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Importance Neoadjuvant systemic therapy (NST) has been associated with pathologic complete response (pCR) in up to 60% of breast cancers (BCs). The findings of this trial question the necessity of surgery. Objective To report preplanned 5-year efficacy outcomes evaluating radiotherapy alone without breast surgery in patients selected with image-guided vacuum assisted biopsy (VAB). Design, Setting, and Participants This single-arm, prospective, phase 2 nonrandomized clinical trial was conducted at 7 US medical centers and included women 40 years or older with cT1-2N0-1M0 ERBB2 -positive (formerly HER2 -positive) or triple-negative invasive BC who showed residual breast lesions after NST of less than 2 cm on imaging. Enrollment was from March 6, 2017, to November 9, 2021. Data analysis was from October to December 2024. Intervention Image-guided VAB of the tumor bed (9G with a minimum of 12 cores) was performed after standard NST. Patients with clinically node-negative disease at diagnosis and no residual cancer in the breast on post-NST VAB underwent whole-breast radiotherapy with a boost without breast or axillary surgery. Patients with initial documented nodal disease and a breast pCR on VAB underwent targeted axillary dissection, while those with residual cancer when undergoing VAB had standard breast and axillary surgery. Patients were monitored with physical examinations and mammography every 6 months. Main Outcome Measures The primary outcome was ipsilateral breast tumor recurrence. Results Fifty patients (median [IQR] age, 62 [55-77] years) were enrolled and underwent post-NST VAB. Twenty-nine (58%) and 21 (42%) patients had ERBB2 -positive and triple-negative invasive BC, respectively. Breast pCR on VAB was identified in 31 patients (62%; 95% CI, 47.2%-75.34%), and axillary pCR was identified among all 8 patients with initial nodal metastases and breast pCR on VAB who underwent targeted axillary dissection. At a median follow-up of 55.4 (IQR, 44.0-63.5) months, the ipsilateral breast tumor recurrence rate was 0%, and disease-free and overall survival rates were 100% for patients without breast surgery. Conclusions and Relevance The results of this nonrandomized clinical trial that reported preplanned 5-year outcomes suggest that omission of breast surgery in select patients after NST may be feasible, with no recurrences seen. More confirmatory studies are necessary before this new approach alters surgical practice. Trial Registration ClinicalTrials.gov Identifier: NCT02945579

Toxins from ingested water can significantly affect overall physical health in children and adults. In the United States, domestic water wells are not commonly tested for any heavy metal contaminants. It is well-known that chronic arsenic ingestion from water is linked to serious health effects. We surveyed patients at our academic institution via emailed questionnaires in 2023 to determine whether those with children living at home reported different patterns of behavior around well water testing as compared to those without. Survey data were collected from 8994 respondents in the U.S. Midwest who reported using residential well water. Results were used to evaluate the influence of children in the home on testing behaviors, and secondarily, whether parental demographics affected testing frequency. Respondents with children at home did not report increased testing frequency compared to those without. In parents who did report testing, having more children, being younger, and living in Wisconsin were associated with an increased frequency. Parental gender, race, and ethnicity did not correlate with testing behaviors. A total of 70% of respondents did not feel concerned about their water safety and 85% were not concerned about arsenic specifically in their water. Increased risk of toxicity to children from arsenic does not appear to influence reported well water testing behavior among parents.

BACKGROUND: In the Myocardial Infarction Genes clinical trial (URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01936675), participants at intermediate risk of coronary heart disease (CHD) were randomized to receive a Framingham risk score (Framingham risk score group, n=103) or an integrated risk score (integrated risk score group [IRS g ], n=104) that additionally included a polygenic risk score. After 6 months, IRS g participants had higher statin initiation and lower low-density lipoprotein cholesterol. We conducted a post hoc 10-year follow-up analysis to investigate whether disclosure of a polygenic risk score for CHD was associated with a reduction in major adverse cardiovascular events (MACE). METHODS: Participants were followed from randomization in October 2013 to September 2023 to ascertain MACE, testing for CHD, and changes in risk factors. The primary outcome was time to first MACE, defined as cardiovascular death, nonfatal myocardial infarction, coronary revascularization, and nonfatal stroke. Statistical analyses included Cox proportional hazards regression and linear mixed-effects models. RESULTS: We followed all participants who completed the trial, 100 in Framingham risk score group and 103 in IRS g (mean age at the end of follow-up, 68.2±5.2; 48% male). During a median follow-up of 9.5 years, 9 MACEs occurred in Framingham risk score group and 2 in IRS g (hazard ratio, 0.20 [95% CI, 0.04–0.94]; P =0.042). In Framingham risk score group, 47 (47%) underwent at least 1 diagnostic test for CHD, compared with 30 (29%) in IRS g (hazard ratio, 0.51 [95% CI, 0.32–0.81]; P =0.004). A higher proportion of IRS g participants were on statin therapy during the first 4 years postrandomization and had a greater reduction in low-density lipoprotein cholesterol for up to 3 years postrandomization. No significant differences were observed between 2 groups in other traditional cardiovascular risk factors during follow-up. CONCLUSIONS: Disclosure of an integrated risk score that included a polygenic risk score to individuals at intermediate risk for CHD was associated with lower MACE incidence after 10 years, likely due to higher statin initiation, leading to lower low-density lipoprotein cholesterol levels.

