Dysregulated STAT3 signaling and T cell immunometabolic dysfunction define a targetable, high mortality subphenotype of critically ill children.

Sepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. Identifying modifiable pathobiology is an essential first step to successful translation of biologic insights into precision therapeutics. We designed a prospective, longitudinal cohort study of 88 critically ill pediatric patients with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define subphenotypes associated with targetable mechanisms of immune dysregulation. We first assessed plasma proteomic profiles and identified shared features of immune dysregulation in MODS patients with and without sepsis. We then employed consensus clustering to define three subphenotypes based on protein expression at disease onset and identified a strong association between subphenotype and clinical outcome. We next identified differences in immune cell frequency and activation state by MODS subphenotype and determined the association between hyperinflammatory pathway activation and cellular immunophenotype. Using single cell transcriptomics, we demonstrated STAT3 hyperactivation in lymphocytes from the sickest MODS subgroup and then identified an association between STAT3 hyperactivation and T cell immunometabolic dysregulation. Finally, we compared proteomics findings between patients with MODS and patients with inborn errors of immunity that amplify cytokine signaling pathways to further assess the impact of STAT3 hyperactivation in the most severe patients with MODS. Overall, these results identify a potentially pathologic and targetable role for STAT3 hyperactivation in a subset of pediatric patients with MODS who have high severity of illness and poor prognosis.

Weight change with antiretroviral switch from integrase inhibitor or tenofovir alafenamide-based to Doravirine-Based regimens in people with HIV.

BACKGROUND: Weight gain has been well-described with integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF). Doravirine (DOR) has been identified as a relatively "weight-neutral" drug; however, there is little data describing its effect on weight change in routine clinical practice. METHODS: We conducted a retrospective chart review of weight change among people with HIV changing from an INSTI- to a non-INSTI regimen with DOR. RESULTS: At the time of ART switch, among 49 people with HIV, the mean age was 47 years, 24% were female, and 75% had HIV-1 viral load <200 copies/mL. Most (55%) people with HIV were taking bictegravir/TAF/emtricitabine prior to the switch. Although 84% switched due to concerns about weight gain, only 16% had a weight gain of ≥10% in the year preceding, and 49% had no substantial change in weight. 86% switched to DOR/lamivudine/tenofovir disoproxil fumarate. A weight decrease (-2.6% [95% CI: -5.1, -0.1%, p = .041] was seen over the year following the ART switch. Weight change prior to switch was greatest in the year 2021 compared to 2019, 2020, and 2022. CONCLUSIONS: Overall, modest changes in weight were seen following ART switch from INSTI-based regimen to a DOR-based, non-INSTI regimen. Further investigations with larger people with HIV cohorts will be helpful to guide clinical practice, while the impact of the COVID-19 pandemic on weight change should also be considered.

A Description and Safety Overview of Irreversible Electroporation for Prostate Tissue Ablation in Intermediate-Risk Prostate Cancer Patients: Preliminary Results from the PRESERVE Trial.

The PRESERVE study (NCT04972097) aims to evaluate the safety and effectiveness of the NanoKnife System to ablate prostate tissue in patients with intermediate-risk prostate cancer (PCa). The NanoKnife uses irreversible electroporation (IRE) to deliver high-voltage electrical pulses to change the permeability of cell membranes, leading to cell death. A total of 121 subjects with organ-confined PCa ≤ T2c, prostate-specific antigens (PSAs) ≤ 15 ng/mL, and a Gleason score of 3 + 4 or 4 + 3 underwent focal ablation of the index lesion. The primary endpoints included negative in-field biopsy and adverse event incidence, type, and severity through 12 months. At the time of analysis, the trial had completed accrual with preliminary follow-up available. Demographics, disease characteristics, procedural details, PSA responses, and adverse events (AEs) are presented. The median (IQR) age at screening was 67.0 (61.0-72.0) years and Gleason distribution 3 + 4 (80.2%) and 4 + 3 (19.8%). At 6 months, all patients with available data (n = 74) experienced a median (IQR) percent reduction in PSA of 67.6% (52.3-82.2%). Only ten subjects (8.3%) experienced a Grade 3 adverse event; five were procedure-related. No Grade ≥ 4 AEs were reported. This study supports prior findings that IRE prostate ablation with the NanoKnife System can be performed safely. Final results are required to fully assess oncological, functional, and safety outcomes.

