Citations

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

ABSTRACT Vancomycin is broadly used to treat gram-positive infections in both inpatient and outpatient settings. Its use is primarily for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), which is a common cause of pneumonia, skin and soft tissue infections, and bloodstream infections. Vancomycin therapy requires close clinical monitoring to maintain therapeutic efficacy and, importantly, patient safety. Vancomycin use is associated with acute kidney injury in up to 20% of cases, a number that can be driven down by pharmacokinetic dosing protocols. However, the best mitigation against adverse outcomes associated with vancomycin is to ensure it is only used when needed and rapidly de-escalated when not. As such, many stewardship programs, who are tasked with the safe and effective use of antimicrobial agents, have focused on optimizing vancomycin use. There is a strong correlation with MRSA colonization and infection, and a negative MRSA nares screen has a good negative predictive value for MRSA pneumonia (although this association is less well documented for other infections). As such, detection of MRSA in nares swabs, by nucleic acid amplification tests (NAATs) or culture, is a logical tool for stewarding vancomycin. However, the application of MRSA screening tests as MRSA diagnostics is complex, as these tests are cleared by the U.S. Food and Drug Administration for the detection of MRSA colonization, and not for therapeutic decision making. In this issue of the Journal of Clinical Microbiology, the issue of MRSA nares tests is debated by a clinical pharmacy team and the laboratory. The authors review the clinical evidence and regulatory background in which an MRSA nares NAAT may be used to inform treatment decisions.

Abstract Coccidioidomycosis is an invasive fungal infection that can disseminate and cause severe disease. Fosmanogepix (“gepix”), a first-in-class antifungal available via expanded access (NCT06433128), was successful in 8/11 patients (meningitis, 6/8 [75%]; nonmeningeal dissemination, 2/3 [66%]) and was well tolerated for a median treatment duration of 208 days.

Abstract Objective: To define the incidence of donor-derived infection (DDI) in recipients of solid organ transplant (SOT) from donors with positive blood cultures and to assess the impact of shorter versus longer duration of targeted preemptive antibiotic therapy (PAT). Design: Retrospective, single-center, cohort study. Setting: Mayo Clinic Arizona. Patients: Recipients transplanted between 1/1/2019 and 7/1/2024 who received an organ from a donor with positive blood cultures. Methods: The primary outcome was incidence of DDI. Secondary outcomes included duration of PAT and incidence of donor blood culture contamination. Results: Among 199 SOT recipients from 167 unique donors with positive blood cultures, two recipients developed confirmed DDI within 30 days of SOT. Both cases were gram negative bacillary bacteremia not treated in donors and occurred immediately posttransplant prior to adequate recipient PAT. Six-month graft survival and recipient survival were 96.5% and 97.5% respectively. 139 recipients (69.8%) received PAT for a median duration of 7 days. There was no difference in rate of infections between recipients provided with ≤7 days versus 8–14 days of PAT for donor blood cultures; however, recipients who received 8–14 days had more Clostridioides difficile infections (CDIs) within 60 days of SOT (7.7% vs 1.5% ≤ 7 days, P = .040) and were more often discharged on intravenous antibiotics (32.3% vs 11.3%, P < .001). Conclusion: We observed a low rate of DDI following receipt of organs from donors with positive blood cultures. DDI occurred in cases without adequate donor/recipient treatment. Longer durations of targeted PAT resulted in more CDI and intravenous antibiotics on discharge.

Abstract Background Outpatient antibiotic stewardship programs (ASP) are recommended by the CDC and Joint Commission. We analyzed the impact of annual, focused syndrome-specific ASP interventions on trends in long-duration antibiotic prescribing (LDAP). Methods This was a retrospective, observational, multicenter cohort study from November 2020 through June 2025. All ambulatory encounters generating systemic antibiotic prescriptions within the healthcare enterprise were screened. Hospitalizations, emergency department visits, and infectious diseases encounters were excluded. Encounters generating ≥1 systemic antibiotic with &gt;7 days duration were categorized as long-duration. Targeted departments (primary and urgent care) received direct intervention (eg, education, peer-comparison reporting, data tracking). LDAP was modeled over time by month and compared by diagnosis group (ASP-priority diagnoses vs nonpriority) and provider specialty department (ASP-targeted vs nontargeted) using linear regression models. Results Of 642 579 encounters included, 42.2% were long duration. LDAP in ASP-targeted departments dropped from 46.8% to 34.8% (difference −12 percentage points [pp]), whereas nontargeted departments dropped from 45.5% to 39.1% (difference −6.4 pp). The estimated annual LDAP decrease was 3.4 pp in targeted versus 2.4 pp in nontargeted departments (difference 1.0 pp, P = .009). Within targeted departments, significant LDAP decreases were seen both in priority and nonpriority diagnoses, whereas nontargeted departments showed no change in LDAP in priority diagnoses. In a sensitivity analysis of nonpriority diagnoses, ASP-targeted departments had a larger estimated annual decrease in LDAP versus nontargeted (difference 1.4 pp, P &lt; .001). Conclusions Annual syndrome-specific ASP interventions correlated with improvements in LDAP, including outside of priority syndromes in targeted departments. LDAP is a viable metric for evaluating ambulatory ASPs.