Background/Objectives: This study aimed to establish the clinical utility of a therapeutic drug monitoring (TDM)-supported, model-informed precision dosing (MIPD) approach (precision-guided dosing [PGD]) by assessing the impact of pharmacokinetic (clearance [CL]) and clinical laboratory parameters on adalimumab (ADA) dosage adjustments during maintenance therapy for inflammatory bowel disease (IBD). Methods: In the EMPOWER study, blood was collected at any time post-ADA injection. Pharmacokinetic (PK) testing was conducted in an accredited lab. Inputs for the PGD test included ADA concentrations, antibodies to ADA, albumin levels, and the current dosing regimen. CL was calculated using nonlinear mixed-effect models. Results were reported to health care providers (HCPs) within 3 days. HCPs’ treatment decisions were recorded and classified as treatment reduction, continuation, intensification, or ADA discontinuation. The physician global assessment (PGA) of disease activity was collected. Relationships between drug concentrations, CL, disease activity, and physician decision-making were assessed using logistic regression. Results: A total of 213 cases were assessed by 21 HCPs. ADA treatment was intensified in 24% and discontinued in 13% of cases. An ADA concentration ≤ 10 μg/mL was associated with a 23.7-fold and 3.0-fold higher likelihood of therapy intensification and PGA > 0, respectively, compared to concentrations > 10 μg/mL. An ADA concentration < 5 μg/mL was associated with a 3.3-fold higher likelihood of treatment discontinuation. CL ≥ 0.318 L/day was associated with a 10.4-fold higher likelihood of therapy intensification. Higher CL (>0.8 L/day) was associated with a 3.5-fold and 4.2-fold higher likelihood of treatment discontinuation and PGA > 0, respectively. Conclusions: PGD enables earlier and precise optimization of ADA dosing by predicting trough levels at any time during the therapy cycle. Optimized dosing to achieve target ADA concentrations and low clearance is crucial to mitigate therapy discontinuation and active disease in IBD patients.

Background/Objectives: With the growing population of kidney transplant recipients (KTRs) in intensive care units (ICUs), understanding their prognostic outcomes is critical. As conflicting findings exist, we aim to systematically evaluate and meta-analyze ICU outcomes in kidney transplant recipients compared to non-recipients. Methods: We conducted a comprehensive search of the PubMed, Embase, and Cochrane databases, from inception through 23 December 2024, to identify relevant studies comparing the outcomes of KTRs and non-transplant ICU patients. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes, and weighted mean differences (WMDs) were calculated for continuous outcomes. The risk of bias was assessed using the ROBINS-I V2 tool. The study protocol was registered in the International Prospective Register of Systematic Reviews (CRD42024595104). Results: Seven studies, including 12,062 patients, were analyzed. Demographics, including age and sex, were comparable across groups. No statistically significant associations were found for overall mortality (OR: 1.82, 95% CI: 0.79 to 4.16), ICU mortality (OR: 1.06, 95% CI: 0.45 to 2.48), or 28/30-day mortality (OR: 2.06, 95% CI: 0.30 to 14.10) in KTRs, though there was a trend suggesting a potential increase in the odds of overall mortality. KTRs tended to have longer ICU stays (WMD: +1.96 days, 95% CI: 0.81–3.11) and higher Sequential Organ Failure Assessment (SOFA) scores (WMD: +0.79, 95% CI: −0.78–2.36), but these findings did not reach statistical significance. One study reported higher 1-year and 5-year mortality for KTRs. Sensitivity analyses revealed one influential study. Begg’s test for overall mortality suggested non-significant publication bias (p = 1.0). Conclusions: KTRs in ICUs are at significantly higher risk for long-term mortality, emphasizing the need for tailored critical care strategies and long-term management. Future research should focus on standardizing methodologies, reducing heterogeneity, and addressing gaps in data to improve evidence-based care for this vulnerable population.

