-spectrum antibiotics for treatment of UTI. Design, Setting, and Participants: Cluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time and risk-based CPOE prompts; 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in noncritically ill adults (≥18 years) hospitalized with UTI with an 18-month baseline (April 1, 2017-September 30, 2018) and 15-month intervention period (April 1, 2019-June 30, 2020). Interventions: CPOE prompts recommending empiric standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics who have low estimated absolute risk (<10%) of MDRO UTI, coupled with feedback and education. Main Outcomes and Measures: The primary outcome was empiric (first 3 days of hospitalization) extended-spectrum antibiotic days of therapy. Secondary outcomes included empiric vancomycin and antipseudomonal days of therapy. Safety outcomes included days to intensive care unit (ICU) transfer and hospital length of stay. Outcomes were assessed using generalized linear mixed-effect models to assess differences between the baseline and intervention periods. Results: Among 127 403 adult patients (71 991 baseline and 55 412 intervention period) admitted with UTI in 59 hospitals, the mean (SD) age was 69.4 (17.9) years, 30.5% were male, and the median Elixhauser Comorbidity Index count was 4 (IQR, 2-5). Compared with routine stewardship, the group using CPOE prompts had a 17.4% (95% CI, 11.2%-23.2%) reduction in empiric extended-spectrum days of therapy (rate ratio, 0.83 [95% CI, 0.77-0.89]; P < .001). The safety outcomes of mean days to ICU transfer (6.6 vs 7.0 days) and hospital length of stay (6.3 vs 6.5 days) did not differ significantly between the routine and intervention groups, respectively. Conclusions and Relevance: Compared with routine stewardship, CPOE prompts providing real-time recommendations for standard-spectrum antibiotics for patients with low MDRO risk coupled with feedback and education significantly reduced empiric extended-spectrum antibiotic use among noncritically ill adults admitted with UTI without changing hospital length of stay or days to ICU transfers. Trial Registration: ClinicalTrials.gov Identifier: NCT03697096.

Vulnerable newborn phenotypes in Peru: a population-based study of 3,841,531 births at national and subnational levels from 2012 to 2021.

Background: We aimed to examine the national and subnational prevalence of vulnerable newborn phenotypes in Peru, 2012-2021. Methods: Newborn phenotypes were defined using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight [LBW], non-LBW) using the Peruvian National Birth Registry as six (by excluding birthweight) and ten newborn phenotypes (using all three outcomes). Small phenotypes (with at least one classification of PT, SGA, or LBW) were further considered. Using individual-level data, we stratified the phenotypes by maternal educational level, maternal age, healthcare insurance, altitude of residence, and geographic region (Coast, Andes, and Amazon). Findings: The prevalence of the five vulnerable newborn phenotypes for the study period was LGA+T (15.2%), AGA+PT (5.2%), SGA+T (4.6%), LGA+PT (0.8%), and SGA+PT (0.7%). The Coast had a higher prevalence of newborns with large phenotypes (19.4%) and the Highlands a higher prevalence of newborns with small phenotypes (12.5%). Mothers with poor socioeconomic status, extreme ages and living at high altitude had a higher prevalence of newborns with small phenotypes, and mothers who were wealthier, more educated, and older had a higher prevalence of infants with large phenotypes. Interpretation: Our findings cautiously suggest that socioeconomic and geographic disparities may play a crucial role in shaping vulnerable newborn phenotypes at national and subnational level in Peru. Further studies using longitudinal data are needed to corroborate our findings and to identify individual-level risk factors. Funding: Ter Meulen Grant from the KNAW Medical Sciences Fund of the Royal Netherlands Academy of Arts and Sciences (KNAWWF/1085/TMB406, KNAWWF/1327/TMB202116), Fogarty Program (D43TW011502).