Publications by Year: 2026

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.

BACKGROUND: Immune-mediated inflammatory diseases (IMID) are associated with accelerated atherosclerosis, yet it is unclear whether CT coronary artery calcium scoring (CTCS) captures this excess cardiovascular risk accurately. We hypothesized that in adults undergoing CTCS, IMID modifies the relationship between coronary artery calcium (CAC) score and incident major adverse cardiac events (MACE).

METHODS: Among 43,420 individuals in the CLARIFY Registry (University Hospitals Cleveland, 2014-2020) who underwent no-cost CTCS scans, we identified 545 individuals with IMID. After propensity-score matching on age, sex, race, hypertension, diabetes, and smoking status with a 2:1 ratio, 1635 matched individuals were analyzed (545 with IMID and 1090 matched non-IMID controls). CAC was categorized as 0, 1-99, 100-399, ≥400. The primary outcome of 4-point MACE was analyzed over a median 4.2-year follow-up. Cox models tested CAC categories compared to CAC 0, stratified by IMID. Additionally, a log(CAC+1) × IMID interaction term was modeled, to assess whether the risk gradient of CAC differed by IMID status.

RESULTS: Individuals with IMID exhibited over twice the MACE incidence of matched controls (40.8 vs 17.6 per 1000 person-years). Among those with zero CAC, those with IMID had a three-fold higher event rate (21.98 vs 7.18 per 1000 person-years). In controls, MACE risk rose stepwise with CAC, quadrupling from CAC 0 to ≥400 (adjusted HR = 4.74; p < 0.001), whereas in IMID increasing CAC conferred no significant gradient (p = 0.21). The interaction between CAC and IMID was significant (β = -0.27; HR 0.76, 95% CI 0.55-1.00), indicating an attenuated CAC-MACE relationship in IMID.

CONCLUSION: In IMID, baseline risk is elevated even with zero CAC, with attenuation of the traditional CAC-risk gradient observed in non-IMID controls. These findings suggest that, in IMID (1) a CAC score of zero may not guarantee low cardiovascular risk and (2) CAC has less incremental prognostic value than in the general population.

PURPOSE: To provide evidence-based recommendations for patients with stage IV non-small cell lung cancer with driver alterations.

METHODS: This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized controlled trials (RCTs), with the latest time frame spanning March-October 2025. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts was convened. The literature search included systematic reviews, meta-analyses, and RCTs. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.

RESULTS: This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Thirteen studies were identified in the latest search of literature to date.

RECOMMENDATIONS: Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients with driver alterations.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

Kidney disease affects 850 million people worldwide, with Sub-Saharan Africa bearing a significant burden. People living with HIV (PWH) are at increased risk due to nephrotoxicity of antiretroviral therapy (ART), in part due to widespread use of tenofovir disoproxil fumarate. In response, Uganda recommends routine kidney disease screening by doing a serum creatinine test at ART initiation. However, the extent of adherence to these guidelines remains poorly understood. We extracted clinical data for adults initiating ART between 2017 and 2024 at three large-volume HIV clinics in Uganda. To determine if kidney disease screening rates had increased appropriately over time, we divided the observation period into three eras as per national guidelines: (1) Test and Treat (2017-2019), that recommended screening only PWH and diabetes or hypertension; (2) DTG rollout/COVID-19 (2020-2022); and (3) creatinine-for-all (2023-2024), recommending screening everyone initiating ART. Logistic regression models were fit to identify correlates of renal screening. Of the 17,485 participants, only 22.4% (3,909/17,485) were screened for kidney disease at ART initiation. Screening was more common at the urban site (54.2%) compared to rural sites (10.0%). At rural sites, screening declined over time and individuals were 83% less likely to be screened in the creatinine-for-all era compared to the baseline era (aOR 0.17, 95% CI: 0.13-0.22) while it increased at urban site (aOR 9.27, 95% CI: 7.37-11.66). Male sex (aOR 1.37, 95% CI: 1.20-1.57), older age (≥45 years), hypertension, and non-TDF-based ART regimens were associated with higher screening odds at rural sites. Diabetes, opportunistic infections, and TDF use were not significantly associated with screening likelihood at any site. Kidney disease screening for PWH at ART initiation remains poor in Uganda, even when using a single creatinine test, particularly in rural clinics, highlighting critical challenges in translating national guidelines into practice. Future research should focus on understanding multilevel barriers to screening and evaluating strategies to improve guideline uptake.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. NK cells display marked functional impairment in SLE, including defective cytotoxicity and cytokine production, but the underlying mechanisms remain poorly defined. Here, we show that mitochondrial dysfunction and impaired mitophagy are key contributors to NK cell abnormalities in SLE. Using complementary structural, metabolic, and proteomic analyses, we found that SLE NK cells accumulate enlarged and dysfunctional mitochondria, exhibit impaired lysosomal acidification, and release mitochondrial DNA into the cytosol - features consistent with defective mitochondrial quality control. Transcriptional and proteomic profiling revealed downregulation of key mitophagy-related genes and pathways. These abnormalities correlated with reduced NK cell degranulation and cytokine production. We then tested whether enhancing mitochondrial quality control could restore NK cell function. The mitophagy activator Urolithin A improved mitochondrial and lysosomal parameters and rescued NK cell effector responses in vitro. Hydroxychloroquine partially restored mitochondrial recycling and reduced cytosolic mtDNA. These findings suggest that defective mitophagy and mitochondrial dysfunction are major contributors to NK cell impairment in SLE and that targeting mitochondrial quality control may represent a promising strategy for restoring immune balance in this disease.

