Citations

Abstract Sepsis is a multi-system physiological syndrome defined as a dysregulated host response to infection. Despite recent advances clinicians continue to depend on clinically or physiologically defined syndromes as poor classifiers and therefore fail to accurately predict outcome or responses to treatment. Recent studies suggest that advances in screening, diagnosis, prognosis, and treatment of sepsis can be used to tailor immunomodulatory therapies. In the present narrative review, we critically analyze important academic literature published between January 2025 and June 2026 with a focus on epidemiology, screening, diagnosis, prognosis and personalized management. We believe that sepsis care will soon be defined by the convergence of rapid diagnostics, multi-omics profiling, and artificial intelligence, enabling a shift from generalized treatment approaches toward truly personalized, dynamic patient management. While the scientific and technological foundation for this transformation is emerging rapidly, clinical validation using innovative (adaptive) clinical trial design is required. Successful implementation within routine care will require multidisciplinary collaboration, robust infrastructure, clinician and patient engagement, and healthcare systems capable of integrating innovation into practice. The coming years may see a paradigm shift in sepsis management comparable to advances observed in personalized management of malignancies.

Background: Increased arterial stiffness, a marker of cardiovascular disease (CVD), is prevalent among African American (AA) adults and contributes to persistent CVD disparities. The Cardio-Ankle Vascular Index (CAVI) is a validated measure of arterial stiffness and predictor of adverse CVD outcomes. However, its relationship with the novel American Heart Association’s Life’s Essential 8 (LE8) cardiovascular health (CVH) construct has not been examined among AAs. Hypothesis: We hypothesized that increased arterial stiffness would be associated with lower CVH among AA adults. Methods: We analyzed baseline data from AA adults in the Techquity by FAITH! Trial, a 2-arm cluster randomized controlled trial conducted across 18 AA churches in Rochester and Minneapolis–St. Paul, Minnesota. Eligible participants (age ≥18 years with suboptimal diet or physical activity [PA]) completed validated electronic surveys (e.g., PA patterns) and clinical assessments (e.g., blood pressure [BP], lipids). CAVI was summarized as mean and categorized as normal (<8), borderline (8 to <9), or abnormal (≥9). CVH was assessed using the LE8 score (range 0-100 points) and categorized as low (<50), moderate (50-79), or high (≥80). Associations between CAVI and LE8 were assessed using multivariable linear regression adjusted for age, sex, and income (continuous) and Fisher’s exact test (categorical). LE8 components were compared across CAVI categories using Kruskal–Wallis tests. Results: Among 140 participants (mean age 53.0 years [SD 14.6]; 68% female), the mean LE8 score was 62.7 (SD 14.0). Nicotine exposure LE8 score was the highest (84.6 [SD 26.6]) and diet was the lowest (40.7 [SD 13.7]). Mean CAVI was 7.9 (SD 1.5), with 50% of participants classified as normal, 22% borderline, and 28% abnormal. No association between continuous CAVI and LE8 scores was observed after adjustment (unadjusted R 2 = 3.5%). All participants with high LE8 had normal CAVI, while abnormal CAVI was more prevalent among those with low (40%) and moderate (30%) LE8 scores (p<0.001). LE8 scores differed across CAVI categories for BP (median 50 in normal CAVI vs 30 in borderline/abnormal CAVI; p=0.003) and glucose LE8 scores (median 100 vs 60; p=0.014). Conclusions: Greater arterial stiffness was associated with lower CVH categories, with notable component-level differences in BP and glucose. Although not independently associated with overall LE8, integrating CAVI and LE8 categories may improve CVD risk stratification among AAs.

