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Background: Plantar vein thrombosis (PVT) is a rare cause of unilateral plantar foot pain not commonly assessed during sonographic scans for venous thromboembolic evaluation. The present study aims to increase awareness of PVT when evaluating musculoskeletal conditions and to discuss the utility and characteristic imaging findings of PVT on magnetic resonance imaging (MRI). Methods: This is a retrospective chart review identifying patients with suspected PVT via search of a single institution’s radiology reports. Twelve patients had an available lower extremity MRI. These 12 MRIs were independently reviewed by 2 fellowship-trained musculoskeletal radiologists for common imaging characteristics. Of note, only 7 of the 12 available imaging studies contained MRI findings consistent with PVT as determined by the radiology reviewers. For these 7 patients, clinical characteristics were also recorded. Results: Between both radiology reviewers, there was 100% agreement confirming, localizing, and describing the findings of PVT. Of the 7 cases of MRI-confirmed PVT, 6 of 7 studies were performed without contrast and 1 of 7 was performed with and without contrast. The lateral plantar vein was the predominant vein involved in 85.7% (6/7). All 7 cases showed signs of intraluminal signal change, venous enlargement, and muscle edema. Two cases (28.6%, 2/7) displayed collateralization and/or enlargement of surrounding veins. In the only MRI performed with contrast, perivascular enhancement and a filling defect were noted. Conclusion: In the evaluation of a painful foot, an MRI can be used to diagnose PVT reliably and may have several advantages over compression ultrasonography (US) because of its ability to identify other unsuspected etiologies of a painful foot and elimination of technical limitations of compression US in the plantar foot region.

Objective: To establish benchmark cutoffs for robotic liver resection (R-LR), encompassing both major and minor resections, and to determine the impact of patient selection on outcomes. Background: R-LR is a key advancement in minimally invasive liver surgery but lacks standardized benchmarks, especially for minor resections. While guidelines endorse R-LR, its role in optimizing outcomes remains unclear. This study establishes the first benchmarks for R-LR, enabling comparisons across surgical modalities and refining patient selection. Methods: This retrospective, multicenter study analyzed consecutive adult patients undergoing R-LR at 30 international centers (2020–2023). Benchmark centers had an annual case volume of ≥15 R-LR. Benchmark criteria included ASA ≤2, no major comorbidities, no prior liver resections, and Child-Pugh A status. Benchmark cutoffs for 14 key outcomes were set at the 50th and 75th percentiles of median values across benchmark centers. Multivariable logistic regression identified predictors of textbook outcomes. Results: Eighteen high-volume centers contributed 4028 cases with 2632 (65.3%) meeting benchmark criteria. Malignancy was the indication in 29.6%, most commonly hepatocellular carcinoma followed by colorectal liver metastases. Major liver resection was performed in 42.6%. The distribution of Iwate difficulty scores was low (25.4%), intermediate (53.9%), advanced (15.9%), and expert (4.9%). Benchmark cutoffs were established for minor and major resection, and stratified by Iwate low (0-3), intermediate (4-6) and high (7-12): Open conversion (≤6.5% minor, ≤10.5% major), major complications within 90 days (≤5.2% minor, ≤16.7% major), R1 resection (≤9.2% minor, ≤6.7% major). Benchmark cases performed at low-volume centers were able to achieve outcomes within the corresponding benchmark cutoffs. In fact, patient selection reflected by the proportion of benchmark patients, rather than case volume, was associated with textbook outcomes. Conclusions: This study defines R-LR benchmarks, emphasizing patient selection over center volume for optimal outcomes. Benchmark cutoffs guide training and support the expansion of R-LR.

