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Despite advances in cardiovascular care and improved outcomes, fragmented healthcare systems, nonequitable access to health care, and nonuniform and unbiased collection and access to healthcare data have exacerbated disparities in healthcare provision and further delayed the technological-enabled implementation of precision medicine. Precision medicine relies on a foundation of accurate and valid omics and phenomics that can be harnessed at scale from electronic health records. Big data approaches in noncardiovascular healthcare domains have helped improve efficiency and expedite the development of novel therapeutics; therefore, applying such an approach to cardiovascular precision medicine is an opportunity to further advance the field. Several endeavors, including the American Heart Association Precision Medicine platform and public-private partnerships (such as BigData@Heart in Europe), as well as cloud-based platforms, such as Terra used for the National Institutes of Health All of Us, are attempting to temporally and ontologically harmonize data. This state-of-the-art review summarizes best practices used in cardiovascular genomic and precision medicine and provides recommendations for systems’ requirements that could enhance and accelerate the integration of these platforms.

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol >1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI <30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P < 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.

ABSTRACTThe incidence of ischemic cholangiopathy (IC) is expected to remain significant due to rising rates of transplants performed with livers donated after circulatory death (DCD), despite the use of machine perfusion. Absent established pharmacologic interventions against this progressive etiology of allograft dysfunction and failure, we describe the use of fenofibrate—a cheap and widely‐accessible peroxisome proliferator‐activated receptor agonist that downregulates bile acid production—to impede IC progression in 15 DCD liver recipients who were not responding to reactive, standard‐of‐care management. All patients were undergoing serial endoscopic retrograde cholangiopathy (ERC) to maintain biliary patency but demonstrated progressive cholestasis, with serum alkaline phosphatase (ALP) rising 70.3% over the 90 days preceding fenofibrate. Cholestasis improved in all patients after fenofibrate initiation, with a 63.9% reduction in mean ALP at 90 days, maintained at 270 days (p = 0.02) and 360 days (p = 0.06). ALP improvement was associated with reduced ERC frequency during and after fenofibrate treatment, and this improvement was independent of concurrent ERC or ursodeoxycholic acid use during fenofibrate treatment. In patients who stopped treatment, ALP increased. No fenofibrate‐associated adverse events were seen. These preliminary data support the further study of agents that downregulate bile acid production as a means of impeding IC in DCD livers.

Background: In Kienböck disease with carpal collapse scaphocapitate fusion (SCF) and proximal row carpectomy (PRC), are mainstays of surgical treatment. This study analyzed objective and patient-reported outcomes after SCF or PRC in laborers versus nonlaborers. Methods: A retrospective cohort study of patients who underwent surgery for Kienböck disease within a single health system from 1976 to 2023 was conducted. Postoperative Disabilities of the Arm, Shoulder, and Hand (DASH) and Patient-Rated Wrist Evaluation (PRWE) scores were surveyed from the available population. Labor status, grip, ROM, and return to the operating room were collected and radiographs were analyzed. Results: Sixty-four patients underwent PRC, and 78 underwent SCF. Patients with PRC were significantly older than patients with SCF. Mean follow-up was 29 months (SD, 53 months). There was no significant difference in postoperative ROM or relative grip strength between the cohort groups. Laborers who underwent SCF demonstrated the least disability on DASH scores. There was no significant difference in postoperative DASH scores in PRC when comparing laborers versus nonlaborers. In contrast, the DASH and PRWE scores of patients who underwent SCF postoperatively varied between laborers and nonlaborers (mean ± SD, 11.1 ± 13.9 versus 30.5 ± 24.8, P = 0.005; and 17.5 ± 19.4 versus 42.3 ± 31.4, P = 0.024). Patients who underwent SCF had a greater rate of revision surgery compared with the PRC group (22 of 78 versus 6 of 64; P = 0.026). Wrist fusion rates were 19% for SCF compared with 1.6% for PRC ( P = 0.0007). Conclusions: SCF and PRC demonstrated no difference in postoperative ROM and grip based on labor status. Laborers with SCF had the least postoperative disability on DASH; however, SCF was associated with the need for additional surgical intervention and conversion to total wrist arthrodesis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutc, III.