Abstract Purpose: Homozygous deletion of the 9p21 locus, containing CDKN2A/B and MTAP [CDKN2A/MTAP deletion (CMdel)], underlies emerging therapeutic strategies, including PRMT5/MAT2A inhibition. The clinicogenomic context and treatment outcome associations of CMdel in non–small cell lung cancer (NSCLC) remain incompletely defined. Experimental Design: We analyzed Tempus Lens records with paired DNA (xT) and RNA (xR) sequencing. After quality filtering (purity ≥40%), 16,947 patients were included in the primary dataset, and 10,996 were included in the validation dataset and stratified by deletion status [CMdel vs. CM wild-type (CMwt)]. IFN status was defined by IFN-kappa (IFNK) expression [log2(TPM + 1)] using the 25th percentile of CMwt as the threshold. Immune composition was inferred by quanTIseq. First-line regimens were grouped as immune checkpoint inhibitor (ICI) monotherapy, ICI chemotherapy, chemotherapy, or tyrosine kinase inhibitors (TKI). Best response and time to next treatment (TTNT) with risk-set adjustment and 18-month truncation were assessed. Results: CMdel occurred in 11.7% (n = 1,991) and 15% (n = 1,676), respectively, and was enriched in mucinous histology, stage IV disease, and never smokers. CMdel was associated with EGFR, TERT, and SMARCA4 alterations, whereas CMwt was associated with RB1, SETD2, and ARID2. More than 50% of CMdel tumors harbored targetable coalterations, enriched in EGFR/ALK/RET and relatively depleted in KRAS. CMdel tumors exhibited lower PD-L1, mutation burden, and immune infiltration. TTNT did not differ by CM status for ICI monotherapy or TKI but was shorter in CMdel for ICI chemotherapy and chemotherapy. Discordant and broad deletions were less common and had weaker TTNT association. IFNK-low expression marked immune-excluded subgroups with worse treatment outcomes. Conclusions: CDKN2A/MTAP loss defines a prevalent, genomically distinct NSCLC subset enriched in actionable drivers. CMdel associates with worse outcomes to ICI/chemotherapy-containing regimens. These findings highlight convergent biology at 9p21 and support biomarker-guided development of PRMT5/MAT2A inhibitors in MTAP-deleted NSCLC.

This protocol paper details a single-center, randomized trial to compare greater occipital nerve blocks (GONBs) to multiple peripheral nerve blocks (MPNBs) for acute headache relief and prophylaxis in episodic migraine. GONBs are effective for the treatment and prevention of migraine, but a combination of trigeminal and occipital nerve blocks can be effective when GONBs alone have failed. To test this hypothesis, 60 adult participants will be randomized to receive either bilateral GONB or MPNBs of the bilateral greater occipital, lesser occipital, auriculotemporal, supraorbital, and supratrochlear nerves during an acute migraine with 0.5–1.25 mL bupivacaine 0.5%. Methylprednisolone 10–20 mg will be added only for the occipital nerves. Anesthesia in the distribution of each nerve block will be tested, and reinjection with bupivacaine will be performed until anesthesia is achieved. The primary endpoint will be pain freedom 20 min after injections. Secondary endpoints include pain freedom at 2 and 24 h, headache relief at 2 h, frequency and severity of subsequent migraine, and absenteeism from work/school/life events due to headaches over a 12-week follow-up period compared to a four-week run-in period. Trial Registration: The trial is registered at ClinicalTrials.gov (NCT04278573).

Abstract Introduction Underwater endoscopic mucosal resection (uEMR) technique has gained popularity for removal of large non-pedunculated colorectal polyps (LNPCPs) due to high en-bloc resection rates and lower recurrence rates. However, there is no information regarding outcomes of uEMR for giant colorectal polyps. Therefore, we aimed to evaluate the outcomes of uEMR for giant colorectal polyps across multiple centers in North America. Methods We conducted a multicenter retrospective study of adults with giant colorectal polyps undergoing uEMR between January 2019 and November 2025. Giant colorectal polyps were defined as LNPCPs ≥40 mm. Primary outcomes were technical success and rate of recurrent adenoma. Secondary outcomes were severe adverse events (SAEs) and predictors of technical success, recurrence, and SAEs. Results A total of 137 polyps, with mean polyp size 47.6 mm were included. Majority of the lesions were located in right colon (61%, n = 83) with the most common histopathology being high-grade dysplasia (HGD) (31.4%, n = 43). Technical success was achieved in 90.5% (n = 124) with en-bloc resection rate of 11.7% (n = 16). Polyp fibrosis (OR: 0.08) and HGD (OR: 0.15) were independent predictors of inability to achieve technical success. Of 92 (67.1%) patients with follow-up, recurrent polyp was present in 8.7% (n = 8). SAEs were noted in 9.5%, consisting of delayed bleeding (9.5%, n = 13), while no delayed perforation or post polypectomy syndrome was noted. Discussion Our study demonstrates that uEMR is technically feasible for the removal of giant colorectal polyps with an acceptable safety profile and recurrence rate.