Abstract Background Robotic Whipple holds the promise to overcome safety concerns associated with laparoscopy, paving the way for widespread implementation of minimal-invasive surgery in this complex procedure. However, randomized data comparing robot vs. open Whipple demonstrate more pancreas-specific complications and R1-resections in the robotic arm. Recent international consensus identified establishing benchmarks as critical to ensure safe adoption of the robot. Benchmarking is a validated quality improvement tool, enabling comparison of surgical performance. Aims The aim was to define benchmarks for outcome parameters in robotic Whipple. Methods We analyzed consecutive patients undergoing robotic Whipple from January 2020 until December 2023 in 11 centers across 4 continents, with a minimum one-year follow-up. Centers had to perform ≥15 cases/year and have mounted their learning curve. Benchmark criteria included benign or resectable malignant disease without neoadjuvant therapy, arterial resection, major co-morbidities, or significant previous abdominal surgery. Medians across centers represented benchmark cutoffs. Results Eleven centers performed 1’037 Whipple procedures, of which 603 (58%) were benchmark cases. One third (n=192) were pancreatic ductal adenocarcinoma (PDAC) patients. Key benchmarks at 6 months included ≤1.2% mortality, ≤24.2% major complications, and ≤ 8.7 points Comprehensive Complication Index®. Pancreas-specific cutoffs included ≤13.0% postoperative pancreatic fistula (POPF) B/C and ≤3.4% post-pancreatectomy hemorrhage B/C, with 100% R0-resection and ≥19 harvested lymph nodes in PDAC patients. One-year actuarial overall and recurrence-free survival was 87% and 77%. In the entire cohort POPF B/C occurred in 16% (n=195). Independent POPF predictors included duct diameter ≤4mm (OR 1.79 95%CI [1.27-2.55]), anticoagulation (OR 3.68 95%CI [2.14-6.24]), and indication other than PDAC (OR 3.17, 95%CI [2.13-4.85]). Conclusion This study establishes benchmarks for key outcomes in robotic Whipple, demonstrating oncologic adequacy and morbidity comparable to open surgery. Risk factors for POPF in open surgery also hold true in the robotic approach.

Abstract Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observed comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identified distinct NSCLC-like (KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling revealed stable mutational but shifting transcriptomic landscapes over time. NSCLC-like LCNECs showed elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression, while SCLC-like subtypes expressed higher levels of DLL3. Immunofluorescence confirmed FGL-1 in NSCLC-like LCNECs, and H&E slide analyses indicated fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

INTRODUCTION: The SPEC-AI Nigeria trial (NCT05438576) was designed to use artificial intelligence (AI) to screen for pregnancy-related cardiomyopathy in the peripartum period. Using data from this study, we evaluated the utility of AI-predicted delta age (adjusted AI-predicted age − chronological age) as a surrogate for biological age. METHODS: We included 1,187 pregnant and postpartum women enrolled between August 2022 and September 2023 with follow-up through May 2024. Standard 12-lead electrocardiograms (ECGs) were recorded at study entry to generate AI age predictions. Artificial intelligence-predicted age was adjusted using estimated reference ranges obtained from a community-dwelling cohort of 25,144 individuals with AI-ECG age estimated and documented chronological age. Logistic and Cox-proportional hazards regression were used to examine associations with comorbid cardiovascular conditions and maternal mortality, respectively. RESULTS: Adjusted AI-predicted age was significantly higher among women with any cardiovascular condition, peripartum cardiomyopathy, or who died within 18 months (7, 14, and 23 years older, respectively) compared to those without these conditions who had values similar to the normal reference ranges (adjusted AI-predicted age difference less than 1 year). Artificial intelligence-predicted delta age greater than the 75th percentile was associated with an odds ratio (OR) of 2.06 for any cardiovascular condition, OR of 4.98 for left ventricular systolic dysfunction, and a hazard ratio of 32.81 for all-cause mortality; all values of P<.001. CONCLUSIONS/IMPLICATIONS: Artificial intelligence-ECG-derived biological age appears to be a potentially useful measure of cardiovascular health status and risk among pregnant and postpartum women. However, its role in monitoring maternal health requires further exploration.