The Legacy of Redlining: Increasing Childhood Asthma Disparities Through Neighborhood Poverty.

RATIONALE: Identifying the root causes of racial disparities in childhood asthma is critical for health equity. OBJECTIVES: To determine if the 1930's racist policy of redlining led to present-day disparities in childhood asthma by increasing community-level poverty and decreasing neighborhood socioeconomic position (SEP). METHODS: We categorized census tracts at birth of participants from the Children's Respiratory and Environmental Workgroup birth cohort consortium into A, B, C, or D categories as defined by the Home Owners Loan Corporation (HOLC), with D being the highest perceived risk. Surrogates of present-day neighborhood-level SEP were determined for each tract including the percentage of low-income households, the CDC's social vulnerability index (SVI), and other tract-level variables. We performed causal mediation analysis, which, under the assumption of no unmeasured confounding, estimates the direct and mediated pathways by which redlining may cause asthma disparities through census tract-level mediators adjusting for individual-level covariates. MEASUREMENTS AND MAIN RESULTS: Of 4,849 children, the cumulative incidence of asthma through age 11 was 26.6% and 13.2% resided in census tracts with a HOLC grade of D. In mediation analyses, residing in grade D tracts (aOR = 1.03 [95%CI 1.01,1.05]) was significantly associated with childhood asthma, with 79% of this increased risk mediated by percentage of low-income households; results were similar for SVI and other tract-level variables. CONCLUSIONS: The historical structural racist policy of redlining led to present-day asthma disparities in part through decreased neighborhood SEP. Policies aimed at reversing the effects of structural racism should be considered to create more just, equitable, and healthy communities.

Efficacy and immunogenicity of a single dose of human papillomavirus vaccine compared to multidose vaccination regimens or no vaccination: An updated systematic review of evidence from clinical trials.

Objectives: This study systematically reviewed the published literature from clinical trials on the efficacy and immunogenicity of single-dose HPV vaccination compared to multidose schedules or no HPV vaccination. Methods: Four databases were searched for relevant articles published from Jan-1999 to Feb-2023. Articles were assessed for eligibility for inclusion using pre-defined criteria. Relevant data were extracted from eligible articles and a descriptive quality assessment was performed for each study. A narrative data synthesis was conducted, examining HPV infection, other clinical outcomes and immunogenicity responses by dose schedule. Results: Fifteen articles reporting data from six studies (all in healthy young females) were included. One article was included from each of three studies that prospectively randomised participants to receive a single HPV vaccine dose versus one or more comparator schedule(s). The other 12 articles reported data from three studies that randomised participants to receive multidose HPV vaccine (or control vaccine) schedules; in those studies, some participants failed to complete their allocated schedule, and evaluations were conducted to compare participants who actually received one, two or three doses. Across all efficacy studies, the incidence or prevalence of HPV16/18 infection was very low among HPV-vaccinated participants, regardless of the number of doses received; with no evidence for a difference between dose groups. In immunogenicity studies, HPV16/18 antibody seropositivity rates were high among all HPV-vaccinated participants. Antibody levels were significantly lower with one dose compared to two or three doses, but levels with one dose were stable and sustained to 11 years post-vaccination. Conclusions: Results from this review support recent World Health Organization recommendations allowing either one- or two-dose HPV vaccination in healthy young females. Longer-term efficacy and immunogenicity data from ongoing studies are awaited. Randomised trials of single-dose HPV-vaccination are urgently needed in other populations, e.g. boys, older females and people with HIV.

Respiratory internal kinematics of the tongue base and soft palate in obese minipigs with obstructive sleep apnea.