Despite transformative advances in antiretroviral therapy, HIV remains a lifelong condition driven by durable viral reservoirs, chronic immune dysfunction, and complex interactions with host biology, co-infections, and aging. While implementation science is essential to ensure that effective interventions reach populations most affected by HIV, implementation cannot succeed in isolation from continued discovery or from the political and social contexts in which care is delivered. This editorial highlights critical gaps in our understanding of sex-based immunologic differences, tissue-specific viral persistence, resistance evolution, and the long-term inflammatory and metabolic consequences of treated HIV-gaps that directly constrain the durability, equity, and scalability of prevention, treatment, and cure strategies. We further emphasize that successful translation depends on stable policy environments, sustained public investment, and trust-based partnerships with affected communities, without which even highly effective biomedical advances fail to achieve impact. Sustained investment across the full translational spectrum-from basic and mechanistic science through clinical, behavioral, and implementation research-is therefore essential. HIV research has repeatedly served as a model system driving advances across immunology, vaccinology, oncology, aging, and pandemic preparedness, underscoring its broader relevance to human infectious diseases.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) are effective in managing chronic kidney disease (CKD) and type 2 diabetes (T2D). However, there are concerns about an increased risk of diabetic ketoacidosis (DKA) associated with the use of SGLT2i, particularly in patients with CKD.

METHODS: The is a population-based, new-user, active comparator cohort study comparing SGLT2i vs. GLP1RA initiators using three U.S. healthcare databases: Optum's de-identified Clinformatics® Data Mart (2014-2024), Merative MarketScan (2014-2022), and Medicare Fee-for-Service (2014-2020). The exposure is initiation of either SGLT2i or GLP1RA, defined as a new prescription without prior use in 365 days. The primary outcome was hospitalization with DKA identified via inpatient ICD-9/10 codes. Incidence rates (IRs), rate differences (RDs), and hazard ratios (HRs) were calculated.

RESULTS: After 1:1 propensity score matching, the study population included 143,858 patients, 71,929 in the SGLT2i arm and 71,929 in the GLP1RA arm. The mean age (standard deviation) was 71.28 (8.16) years, and 48.8% were female. Patients initiating SGLT2i had higher risk of hospitalization with DKA compared to GLP1RA initiators (IR 4.37 vs. 3.13 events per 1,000 person-years; RD 1.23 [95% CI 0.54, 1.92]; HR 1.40 [95% CI 1.16, 1.68]). The number needed to harm was 813 per 1,000 person-years for SGLT2i compared to GLP1RA initiation. Results remained consistent in subgroup analyses stratified by age (<70 vs. ≥70 years), sex, body mass index (<30 vs. ≥30 kg/m2), frailty status, baseline cardiovascular disease, diabetic retinopathy, hyperglycemia, metformin use, and insulin use.

CONCLUSIONS: The incidence rate of DKA among SGLT2i and GLP1RA initiators remained low overall. However, SGLT2i use was associated with a 40% increased risk of hospitalization with DKA compared to GLP1RA use among patients with CKD stages 3-4 and T2D. Clinicians should remain vigilant when monitoring patients with CKD and T2D treated with SGLT2i.

OBJECTIVE: This scoping review aims to provide a comprehensive understanding of digital navigators in health care settings.

INTRODUCTION: Digital navigators have emerged to assist patients and clinicians in adopting and effectively using digital health technologies to achieve desired health outcomes. First introduced in the literature in 2015, this role has shown promise in selected health care settings, and more evidence is needed to formalize and scale this role across diverse clinical settings.

INCLUSION CRITERIA: This review will include both academic and gray literature that describe digital navigators in any health care setting for any patient-facing health care technology. There will be no country restrictions; however, due to the resources available to the research team, papers must be available in English.

METHODS: This review will adhere to the JBI scoping review methodology. A comprehensive search will be conducted across the following databases: MEDLINE, PsycINFO, CINAHL, Embase, and Web of Science. Targeted Google searches and expert consultations will supplement the database searches. All search results will be assessed against the eligibility criteria, and relevant data will be extracted by 2 independent reviewers. The findings will be characterized using multiple frameworks and presented in the final scoping review report accompanied by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

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.

BACKGROUND: Ensuring that school-age students have the skills and resources to thrive today as well as the opportunities to forge a path towards long-term wellbeing and success is a primary responsibility of public schools and of communities. This can be challenging, especially in low-resource settings with a preponderance of recent immigrant and non-English speaking students.

CONTRIBUTIONS TO PRACTICE: Waltham partnership for youth (WPY) is a community-based nonprofit that has been working for over 30 years to meet the needs of students in the city of Waltham in eastern Massachusetts. Here, we review WPY's history, organizational structure, and flagship programs. We present data to demonstrate the success it has had in increasing high-school advancement/graduation rates, reducing school dropout rates, and addressing mental health.

IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: Partnering with community-based nonprofits can help public schools address some of the underlying social determinants, thereby improving the long-term success and wellbeing of school-aged youth.

CONCLUSIONS: WPY represents a model organization of how to partner with public school systems to access, coordinate, and deliver social support resources to better support the youth in their community.