Background: When injuring the anterior cruciate ligament (ACL), simultaneous meniscal tears often occur. However, little data describe ACL reconstruction (ACLR) and the subsequent risk of revision ACLR, as well as cartilaginous and meniscal damage after primary ACLR with different treatments for injury of the lateral meniscus (LM). Purpose: To investigate (1) how different LM treatments during primary ACLR affect the odds of revision ACLR and the cartilaginous and meniscal status at revision in a long-term follow-up and (2) whether the increased risk of subsequent meniscal and cartilaginous injuries seen with meniscal resection in the short term would continue in the long term, and (3) the increased risk with subsequent meniscal injuries with meniscal repair. Study Design: Cohort study; Level of evidence, 3. Methods: Data from the Swedish National Knee Ligament Registry were used. The study compared 2 groups: patients with isolated ACLR and patients with ACLR and concomitant LM injury, further subdividing the latter into 4 treatment types: repair, resection, both, and left in situ. Patients with medial meniscal injuries were excluded. The main outcomes studied were the odds for revision ACLR and the cartilaginous and meniscal status at revision 5 and 10 years after primary surgery. Results: Data for 5 years were available for 22,208 patients and data for 10 years were available for 11,058 patients. Compared with isolated ACLR, patients with concomitant LM injury left in situ had higher odds of revision ACLR at both 5 years (odds ratio [OR], 1.49; 95% CI, 1.14-1.95; P = .004) and 10 years (OR, 1.55; 95% CI, 1.09-2.19; P = .01), while those with LM repair had higher odds at 5 years (OR, 1.73; 95% CI, 1.23-2.43; P = .002). LM repair also increased the odds of subsequent meniscal injuries at 5 years (OR, 3.52; 95% CI, 1.76-7.03; P = .0004) and 10 years (OR, 7.26; 95% CI, 1.67-31.52; P = .008). Partial meniscectomy did not show an increased risk of cartilage injury, subsequent meniscal injury, or revision ACLR at long-term follow-up compared with the control group. Conclusion: This demonstrates that over 5 and 10 years, LM repair during primary ACLR is associated with an increased risk of revision ACLR and subsequent meniscal injuries. The higher risk of revision ACLR when the LM is left in situ emphasizes the need for careful consideration of treatment methods. Conversely, partial meniscectomy did not show an associated increased risk of cartilaginous injury in the long term and is associated with a lower risk of subsequent meniscal injury and revision ACLR than other treatment options, raising questions about whether preserving the meniscus at all costs is always the best approach.

Abstract The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. ctDNA minimal residual disease after chemoradiotherapy (CRT) for non–small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. In this study, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration is prognostic for disease progression and integrate additional pre-CRT risk factors, including radiomics, into a combined model that improves outcome prediction. Our results suggest that tumor features, radiomics, and mid-CRT ctDNA analysis are complementary and can identify patients at high and low risk of progression to potentially enable response-adapted therapies. Significance: This study demonstrates that combining tumor features, radiomics, and ctDNA analysis improves outcome prediction in NSCLC treated with CRT therapy. Our integrated model could enable personalized and response-adapted therapies to reduce toxicity and improve outcomes in patients. See related commentary by Anagnostou and Aggarwal, p. 1534

Background We hypothesized treatment with nivolumab and stereotactic radiosurgery (SRS) would be feasible, well tolerated, and may improve intracranial tumor control over SRS alone for breast cancer brain metastases (BCBM). Methods The study is a phase Ib trial of nivolumab and SRS for BCBM. Clinical trial information: NCT03807765 . Key eligibility criteria include BCBM of all subtypes, age ≥18, Eastern Cooperative Oncology Group Performace Status (ECOG-PS)≤2 with ≤10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg intravenously) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. Blood was collected at baseline and every 4 weeks for flow cytometry and cell-free DNA (cfDNA) assessment. Results A total of 12 patients received SRS to 17 brain metastases. Breast cancer subtypes included triple negative (50%), hormone receptor (HR)+/HER2− (33%), and HR−/HER2+ (17%). Median follow-up from start of protocol therapy is 56 months. No cases of radionecrosis were noted. Two lesions were noted to undergo local failure, both pathologically confirmed, for a 12-month local control of 94%. Median distant intracranial control was 7.4 months with a 12-month control rate of 33%. Median systemic progression-free survival was 7.7 months with a 12-month rate of 42%. Median overall survival (OS) was 24.7 months with a 12-month OS of 75%. Most patients were noted to have an increase in cfDNA throughout study treatment, at week 5 compared with baseline (83%), week 25 compared with baseline (89%), and 100% at first follow-up. Intracranial control was associated with lower levels of CD4 regulatory T cells (Treg) (p=0.03) and higher levels of CD4 T effector memory (p=0.04). Conclusions Nivolumab and SRS is a safe and feasible treatment option in BCBM. Long-term follow-up revealed no cases of radiation necrosis. Trial registration number NCT03807765 .

Purpose: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) improves prostate cancer (PCa) localization, particularly in biochemical recurrence (BCR). The primary objective was to assess management patterns after PSMA-PET for BCR at 2 academic centers. Methods: This study evaluated clinical management within 6 months after first PSMA-PET for patients with BCR after local therapy. Management categories included no treatment, local therapy, systemic therapy, and metastasis-directed therapy (MDT). We also evaluated clinical management decision variation across strata of PSMA-PET results PSA levels (<2.0, 2.0-4.99, and ≥5.0 ng/mL) at time of imaging. Results: We identified 581 patients who received PSMA-PET from February 2021 to June 2023. PSMA-PET findings were negative in 142 (24%) and demonstrated localized recurrence in 86 (15%), regional nodal disease in 60 (10%), and distant metastasis in 293 (50%). Distant metastasis was identified in 105 (35%) patients with PSA < 2.0, 67 (60%) with PSA 2.0 to 4.99, and 115 (71%) with PSA ≥ 5.0. In patients with negative PSMA-PET, 63 (44%) received treatment. Conversely, 92% with detected metastases were treated (systemic therapy in 189 [64%], MDT in 75 [26%], and local therapy in 7 [2%]). Treatments differed by the PSA level within strata of PSMA-PET findings. Among 293 patients with metastases, MDT was used more commonly in patients with PSA < 2.0 (37%) than PSA 2.0 to 4.99 (30%) or PSA ≥ 5.0 (13%). Conclusions: Most patients undergoing PSMA-PET for BCR had identifiable disease and initiated therapy within 6 months. Identification of distant metastases and treatment choices differed by the PSA level at imaging. Prospective research is needed to determine whether earlier detection and treatment initiation improve clinical outcomes.