It is largely unknown how the tongue base and soft palate deform to alter the configuration of the oropharyngeal airway during respiration. This study is to address this important gap. After live sleep monitoring of five Yucatan and two Panepinto minipigs to verify obstructive sleep apnea (OSA), eight and four ultrasonic crystals were implanted into the tongue base and soft palate to circumscribe a cubic and square region, respectively. The 3D and 2D deformational changes of the circumscribed regions were measured simultaneously with electromyographic activity of the oropharyngeal muscles during spontaneous respiration under sedated sleep. The results indicated that both obese Yucatan and Panepinto minipigs presented spontaneous OSA, but not in three nonobese Yucatan minipigs. During inspiration, the tongue base showed elongation in both dorsal and ventral regions but thinning and thickening in the anterior and posterior regions, respectively. The widths showed opposite directions, widening in the dorsal but narrowing in the ventral regions. The soft palate expanded in both length and width. Compared to normal controls, obese/OSA ones showed similar directions of deformational changes, but the magnitude of change was two times larger in the tongue base and soft palate, and obese/OSA Panepinto minipigs presented 10 times larger changes in all dimensions of both the tongue base and the soft palate. The distance changes between the dorsal surface of tongue base and soft palate during inspiration increased in normal but decreased in obese OSA minipigs.

Treatment of Advanced BP-NETS with Lanreotide Autogel/Depot vs Placebo: the Phase III SPINET Study.

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical and atypical carcinoids [TCs and ACs]). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) versus placebo plus BSC, with an optional open label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n=51 [TCs, n=29; ACs, n=22]; placebo, n=26 [TCs, n=16; ACs, n=10). Median (95% confidence interval [CI]) PFS during double-blind and OL phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable [NC]) months in TCs and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN versus 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients' quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR positive TCs and ACs and suggests clinical benefit in TCs.

Alternative proteoforms and proteoform-dependent assemblies in humans and plants.

The variability of proteins at the sequence level creates an enormous potential for proteome complexity. Exploring the depths and limits of this complexity is an ongoing goal in biology. Here, we systematically survey human and plant high-throughput bottom-up native proteomics data for protein truncation variants, where substantial regions of the full-length protein are missing from an observed protein product. In humans, Arabidopsis, and the green alga Chlamydomonas, approximately one percent of observed proteins show a short form, which we can assign by comparison to RNA isoforms as either likely deriving from transcript-directed processes or limited proteolysis. While some detected protein fragments align with known splice forms and protein cleavage events, multiple examples are previously undescribed, such as our observation of fibrocystin proteolysis and nuclear translocation in a green alga. We find that truncations occur almost entirely between structured protein domains, even when short forms are derived from transcript variants. Intriguingly, multiple endogenous protein truncations of phase-separating translational proteins resemble cleaved proteoforms produced by enteroviruses during infection. Some truncated proteins are also observed in both humans and plants, suggesting that they date to the last eukaryotic common ancestor. Finally, we describe novel proteoform-specific protein complexes, where the loss of a domain may accompany complex formation.

Interferon signaling gene expression as a diagnostic biomarker for monogenic interferonopathies.

Interferon signaling gene (ISG) expression scores are potential markers of inflammation with significance from cancer to genetic syndromes. In Aicardi Goutières Syndrome (AGS), a disorder of abnormal DNA and RNA metabolism, this score has potential as a diagnostic biomarker, although the approach to ISG calculation has not been standardized or validated. To optimize ISG calculation and validate ISG as a diagnostic biomarker, mRNA levels of 36 type I interferon response genes were quantified from 997 samples (including 334 AGS), and samples were randomized into training and test datasets. An independent validation cohort (n = 122) was also collected. ISGs were calculated using all potential combinations up to 6 genes. A 4-gene approach (IFI44L, IFI27, USP18, IFI6) was the best-performing model [area under the curve (AUC) of 0.8872 (training dataset), 0.9245 (test dataset)]. The majority of top performing gene combinations included IFI44L. Performance of IFI44L-alone was 0.8762 (training dataset) and 0.9580 (test dataset) by AUC. The top approaches were able to discriminate cases of genetic interferonopathy from control samples. This study validates the context of use for the ISG score as a diagnostic biomarker and underscores the importance of IFI44L in diagnosis of genetic interferonopathies.

The Safety of Contraction of Subcutaneous Tissue Following Liposuction Procedures.