ABSTRACT Importance Rural-urban disparities in chronic disease prevalence are well established; however, the extent to which individual-level socioeconomic status (SES) contributes to these disparities remains unclear. Objective To examine the associations of rurality and SES with the prevalence of five most burdensome chronic diseases among adults. Design We conducted a retrospective cross-sectional study of adults across 27 Upper Midwest counties using the Expanded Rochester Epidemiology Project (E-REP) medical record data linkage system to evaluate associations between rurality, SES and chronic disease prevalence. Prevalence of clinically diagnosed asthma, diabetes, hypertension, coronary heart disease, and mood disorders was identified from International Classification of Diseases ICD9/10 codes over a five-year period (2014-2019). Setting Population based Participants Adults over 18 years residing in the 27 E-REP counties, excluding those missing rural-urban residence status. Exposure HOUSES index, an individual-level measure of SES, served as the primary measure, while rurality based on Rural Urban Commuting Area (RUCA) codes 4-10 was the secondary measure. Main Outcome Prevalence of the five clinically diagnosed chronic diseases was identified using ICD9/10 codes from 2014–2019. Mixed effect logistic regression models were used and adjusted for demographics and general medical examination receipt, to assess rural-urban and SES differences for prevalence of each chronic disease. Results Among 455,802 adults with available HOUSES index, 42.8% lived in rural areas, 53.8% were female and 87.4% were non-Hispanic White. In the unadjusted analysis, rural and urban populations showed comparable asthma and CHD prevalence, while mood disorders, hypertension, and diabetes were more common in urban areas. After adjusting for demographic factors and healthcare utilization, rural-urban differences were no longer statistically significant, whereas SES remained strongly associated with all diseases in a dose response manner (e.g., adjusted Odds Ratio for hypertension (ref: HOUSES index Q4): 1.14, 1.27, and 1.42 for HOUSES index Q3, Q2, and Q1, respectively). Conclusions and Relevance Individual-level SES measured by the HOUSES index, was more strongly associated with chronic disease prevalence than rurality, supporting its integration into population health assessment and risk stratification.

Abstract Background and Aims Stroke and systemic embolism are recognized but poorly characterized complications of atrial fibrillation (AF) and left atrial flutter (AFL) catheter ablation. Their incidence, outcomes, and procedural associations remain insufficiently defined. Methods Retrospective global registry was initiated by the European Heart Rhythm Association Scientific Committee. A secure database captured data from ablation centres worldwide on general AF and left AFL ablation activity, as well as detailed information on patients with symptomatic embolic events between 2017 and 2024. Results Overall, 204 centres reported 335 743 ablation procedures and 550 embolic events (incidence 0.16%). Centre-level rate ranged from 0% to 3.1%. Most events were cerebral (94%), followed by peripheral (5%), and combined (1%). Coronary air embolism accounted for 62% of all peripheral events. Intraprocedural events occurred in 93 patients (17%), within 72 h in 357 (78%) and beyond 72 h in 100 (22%); 128 cases (23%) were diagnosed after hospital discharge. Nonparoxysmal AF (0.23% vs 0.15%; P &lt; .001), centre experience, and ablation energy source (radiofrequency, 0.16%; cryoballoon, 0.16%; pulsed field ablation, 0.25%; laserballoon, 0.88%; P &lt; .001) were associated with embolic risk. Median NIHSS score after stroke was 4 (interquartile range, 2–9). Three-month follow-up was available for 518 patients with embolism (95%): 181 (35%) had sequelae and 16 (3%) died. Conclusions Symptomatic embolic events are infrequent but associated with significant morbidity and mortality. Most events occur early, though a substantial proportion arise later. Higher event rates were observed with laser and possibly with pulsed field ablation. A greater centre experience was associated with a lower embolism incidence.

