Publications by Year: 2026

BACKGROUND: Age remains an important factor in decision-making and operative outcomes in patients with chronic limb-threatening ischemia (CLTI). Prior studies have used arbitrary age categories. Our aim is to identify an evidence-based age cutoff to differentiate patient outcomes between open and endovascular therapy (ET) in Best Endovascular vs Best Surgical Therapy in Patients with CLTI.

METHODS: The Best Endovascular vs Best Surgical Therapy in Patients with CLTI trial dataset was queried to include all patients who underwent open surgical bypass or ET. Patient age on the day of the index revascularization was identified as a continuous variable. Restricted cubic splines were generated to examine the moderating effect of age on the outcomes of procedure type in cohort 1 (bypass with single-segment saphenous vein [SSGSV] vs ET) and cohort 2 (bypass with an alternative conduit vs ET). Four separate spline models for each cohort were generated corresponding to our outcomes of interest: major amputation (above ankle), all-cause mortality, major adverse limb events (MALE defined as above-ankle amputation or major reintervention), and MALE/death.

RESULTS: Our study included 1780 patients with a mean age of 67.2 ± 9.7 years (range, 27.9-94.1 years). In cohort 1, the MALE/death spline model showed a lower hazard for SSGSV compared with ET across all ages; however, the upper limit of the hazard ratio confidence interval approaches 1.0 at age 72. There was no age inflection point identified with regard to mortality. Amputation risk was lower with SSGSV compared with ET up to around the age of 57, beyond which there was no difference between the two treatment modalities. Furthermore, the risk of MALE was consistently lower with SSGSV for patients up to age 83. In contrast, in cohort 2, age was not found to be an effect modifier in revascularization outcomes or survival among patients undergoing bypass with an alternative conduit compared with ET.

CONCLUSIONS: In this study, we confirmed that bypass with SSGSV was associated with superior MALE-free survival compared with ET up to the age of 72, beyond which there was no significant difference in outcomes between the two strategies. MALE was significantly higher for ET for patients up to age 83. Patient age was not found to favor one revascularization method over the other if the bypass was performed using an alternative conduit. Further studies are needed to compare the effectiveness of revascularization strategies among older patients with CLTI.

Older adults with cirrhosis commonly experience chronic noncancer pain managed with chronic opioid therapy. Current guidelines recommend opioid deprescribing for high-risk populations, including in cirrhosis, but data on tapering and discontinuation are scarce. We described opioid discontinuation rates and identified predictors of tapering or discontinuation. This retrospective cohort study of Medicare fee-for-service beneficiaries (N = 800,763) ≥ 65 years with continuous opioid use for ≥ 90 days. The primary outcome was opioid discontinuation (i.e., a gap in refills > 30 days). The secondary outcome included opioid tapering (i.e., a 35% decrease in average daily morphine milligram equivalents; [yes/no]). The primary exposure was diagnosed cirrhosis severity (i.e., none, compensated, decompensated). We estimated discontinuation rates using the Kaplan-Meier method, time to opioid discontinuation using proportional hazards regression, and predictors of tapering with logistic regression. After 1 year, 37% (95% CI = 37-37%) of individuals without cirrhosis discontinued opioids, similar to those with compensated (36% (34-37%)) and decompensated (37% (35-39%)) cirrhosis. Age did not modify the adjusted association between cirrhosis status and discontinuation (Wald χ2(4) = 7.72, p = 0.10) but calendar year (pre/post COVID-19) did (Wald χ2(1) = 26.57, p < 0.001). This finding indicated higher deprescribing rates prior to the pandemic, especially for those without cirrhosis (HR, 1.32; 95% CI, 1.31-1.33) compared with those with cirrhosis (HR, 1.13; 95% CI, 1.06-1.20). Non-opioid analgesic use, fall history, and frailty significantly increased the odds of tapering. In conclusion, these findings may reflect a lack of safe analgesic alternatives or higher pain burden in cirrhosis.

BK polyomavirus-associated carcinoma of the kidney or bladder following cardiac or pulmonary transplantation has been reported in only 7 individuals, all but 1 being adults. We now report 2 additional pediatric patients, the first having received a lung transplant at the age of 21 months and developing a renal cell carcinoma at 14 years, and the second receiving a heart transplant at 20 months and developing a bladder urothelial carcinoma at 21 years.