This paper examines the practice of using a helium plasma radiofrequency (RF) device for contracting subcutaneous soft tissue following liposuction in all body areas. A review of the data from 6 industry-sponsor-initiated retrospective studies was performed, wherein 483 real-world patients underwent liposuction followed by contraction of the subcutaneous soft tissue with the helium plasma RF system. These data were evaluated to determine if any new or increased risks were introduced compared to the risks of liposuction alone. The totality of the real-world data demonstrates there are no new or increased risks for helium plasma RF procedures following liposuction compared to liposuction alone. These data support the safety of helium plasma RF for subcutaneous soft-tissue contraction following liposuction. There are currently no alternative therapies specifically cleared by the FDA that can claim use following liposuction for the purpose of contracting the subcutaneous soft tissue.

Mining patents with large language models elucidates the chemical function landscape.

The fundamental goal of small molecule discovery is to generate chemicals with target functionality. While this often proceeds through structure-based methods, we set out to investigate the practicality of methods that leverage the extensive corpus of chemical literature. We hypothesize that a sufficiently large text-derived chemical function dataset would mirror the actual landscape of chemical functionality. Such a landscape would implicitly capture complex physical and biological interactions given that chemical function arises from both a molecule's structure and its interacting partners. To evaluate this hypothesis, we built a Chemical Function (CheF) dataset of patent-derived functional labels. This dataset, comprising 631 K molecule-function pairs, was created using an LLM- and embedding-based method to obtain 1.5 K unique functional labels for approximately 100 K randomly selected molecules from their corresponding 188 K unique patents. We carry out a series of analyses demonstrating that the CheF dataset contains a semantically coherent textual representation of the functional landscape congruent with chemical structural relationships, thus approximating the actual chemical function landscape. We then demonstrate through several examples that this text-based functional landscape can be leveraged to identify drugs with target functionality using a model able to predict functional profiles from structure alone. We believe that functional label-guided molecular discovery may serve as an alternative approach to traditional structure-based methods in the pursuit of designing novel functional molecules.

Microphthalmia and disrupted retinal development due to a LacZ knock-in/knock-out allele at the Vsx2 locus.

Visual System Homeobox 2 (Vsx2) is a transcription factor expressed in the developing retina that regulates tissue identity, growth, and fate determination. Several mutations in the Vsx2 gene exist in mice, including a spontaneous nonsense mutation and two targeted missense mutations originally identified in humans. Here, we expand the genetic repertoire to include a LacZ reporter allele (Vsx2 LacZ ) designed to express beta-Galactosidase (b-GAL) and simultaneously disrupt Vsx2 function (knock-in/knock-out). The retinal expression pattern of b-GAL is concordant with VSX2, and the mutant allele is recessive. Vsx2 LacZ homozygous mice have congenital bilateral microphthalmia accompanied by defects in retinal development including ectopic expression of non-retinal genes, reduced proliferation, delayed neurogenesis, aberrant tissue morphology, and an absence of bipolar interneurons - all hallmarks of Vsx2 loss-of-function. Unexpectedly, the mutant VSX2 protein is stably expressed, and there are subtle differences in eye size and early retinal neurogenesis when compared to the null mutant, ocular retardation J. We propose that b-GAL expression from the Vsx2 LacZ allele is a reliable reporter of VSX2 expression and that the allele exhibits loss-of-function characteristics. However, the perdurance of the mutant VSX2 protein combined with subtle deviations from the null phenotype leaves open the possibility that Vsx2 LacZ allele is not a complete knock-out. The Vsx2 LacZ allele adds to the genetic toolkit for understanding Vsx2 function.

Correction: Seasonal influenza: Modelling approaches to capture immunity propagation.

[This corrects the article DOI: 10.1371/journal.pcbi.1007096.].

Ancient eukaryotic protein interactions illuminate modern genetic traits and disorders.