Background: Currently, biomarkers do not have a role in diagnosis or outcome prediction models for patients with recurrent anterior shoulder instability. Purpose/Hypothesis: The purpose of this study was to compare gene expression differences in the blood and tissue of patients with anterior shoulder instability with and without significant glenoid bone loss (GBL). The hypothesis was that the severity of GBL would be associated with the expression level of genes in the blood and capsular tissue of patients with anterior shoulder instability. Study Design: Descriptive laboratory study. Methods: Consecutive patients with anterior shoulder instability undergoing arthroscopic and open shoulder stabilization were prospectively enrolled. Blood and anterior capsular tissue specimens obtained during surgery were compared between patients with significant GBL (≥10%) and patients without significant GBL (<10%). RNA was extracted, and a panel of 277 inflammatory genes was utilized to quantify gene expression at the RNA level using a probe-based RNA quantification platform. Differential expression analysis was performed to identify genes expressed at different levels between patients with and without significant GBL. The expression levels of the subset of genes identified were used to generate a ridge regression model to predict the severity of GBL. Quantitative polymerase chain reaction was performed to confirm probe-based RNA findings. Results: A total of 17 patients were included, with a mean age of 26 years. Overall, 7 patients had <10% GBL (mean, 2.3%), and 10 patients had ≥10% GBL (mean, 16.4%). There were 9 genes that were identified as significantly differentially expressed in the blood, and 5 of these ( IFIT1 , IFIT3 , IFI44 , PRKCB , and OAS2 with P values of 1 × 10 −5 , 1 × 10 −4 , 1 × 10 −4 , 1 × 10 −4 , and 6 × 10 −4 , respectively) were confirmed using nonparametric tests. The authors developed a model using the 5 genes to predict the severity of GBL, and this had an accuracy of 88% (95% CI, 64%-99%). By quantitative polymerase chain reaction, IFIT3 was confirmed to be significantly differentially expressed ( P = .012). Conclusion: There were significant gene expression differences in the blood of patients with (≥10%) and without (<10%) significant GBL. The differential expression of 5 genes allowed for the development of an accurate predictive model and transcriptomic biomarker to predict the severity of GBL. Clinical Relevance: The addition of a blood biomarker to current outcome prediction models may provide increased accuracy in identifying those at risk of failure from arthroscopic Bankart repair.

Importance Circulating tumor human papillomavirus DNA (ctHPVDNA) is an important biomarker for the presence of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), but little is known about early postoperative kinetics of ctHPVDNA clearance. Objective To investigate early postoperative kinetics of ctHPVDNA in patients with HPV-associated OPSCC. Design, Setting, and Participants This prospective cohort study was conducted at a single tertiary care center from January 4, 2020, to January 26, 2023. Patients with newly diagnosed HPV-associated OPSCC undergoing surgical management were enrolled. HPV status was defined as positive if findings of p16 immunohistochemistry and/or HPV DNA in situ hybridization and/or E6/E7 RNA in situ hybridization were positive. Exclusion criteria included history of prior head and neck cancer and metastatic disease at presentation. Data were analyzed from September 1, 2024, to April 25, 2025. Exposures Transoral robotic surgery with concurrent neck dissection. Main Outcomes and Measures Blood was drawn prior to surgery (pretreatment), 1 to 2 days after surgery (postoperative days 1 to 2), and approximately 2 weeks after surgery (postoperative week 2; range, 8 to 20 days). ctHPVDNA was quantified by a tumor tissue–modified viral (TTMV) HPV DNA test. Correlations were tested between the pretreatment and postoperative day 1 to 2 TTMV HPV DNA levels using Gaussian regression. Concordance between detectability at postoperative day 1 to 2 and postoperative week 2 was explored using negative predictive value and positive predictive value. Results Of 57 included patients with detectable pretreatment TTMV HPV DNA, 51 (89%) were male, and the median (IQR) age was 59 (54-66) years. A total of 35 patients (61%) had blood draws at all 3 time points; 16 (28%) had detectable TTMV HPV DNA on postoperative day 1 to 2. Pretreatment and postoperative day 1 to 2 TTMV HPV DNA levels had a medium positive linear correlation ( r = 0.31; 95% CI, 0.04-0.54). Undetectable TTMV HPV DNA on postoperative day 1 to 2 blood draw had a negative predictive value of 0.95 (95% CI, 0.74-1.00) for an undetectable level on postoperative week 2 blood draw, but a detectable level on postoperative day 1 to 2 blood draw only had a positive predictive value of 0.19 (95% CI, 0.04-0.46). Of the 16 patients with detectable TTMV HPV DNA pretreatment and at postoperative day 1 to 2, only 3 (19%) continued to have detectable TTMV HPV DNA at postoperative week 2. One patient had undetectable levels at postoperative day 1 to 2 and detectable levels at postoperative week 2. Conclusions and Relevance In this study, ctHPVDNA detectability early after surgery did not predict detectability at 2 weeks after surgery. ctHPVDNA clearance early after surgery could predict a negative test at 2 weeks. A negative blood draw finding on postoperative day 1 may be used to omit a postoperative blood draw at 2 weeks for minimal residual disease detection in future clinical trials.