A Disintegrin and metalloprotease (ADAM) family encompasses a diverse array of widely expressed proteases functioning in pathological processes. ADAM15 stands out as a pivotal mediator in multiple tumor types, responding to immune checkpoint inhibitors (ICI) significantly. By promoting pro-angiogenic genes, potentiating integrin binding as well as modulating the inflammatory response, ADAM15 orchestrates cellular adhesion and migration, thereby fostering tumor progression. Despite these compelling insights, the intricate roles of ADAM15 in prediction, immune modulation, and therapeutic targeting among malignant disorders remain largely unexplored. To decipher the pan-cancer landscape of ADAM15, we integrated data from multiple databases. Immunohistochemical profiles of ADAM15 were retrieved from the human protein atlas (HPA) database. Furthermore, the tumor immune estimation resource (TIMER) and the ESTIMATE (Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data) algorithm were harnessed to dissect the immune infiltration patterns and immune checkpoint genes associated with ADAM15. The tumor immune single-sample gene set enrichment analysis (TISMO) was employed to explore the impact of ADAM15 on the tumor immune microenvironment. Additionally, drug sensitivity analysis and subsequent molecular docking studies were conducted to identify potential therapeutic compounds targeting ADAM15. These findings were rigorously validated through reverse transcription-polymerase chain reaction (RT-PCR), western blotting (WB), and immunohistochemistry (IHC) by cell lines and clinical samples from hepatocellular carcinoma (HCC) as well as colon adenocarcinoma (COAD). Our comprehensive analysis revealed that ADAM15 is markedly upregulated in diverse cancer types. IHC, WB, and RT-PCR assays of HCC and COAD confirmed these findings. Notably, elevated ADAM15 correlates with adverse prognosis in pan-cancer, positioning it as a promising novel biomarker. Drug sensitivity profiling unveiled a positive and statistically significant association between ADAM15 and AZD-8055 and Nitazoxanide, whereas a negative correlation was observed with Oxaliplatin and Ponatinib. These findings were further corroborated by molecular docking simulations, highlighting the potential of these compounds as therapeutic targets for ADAM15-driven cancers. Our study underscores the multifaceted role of ADAM15 in cancer progression, immune evasion, and response to therapy. By elucidating the intricate interplay between ADAM15 and the tumor microenvironment (TME), we have identified novel diagnostic biomarkers and potential therapeutic avenues.

The present three-wave longitudinal study tested two transdiagnostic mediators - anger and racism-related vigilance - of the link between racism and internalizing and externalizing problems. At Wave 1, the sample included 344 Mexican-origin adolescents (Mage = 13.5 years; 51.7% male, 45.9% female; 2.3% non-binary) residing in the Midwestern United States. Data across the three waves were collected from April 2021 through October 2024. The study examined how both direct and vicarious racism were related to internalizing and externalizing problems over time. Results from latent growth curve mediation analyses indicated that outward anger expression was a significant mediator; both direct and vicarious racism at Wave 1 were significantly associated with higher levels of anger at Wave 2, which in turn, were associated with higher levels of internalizing and externalizing problems at Wave 3. Racism-related vigilance was a significant mediator of the association between vicarious racism and internalizing problems only, according to results from post hoc sensitivity analyses. Implications for future theory, research, and clinical practice are discussed to help mitigate the effects of racism in new migration contexts for this vulnerable population.

Cortical interneuron (cIN) dysfunction is associated with various neurodevelopmental and neurological disorders, including developmental epilepsies, autism spectrum disorders, and intellectual disabilities. Mutations in ARX (aristaless-related homeobox) are linked to these conditions, with or without accompanying structural brain anomalies. We have previously demonstrated that the loss of Arx in the mouse ganglionic eminence, the birthplace of cINs, is associated with seizures in mice, whereas the loss in cortical excitatory neuron progenitor cells results in structural anomalies but no seizures. To elucidate the pathophysiological role of ARX in cINs and their relationship to the seizure phenotype, Arx conditional mutant mouse lines were interrogated using Gad2- and Nkx2.1-Cre drivers to target distinct populations in the cIN lineage. Our data demonstrate that the abrogation of ARX results in cIN density and distribution defects as well as perinatal lethality. In these mice, we observed defects in cell cycle exit, a biased loss of the marginal zone migration stream of cINs, shifts in cell fate from caudal ganglionic eminence (CGE) to medial ganglionic eminence (MGE) identity, and a reduced number of parvalbumin⁺ and somatostatin⁺ cINs, with parvalbumin⁺ cINs being more severely affected. Single-cell RNA sequencing combined with chromatin immunoprecipitation (ChIP)-seq revealed ARX regulates key processes involved in cell cycle progression, cIN subtype differentiation, guidance cues and receptors, as well as other transcription factors. Interrogation of one downregulated target gene, Lmo1, uncovered a potential mechanism by which ARX regulates cIN number and distribution in the cortex. Cortical slice cultures demonstrate that LMO1 inhibits cIN migration by repressing Cxcr4 expression, which encodes a key receptor involved in cortical guidance. These data indicate ARX positively regulates cIN migration by derepressing LMO1's repressive role. Consistent with our mouse model, we observed a significant loss of parvalbumin+ and somatostatin+ cINs in the brain of a patient carrying a pathogenic variant of ARX and diagnosed with developmental epileptic encephalopathy. Together our data provide novel insights into how ARX and its target genes regulate cIN development and migration and the pathogenic mechanisms of a spectrum of neurodevelopmental disorders linked to loss of ARX.

BACKGROUND: Total knee arthroplasty (TKA) and distal femoral replacement (DFR) can be used in limb-salvage after resection of bony tumors, but few reports have examined patient-reported outcome measurements (PROMs) with survival data in young patients. This study analyzed individuals who underwent TKA/DFR for neoplasm at a young (≤40) age, to report outcomes and survival experience.