All eukaryotes share a common ancestor from roughly 1.5 - 1.8 billion years ago, a single-celled, swimming microbe known as LECA, the Last Eukaryotic Common Ancestor. Nearly half of the genes in modern eukaryotes were present in LECA, and many current genetic diseases and traits stem from these ancient molecular systems. To better understand these systems, we compared genes across modern organisms and identified a core set of 10,092 shared protein-coding gene families likely present in LECA, a quarter of which are uncharacterized. We then integrated >26,000 mass spectrometry proteomics analyses from 31 species to infer how these proteins interact in higher-order complexes. The resulting interactome describes the biochemical organization of LECA, revealing both known and new assemblies. We analyzed these ancient protein interactions to find new human gene-disease relationships for bone density and congenital birth defects, demonstrating the value of ancestral protein interactions for guiding functional genetics today.

RicePilaf: a post-GWAS/QTL dashboard to integrate pangenomic, coexpression, regulatory, epigenomic, ontology, pathway, and text-mining information to provide functional insights into rice QTLs and GWAS loci.

BACKGROUND: As the number of genome-wide association study (GWAS) and quantitative trait locus (QTL) mappings in rice continues to grow, so does the already long list of genomic loci associated with important agronomic traits. Typically, loci implicated by GWAS/QTL analysis contain tens to hundreds to thousands of single-nucleotide polmorphisms (SNPs)/genes, not all of which are causal and many of which are in noncoding regions. Unraveling the biological mechanisms that tie the GWAS regions and QTLs to the trait of interest is challenging, especially since it requires collating functional genomics information about the loci from multiple, disparate data sources. RESULTS: We present RicePilaf, a web app for post-GWAS/QTL analysis, that performs a slew of novel bioinformatics analyses to cross-reference GWAS results and QTL mappings with a host of publicly available rice databases. In particular, it integrates (i) pangenomic information from high-quality genome builds of multiple rice varieties, (ii) coexpression information from genome-scale coexpression networks, (iii) ontology and pathway information, (iv) regulatory information from rice transcription factor databases, (v) epigenomic information from multiple high-throughput epigenetic experiments, and (vi) text-mining information extracted from scientific abstracts linking genes and traits. We demonstrate the utility of RicePilaf by applying it to analyze GWAS peaks of preharvest sprouting and genes underlying yield-under-drought QTLs. CONCLUSIONS: RicePilaf enables rice scientists and breeders to shed functional light on their GWAS regions and QTLs, and it provides them with a means to prioritize SNPs/genes for further experiments. The source code, a Docker image, and a demo version of RicePilaf are publicly available at https://github.com/bioinfodlsu/rice-pilaf.

Survivorship and Outcomes of 2-Stage Revision for Infected Total Hip Arthroplasty at a Mean of 7-Year Follow-Up.

BACKGROUND: Periprosthetic joint infection (PJI) continues to be one of the leading causes of failure following total hip arthroplasty (THA). The objectives of the study were to (1) determine the minimum 2-year infection-free survivorship of 2-stage revision THA, (2) determine the causative organisms for repeat 2-stage revision THA, and (3) characterize the results of failed 2-stage revisions and evaluate patient-reported outcome measures (PROMs). METHODS: A retrospective chart review was completed for patients who underwent 2-stage revision THA for PJI. Prospective data were collected on each patient, including demographics, causative organisms, complications, and type of reoperation. The PROMs, including Harris Hip Score, 12-item Short-Form Health Survey, and Western Ontario and McMaster Universities Osteoarthritis Index scores were obtained prior to 2-stage revision THA surgery and annually as part of standard clinical and radiographic follow-up. RESULTS: A total of 328 patients who underwent a 2-stage revision THA for a PJI were included in the study (mean age 67 years [range, 28 to 90], mean body mass index of 30.6 [range, 15 to 57]). The overall infection-free survivorship for 2-stage revision THA was 73.8% at a minimum of 2 years (range, 2 to 20). Overall, 194 (59.1%) patients who had successful infection eradication underwent a 2-revision THA only. The most common single organisms infected were Staphylococcus aureus (12.5%) and Staphylococcus epidermidis (11%). Higher reoperation rates were found in cases with methicillin-resistant Staphylococcus aureus and polymicrobial infections. All PROMs showed statistical improvement from preoperatively to the latest follow-up appointment. CONCLUSIONS: Two-stage revision THA is associated with a good success rate in the treatment of PJIs at mid-term to long-term follow-up. Polymicrobial and methicillin-resistant Staphylococcus aureus infections are poor prognostic factors, making the eradication of infection more difficult. The management of PJIs continues to be one of the most important orthopaedic challenges to treat.