Abstract Background Preexisting diabetes (PDM) increases the risk of maternal and perinatal mortality and morbidity. Reduction of maternal hyperglycemia prior to and during pregnancy can reduce these risks. Despite compelling evidence that preconception care (PCC), which includes achieving strict glycemic goals, reduces the risk of congenital malformations and other adverse pregnancy outcomes, only a minority of individuals receive PCC. Suboptimal pregnancy outcomes demonstrated in real-world data highlight the need to further optimize prenatal glycemia. New evolving technology shows promise in helping to achieve that goal. Dysglycemia is not the only driver of poor pregnancy outcomes in PDM. The increasing impact of obesity on pregnancy outcomes underscores the importance of optimal nutrition and management of insulin sensitizing medications during prenatal care for PDM. Objective To provide recommendations for the care of individuals with PDM that lead to a reduction in maternal and neonatal adverse outcomes. Methods The Guideline Development Panel (GDP) composed of a multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 10 clinically relevant questions related to the care of individuals with diabetes before, during and after pregnancy. The GDP prioritized randomized controlled trials (RCTs) evaluating the effects of different interventions (eg, PCC, nutrition, treatment options, delivery) during the reproductive life cycle of individuals with diabetes, including type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Systematic reviews queried electronic databases for publications related to these 10 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and develop recommendations. The approach incorporated perspectives from 2 patient representatives and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. Results In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest asking a screening question about pregnancy intention at every reproductive, diabetes, and primary care visit. Screening for pregnancy intent is also suggested at urgent care/emergency room visits when clinically appropriate (2 | ⊕OOO). This was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced glycated hemoglobin (HbA1c) at the first prenatal visit and congenital malformations. In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest use of contraception when pregnancy is not desired (2 | ⊕⊕OO). This was suggested based on indirect evidence in women with diabetes, where PCC—including contraception as a key component—showed a clinically significant association with improvements in first-trimester HbA1c and the rate of congenital malformations, together with indirect evidence from the general population regarding the reduction of unplanned pregnancies and pregnancy terminations with the use of contraception. In individuals with T2DM, we suggest discontinuation of glucagon-like peptide-1 receptor agonist (GLP-1RA) before conception rather than discontinuation between the start of pregnancy and the end of the first trimester (2 | ⊕OOO). This was suggested based on limited data on risk of exposure to GLP-1RA receptor agonists during pregnancy. In pregnant individuals with T2DM already on insulin, we suggest against routine addition of metformin (2 | ⊕OOO). This was suggested based on the GDP judgment that the benefit of adding metformin to insulin to achieve decrease in rates of large for gestational age infants did not outweigh the potential harm of increasing the risk of small for gestational age infants or adverse