METHODS: A retrospective study on 12 TKAs/23 DFRs was conducted between January 1990-2020 in 35 patients ≤40 years old. Electronic medical records were reviewed to identify patients with neoplasm, and collect data. Patients were contacted to obtain PROMs.

RESULTS: The median age (interquartile range) at surgery for TKAs and DFRs was 26.7 (22.7-34.0) and 24.6 years (20.9-28.4), respectively. Median follow-up was 3.95 (0.33-8.14) and 3.01 years (1.72-6.07). TKAs were more commonly due to complications after allograft reconstruction (75.0% vs. 0.00%, p < 0.0001), had lower blood loss (250 vs. 800 ml, p = 0.01) and a higher rate of tourniquet use (75.0% vs. 34.8%, p = 0.04). Revision-free survival (8-year) was 54.7% (95% confidence interval (CI): 13.7%-83.3%) for TKAs and 37.9% (95% CI: 10.4%-66.0%, p = 0.12) for DFRs. For TKAs, median KOOS Jr. was 76.3 (76.3-79.9), VR-12-Physical was 50.0 (40.5-51.7), VR-12-Mental was 40.8 (32.6-45.8), LEAS was 12.0 (12.0-13.0), and FJS was 23.0 (19.0-25.0), without statistical difference from the DFR group.

CONCLUSION: Patients ≤40 years old who underwent TKAs/DFRs for neoplastic disease demonstrated a similarly high postoperative complication rate and poor long-term survival. Almost all PROMs were favorable, reflecting a more promising postoperative experience than survival curves might demonstrate.

Limited information on the business practices of liver transplant (LT) centers worldwide has been published. Characterizing this data could help identify best practices as well as opportunities for improvement. As such, the International Liver Transplant Society (ILTS) Business Practice Committee conducted a global online survey of LT centers, which was sent to the ILTS membership. Questions focused on 5 main domains: transplant practice and volumes, workforce, finances, quality assessment and performance improvement, and overall program function. Data was compared across program geographic regions and transplant volume. A total of 89 discrete centers were represented, of which 76.4% were academic/university-affiliated, and about one-third each were from Europe (36.0%) and North America (31.5%). The top 3 problems programs reported were finances/funding (60.7%), adequate program support/guidance (48.3%), and transplant volumes (43.8%). In all, 59.6% of respondents felt their salary was undercompensated, consistent across geographic regions. In addition, 69.7% felt their center was not adequately funded to meet program goals, with programs in Europe (N=28/32, 87.5%) and Oceania (N=2/3, 66.7%) most impacted. Transplant surgeon retainment was noted as more difficult for lower volume programs (<50 liver transplants/year, N=13/31). Nearly half (42.7%) of all programs felt under-resourced to provide high-quality care, and the majority (80.9%) felt there was room for growth and improvement under their current model. While international concerns varied widely among LT centers, inadequate salary and center funding, low transplant and referral volumes, and staff retainment were persistent themes. Focusing on adopting region-specific best practices and developing transplant systems of care that focus on these elements is critical to provide optimal care to LT patients worldwide.

UNLABELLED: Policy Points Ultraprocessed foods (UPFs) are engineered to heighten reward and accelerate delivery of reinforcing ingredients, driving compulsive consumption and disrupting appetite regulation. This is a growing challenge for health policy. UPFs share key engineering strategies adopted from the tobacco industry, such as dose optimization and hedonic manipulation. These parallels should inform how we classify and regulate UPFs. Policy tools that helped reduce tobacco-related harm, including restrictions on child-targeted marketing, taxes, improved labeling, limits on availability in schools and hospitals, and litigation, should be adapted to address the public-health threat posed by UPFs.

CONTEXT: Ultraprocessed foods (UPFs) now dominate the global food supply and are strongly associated with risks for heart disease, cancers, metabolic disease, diabetes, and obesity. UPFs are likely associated with rates of neurologic issues such as dementia and Parkinson's disease and predict premature death. Drawing on the history of tobacco regulation, we examine how the design, marketing, and distribution of UPFs mirror those of industrial tobacco products. Such information speaks to the sophistication and aims of food product manipulation and its consequences.

METHODS: This review synthesizes findings from addiction science, nutrition, and public health history to identify structural and sensory features that increase the reinforcing potential of both cigarettes and UPFs. We focus on five key areas: dose optimization, delivery speed, hedonic engineering, environmental ubiquity, and deceptive reformulation.

FINDINGS: Cigarettes and UPFs are not simply natural products but highly engineered delivery systems designed specifically to maximize biological and psychological reinforcement and habitual overuse. Both industries have used similar strategies to increase product appeal, evade regulation, and shape public perception, including adding sensory additives, accelerating reward delivery, expanding contextual access, and deploying health-washing claims. These design features collectively hijack human biology, undermine individual agency, and contribute heavily to disease and health care costs.

CONCLUSIONS: UPFs should be evaluated not only through a nutritional lens but also as addictive, industrially engineered substances. Lessons from tobacco regulation, including litigation, marketing restrictions, and structural interventions, offer a roadmap for reducing UPF-related harm. Public health efforts must shift from individual responsibility to food industry accountability, recognizing UPFs as potent drivers of preventable disease.