Abstract The advent of high-throughput sequencing has led to an exponential increase in genomic data, highlighting the need for efficient and accurate models to analyze and interpret this information. Here, we introduce a novel, exomic foundational model that leverages a combination of human reference genome and multispecies data to improve variant detection and interpretation. Our model utilizes a short- range transformer architecture and is trained on a large dataset of human exomic sequences derived from the Tapestry study. Through a series of ablation studies and scaling experiments, we demonstrate the effectiveness of our model in pre- dicting next token accuracy and identifying clinically pathogenic variants. We also show that our model outperforms existing models in a range of downstream tasks, including variant effect prediction and disease state identification. In fact, our largest STRAND variant (1B parameters) surpassed previous benchmarks, demonstrating a mean accuarcy of 0.880 (8.2% improvement over the original NT and 7% improvement over NT-v2). Furthermore, we construct a unique exomic ClinVar dataset to evaluate the model’s performance on pathogenicity and disease states. Our results highlight the potential of this model to improve our understanding of the human exome and its role in disease. The model and its applications have significant implications for genomic based diagnosis and personalized medicine including tailored therapeutic development.

INTRODUCTION: Building on prior results, we hypothesized that an electrocardiogram (ECG)-enabled machine learning (ML) model could be used to detect advanced chronic liver disease (CLD). METHODS: A cohort with CLD and 12-lead ECGs was matched with controls from electronic health records. A ML model was trained as a binary classifier. RESULTS: There are 12,930 patients with CLD and 64,577 controls in the cohort. The model's discriminative ability to classify CLD showed an area under the receiver-operating characteristic curve 0.858 (95% confidence interval: 0.850–0.866), and at the chosen threshold, CLD ECGs had 12 times higher odds of being classified as CLD (diagnostic odds ratio 12.33, 95% confidence interval: 11.16–13.63). DISCUSSION: An ECG-enabled ML model affords great promise in identifying advanced CLD in low resource areas.

INTRODUCTION: Patients with inflammatory bowel disease (IBD) are at an increased risk of infections. Before the COVID-19 pandemic, respiratory syncytial virus (RSV) followed predictable seasonal patterns, which have been recently disrupted. This study aimed to investigate whether severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) infection is associated with an increased risk of RSV infection in patients with IBD compared with those without a history of SARS-CoV-2 infection. METHODS: This retrospective cohort study used the TriNetX database to identify patients aged 18 years and older with IBD and SARS-CoV-2 infection (IBD-SARS-CoV-2 cohort) during the 2022 and 2023 RSV seasons. A 1:1 propensity score matching was used to compare patients with IBD but no history of SARS-CoV-2 infection (IBD non-SARS-CoV-2 cohort). RESULTS: In the 2022 IBD-SARS-CoV-2 cohort (mean age: 53.7 ± 17.6 years; 59% female; 77% White), the RSV infection risk was 0.47%, higher than 0.19% in the matched IBD non-SARS-CoV-2 cohort (adjusted odds ratio [aOR]: 2.4; 95% CI: 1.5–3.6). The risk was highest 30–60 days after SARS-CoV-2 infection (aOR: 2.9; 95% CI: 1.7–4.9), particularly in those aged 60 years and older (aOR: 2.5; 95% CI: 1.3–4.5). The use of systemic corticosteroids (aOR: 2.3; 95% CI: 1.1–4.6) or immune-modifying therapies (aOR: 3.9; 95% CI: 2–7.1) was associated with higher RSV infection risk. Similar trends were observed during the 2023 RSV season, with no significant differences in RSV-related hospitalizations. DISCUSSION: Adults with IBD have a higher risk of RSV infection after SARS-CoV-2 infection, particularly those receiving steroids or immune therapies. SARS-CoV-2 infection may have contributed to the recent RSV infection surge in this population, warranting further research.