childhood outcomes related to changes in body composition. In individuals with PDM, we suggest either a carbohydrate-restricted diet (&lt;175 g/day) or usual diet (&gt;175 g/day) during pregnancy (2 | ⊕OOO). This was suggested based on the GDP judgment that the available evidence was limited and very indirect, resulting in significant uncertainty about the net benefits or harms. As such, the evidence was insufficient to support a recommendation either for or against a carbohydrate intake cutoff of 175 g/day. In pregnant individuals with T2DM, we suggest either the use of a continuous glucose monitor (CGM) or self-monitoring of blood glucose (SMBG) (2 | ⊕OOO). There is lack of direct evidence supporting superiority of CGM use over SMBG for T2DM during pregnancy. There is indirect evidence supporting improved glucometrics with the use of CGM for individuals with T2DM outside of pregnancy, substantial improvements in neonatal outcomes for individuals with T1DM using CGM during pregnancy and the potential for decreasing adverse pregnancy outcomes with improved glucometrics in individuals with T2DM. In individuals with PDM using a CGM, we suggest against the use of a single 24-hour CGM target &lt;140 mg/dL (7.8 mmol/L) in place of standard-of-care pregnancy glucose targets of fasting &lt;95 mg/dL (5.3 mmol/L), 1-hour postprandial &lt;140 mg/dL (7.8 mmol/L), and 2-hour postprandial &lt; 120 mg/dL (6.7 mmol/L) (2 | ⊕OOO). This was suggested based on indirect evidence that associated adverse pregnancy outcomes with a fasting glucose &gt; 126 mg/dL (7 mmol/L). In individuals with T1DM who are pregnant, we suggest the use of a hybrid closed-loop pump (pump adjusting automatically based on CGM) rather than an insulin pump with CGM (without an algorithm) or multiple daily insulin injections with CGM (2 | ⊕OOO). This was suggested based on a meta-analysis of RCTs which demonstrated improvement in glucometrics with increased time in range (MD +3.81%; CI −4.24 to 11.86) and reduced time below range (MD −0.88%; 95% CI: −2.04 to 0.27) with the use of hybrid closed-loop pump technology. In individuals with PDM, we suggest early delivery based on risk assessment rather than expectant management (2 | ⊕OOO). This was suggested based on indirect evidence that risks may outweigh benefits of expectant management beyond 38 weeks gestation and that risk assessment criteria may be useful to inform ideal delivery timing. In individuals with PDM (including those with pregnancy loss or termination), we suggest postpartum endocrine care (diabetes management), in addition to usual obstetric care (2 | ⊕OOO). As the postpartum period frequently overlaps with preconception, this was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced HbA1c at the first prenatal visit and congenital malformations. Conclusion The data supporting these recommendations were of very low to low certainty, highlighting the urgent need for research designed to provide high certainty evidence to support the care of individuals with diabetes before, during, and after pregnancy. Investment in implementation science for PCC is crucial to prevent significant mortality and morbidity for individuals with PDM and their children. RCTs to further define glycemic targets in pregnancy and refinement of emerging technology to achieve those targets can lead to significant reduction of harm and in the burden of diabetes care. Data on optimal nutrition and obesity management in pregnancy are lacking. More research on timing of delivery in women with PDM is also needed.