Oncolytic adenoviral therapy plus pembrolizumab in BCG-unresponsive non-muscle-invasive bladder cancer: the phase 2 CORE-001 trial.

Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously tested as monotherapy in bacillus Calmette-Guérin (BCG)-experienced non-muscle-invasive bladder cancer. In this phase 2 study, we assessed the potential synergistic efficacy between intravesical cretostimogene and systemic pembrolizumab in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ (CIS). Thirty-five patients were treated with intravesical cretostimogene with systemic pembrolizumab. Induction cretostimogene was administered weekly for 6 weeks followed by three weekly maintenance infusions at months 3, 6, 9, 12 and 18 in patients maintaining complete response (CR). Patients with persistent CIS/high-grade Ta at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months. The primary endpoint was CR at 12 months as assessed by cystoscopy, urine cytology, cross-sectional imaging and mandatory bladder mapping biopsies. Secondary endpoints included CR at any time, duration of response, progression-free survival and safety. The CR rate in the intention-to-treat population at 12 months was 57.1% (20 out of 35, 95% confidence interval (CI) 40.7-73.5%), meeting the primary endpoint. A total of 29 out of 35 patients (82.9%, 95% CI 70.4-95.3%) derived a CR at 3 months. With a median follow-up of 26.5 months, the median duration of response has not been reached (95% CI 15.7 to not reached). The CR rate at 24 months was 51.4% (18 out of 35) (95% CI 34.9-68.0%). No patient progressed to muscle-invasive bladder cancer in this trial. Adverse events attributed to cretostimogene were low grade, self-limiting and predominantly limited to bladder-related symptoms. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects. There was no evidence of overlapping or synergistic toxicities. Combination intravesical cretostimogene and systemic pembrolizumab demonstrated enduring efficacy. With a toxicity profile similar to its monotherapy components, this combination may shift the benefit-to-risk ratio for patients with BCG-unresponsive CIS. ClinicalTrials.gov Identifier: NCT04387461 .

Detection of clinically significant prostate cancer following initial omission of biopsy in multiparametric MRI era.

BACKGROUND: Multiparametric prostate MRI (mpMRI) is being increasingly adopted for work-up of prostate cancer. For patients selected to omit biopsy, we identified factors associated with repeat MRI, eventual prostate biopsy, and subsequent detection of clinically significant prostate cancer (csPCa, Grade Group ≥2). METHODS: We identified biopsy-naïve men presenting with PSA 2-20 ng/mL (March 2018-June 2021) undergoing initial mpMRI with PIRADS 1-3 lesions who were not selected for biopsy with ≥6 months follow-up. We examined factors associated with repeat mpMRI, progression to biopsy, and subsequent detection of csPCa with univariable and multivariable logistic regression. RESULTS: Of 1494 men, 31% (463/1494) did not pursue biopsy. PSA density (PSAD) ≤ 0.1, prostate health index (PHI) < 55, and PIRADS 1-2 were associated with omission of prostate biopsy. csPCa diagnosis-free survival was 97.6% (326/334) with median follow up of 23.1 months (IQR 15.1-34.6 months). Black race, PSA, PHI, PSA density, and PSA and PHI velocity were significant predictors of undergoing repeat mpMRI (15.6%, 52/334) and subsequent biopsy (8.4%, 28/334). 8 men were subsequently diagnosed with csPCa (N = 7 on prostate biopsy; N = 1 incidentally on holmium enucleation of prostate). All patients diagnosed with csPCa had PIRADS 4-5 on repeat mpMRI. CONCLUSIONS: The subsequent detection rate of csPCa among patients not initially biopsied after mpMRI was low at 2.4%. Decisions to omit biopsy after initial reassuring PHI, PSAD, and mpMRI appear safe with subsequent reassuring serum biomarkers and for cause mpMRI during follow-up.