Abstract Education and allergy referral via nurse-driven online messaging to patients (n = 1,284) with penicillin allergy labels (PALs) reduced PALs by 8.6%. The percentage decrease of “unknown” (14.8%) and “rash” (7.9%) PALs were higher vs “hives” (6.1%) and “itching” (1.4%) reaction types.

Summary The American Society of Clinical Psychopharmacology convened a 45-member international expert task force to identify circumstances supporting the deprescribing of core psychotropic medications for major depressive disorder (MDD) and bipolar disorders. Three Delphi survey rounds plus a selective literature review identified points of consensus (predefined as ≥75% agreement) about when antidepressant, antipsychotic, mood stabiliser and sedative-hypnotic deprescribing is warranted. Twenty out of 32 statements (63%) achieved consensus across seven thematic areas. In MDD, panellists favoured discontinuing antidepressants when mechanisms of action are duplicative, adequate trials produce ≤25% improvement or loss of prior efficacy cannot be regained through dose increases or augmentations. Indefinite antidepressant maintenance in MDD was favoured after three or more lifetime episodes. In bipolar disorder, antidepressant deprescribing was favoured in the setting of rapid cycling, mixed features or emerging mania/hypomania symptoms; and discouraged if prior antidepressant cessation led to relapse. In nonpsychotic mood disorders, panellists favoured deprescribing antipsychotics that caused significant weight gain or tardive dyskinesia over adding pharmacological antidotes. Deprescribing to achieve an eventual medication-free status was considered inappropriate, in bipolar type 1, but not necessarily bipolar type 2 disorder. Although individualised circumstances necessarily inform psychopharmacology management, clinical presentations that misalign with existing pharmacotherapies may signal the desirability of cautious deprescribing.

Abstract Background Artificial intelligence (AI)–based, mammography breast cancer risk prediction models show improved discriminatory accuracy relative to clinical risk models. However, data on their calibration are limited. This study compared model performance of 3 clinical breast cancer risk models: Gail, Tyrer–Cuzick v8, and Breast Cancer Surveillance Consortium v3 with the MIRAI AI-risk model. Methods Digital mammograms were ascertained from a screening mammography cohort of 12 308 women within the Mayo Clinic Biobank with 250 incident breast cancers (176 invasive) within 5 years. We predicted 5-year breast cancer risk, estimated discriminatory accuracy (C-index), and calibration (observed-to-expected ratio) of both overall and invasive breast cancer and compared estimates using bootstrapping approaches. Results MIRAI demonstrated similar or improved discriminatory accuracy of overall breast cancer (C-index = 0.71, 95% confidence interval [CI] = 0.68 to 0.74) and invasive breast cancer (C-index = 0.71, 95% CI = 0.67 to 0.75) compared with clinical models (overall breast cancer: C-index = 0.59-0.68; invasive breast cancer: C-index = 0.60-0.68). MIRAI’s calibration for risk of overall breast cancer (observed-to-expected ratio = 0.96, 95% CI = 0.85 to 1.08) was improved compared with Gail (observed-to-expected ratio = 1.22, 95% CI = 1.07 to 1.38) and Breast Cancer Surveillance Consortium (observed-to-expected ratio = 1.38, 95% CI = 1.22 to 1.56) but similar to TC with volumetric percent density and polygenic risk score (observed-to-expected ratio = 0.99, 95% CI = 0.87 to 1.13). However, for low-risk women (approximately 50%), MIRAI overestimated risk of overall breast cancer. MIRAI also overestimated risk of invasive breast cancer across the risk spectrum (observed-to-expected ratio = 0.68, 95% CI = 0.58 to 0.78), whereas clinical models had good calibration (observed-to-expected ratio = 0.86–0.99). Conclusion MIRAI demonstrated stronger discriminatory accuracy than clinical models for 5-year overall and invasive breast cancer risk prediction but overestimated risk for both breast cancer endpoints. AI-based risk models should consider discriminatory accuracy and calibration for invasive cancer before implementation.