Abstract Rationale Extracellular matrix (ECM) accumulation results from an imbalance between ECM deposition and degradation, due to persistently increased ECM synthesis or reduced resorption. Fibroblasts, as key regulators of ECM homeostasis in both health and disease, are essential targets to rebalance ECM turnover. Recent findings indicate that fibroblasts are regulated by immune cells, which can influence ECM deposition. Specifically, myeloperoxidase (MPO), an enzyme produced by neutrophils, has been shown to enhance fibroblast-driven ECM accumulation in various diseases. In patients with radiographic Interstitial Lung Disease (ILD), elevated MPO levels have been correlated with reduced lung capacity (Cantin et al., 1987), while recent studies report increased MPO levels in the bronchoalveolar lavage fluid of ILD patients (Ngo et al., EJROR 2024). Additionally, MPO and related immune dysregulation proteins are found in fibrotic alveoli in Idiopathic Pulmonary Fibrosis (IPF) (Herrera et al., JCI Insight 2022). These findings suggest an association between MPO and lung fibrosis, yet it remains uncertain whether MPO directly influences ECM accumulation in fibrotic progression. Methods Patient tissue and serum samples were collected with consent, and MPO levels were quantified using ELISA and immunofluorescence techniques. Biochemical assays were performed using MPO isolated from human leukocytes, recombinant cathepsin K, and hydrogen peroxide to investigate whether MPO influences cathepsin K activity. Precision cut lung slices (PCLS) were prepared from untreated C57BL/6 mice and treated with transforming growth factor-beta (TGFβ) and/or MPO for four days, with cathepsin K activity assessed using fluorescence assays. Additionally, MPO-knockout and wild-type mice received intratracheal bleomycin, and after 14 days, cathepsin K activity was quantified via in vivo imaging. Collagen content, as an indicator of fibrosis, was measured by quantifying hydroxyproline in harvested lung tissue. Results/Discussion/Conclusion Increased MPO levels were observed in immunofluorescent-stained samples (57%; 4/7) and serum samples (30%; 3/10) from IPF patients. Biochemical assays demonstrated that physiological levels of MPO (0.2 µg/ml) combined with H2O2 reduced recombinant cathepsin K activity by 85%. In PCLS treated with MPO, cathepsin K activity decreased by 50% with or without TGFβ. After bleomycin treatment, wild-type mice showed reduced cathepsin K activity, while MPO-knockout mice maintained activity levels. Both survival and weight loss were similar between wild-type and MPO-knockout mice; however, collagen content was significantly higher in wild-type mice, whereas MPO-knockout mice were protected from bleomycin-induced collagen accumulation. These findings suggest that MPO contributes to ECM accumulation in lung fibrosis, potentially through inhibition of collagenolytic enzymes such as cathepsin K.

Abstract Rationale: Disparities in unilateral clinician decisions to decline initiating or maintaining life-sustaining treatment (LST) exist. We aimed to determine 1) which US state statutes support unilateral clinician decisions to decline initiating or maintaining LST; 2) what requirements, if any, must be met for these unilateral clinician decisions to occur; and 3) which state statutes address concerns for sociodemographic disparities associated with these decisions. Methods: Between September and October 2024, we used Fastcase, Casetext and official US state government websites to identify statutes for all US states and Washington, DC that addressed clinician decisions to decline to initiate or maintain LST. We defined reason of conscience as explicit mention of conscience, religion, ethics or moral reasons supporting unilateral clinician decision-making. Two reviewers independently analyzed each statute resolving disagreements with consensus adjudication. Results: Almost all (98%, n=50/51) statutes explicitly support unilateral clinician decisions to decline initiating or maintaining at least one form of LST. Reasons supporting these decisions varied across states including medical reasons only (16%), reasons of conscience only (22%), both medical reasons and reasons of conscience (35%), or no medical or conscience reason explicitly provided (25%). Medical reasons supporting unilateral clinician decisions included if LST was “medically ineffective” (24%), “contrary to medical standards” (14%), “medically inappropriate” (10%), or “nonbeneficial” (8%). For states supporting unilateral clinician decisions if LST was medically ineffective, 75% also supported LST to be declined for reason of conscience while 25% did not. When using medical reasons to support unilateral clinician decisions to decline LST, many statutes require that clinicians must first inform patient/surrogate of this decision (37%) and cooperate with transferring the patient to another clinician or institution (75%). Statutes rarely directly required clinicians to obtain a second medical opinion (8%), pursue a medical ethics committee review (6%), or address conflict (2%) in these situations. Although no state statutes explicitly acknowledged the existence of sociodemographic disparities associated with unilateral clinician decisions to initiate or maintain LST, 27% included guidance that addressed decisions to withhold or withdraw LST in specific marginalized groups. Conclusions: While almost all US state statutes allowed clinicians to decline to initiate or maintain LST, the reasons supporting and actions required to pursue these decisions varied. No statute explicitly addressed sociodemographic disparities associated with these decisions, which may perpetuate these disparities across the US.