Importance Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used. Objective To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads. Data Sources PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025). Study Selection Studies were included if they provided Centiloids, radiotracer, age, and sex. Data Extraction and Synthesis Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis. Main Outcomes and Measures Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available. Results This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I 2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I 2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I 2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I 2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I 2 = 80%). Conclusions and Relevance In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.

Background/Objectives: Patients with relapsed/refractory multiple myeloma (RRMM) have poor survival outcomes and limited treatment options. The increasing utilization of multiagent therapies for earlier lines of treatment and novel drug classes including BCMA-targeting agents in subsequent lines of therapy has created a need for innovative treatment platforms in patients who have relapsed after or are refractory to these current standard-of-care approaches. Iopofosine I 131 is a 131iodide (131I)–phospholipid conjugate that exploits the selective uptake and retention of phospholipid ethers through lipid rafts to facilitate tumor delivery of 131I. Methods: The objective of this phase 1 dose-escalation study was to assess the safety and tolerability of single and fractionated dose schedules of iopofosine I 131 + low-dose dexamethasone in heavily pretreated patients with RRMM. Results: The most common AEs overall were cytopenias, notably thrombocytopenia (93.5%), lymphopenia (74.2%), anemia (71%), leukopenia (61.3%), and neutropenia (58.1%). All patients experiencing hematologic adverse events recovered from those events with median time of recovery 21 days post-nadir. Nonhematologic adverse events were mostly limited to Grade 1 and 2. Dose-limiting toxicities included four Grade 4 thrombocytopenia events lasting longer than 7 days, one Grade 4 neutropenia, and one Grade 3 insomnia. The DMC determined 31.25 mCi/m2 was the maximum tolerated dose in the single-dose group, and 20 mCi/m2 × 2 doses was the maximum tolerated dose in the fractionated-dose group. For patients monitored through 85 days following the first infusion, 22 of 26 (84.6%) achieved stable disease after treatment, and 4 of 26 (15.4%) achieved a partial response. Conclusions: A favorable safety and tolerability profile and preliminary clinical activity support further development of iopofosine I 131 in RRMM.

Abstract Background Radiation-induced heart disease (RIHD) may develop months to years following radiation therapy for cancers near the heart such as lung or breast cancer. Several mouse models of RIHD exist to study the pathogenesis of disease, but to our knowledge no studies have examined whether sex differences exist in RIHD in mice. Methods Female and male BALB/cJ mice received one whole heart dose of 22 Gray (Gy) radiation via a C5 collimator vs. sham controls that received 0 Gy, anesthesia and were placed in the X-ray machine for the same length of time. Mechanisms of cardiotoxicity were examined at 24 h (innate cardiotoxicity), day 10 (acute cardiotoxicity) and day 35 (chronic cardiotoxicity) post irradiation. Results Females and males developed dsDNA breaks from radiation at day 10 but females had more damage than males ( p < 0.001). Vessel area and cardiac hypertrophy were increased by radiation at day 10 and 35 but were higher in males than females at day 35 ( p < 0.001, p = 0.001, respectively). Bulk RNA sequencing of the heart at day 10 revealed that females and males developed similar gene pathway responses to radiation by upregulating cellular repair pathways and downregulated mitochondrial function. However, females upregulated the master regulator of mitochondrial function, Pgc1α ( p = 0.0001), suggesting improved mitochondrial repair in females. By day 35, males developed heart failure with reduced ejection fraction (HFrEF), inflammatory dilated cardiomyopathy (iDCM) and fibrosis while females developed heart failure with preserved ejection fraction (HFpEF) without inflammation or fibrosis. Conclusions We observed sex differences in nearly every cardiac parameter that we examined following radiation exposure. BALB/c males exposed to 22 Gy radiation developed HFrEF and iDCM by day 35 while females developed HFpEF. Further research is needed to better understand mechanisms driving sex differences in RIHD using translational animal models.