Publications

BACKGROUND: Low-carbohydrate diet (LCD) and low-fat diet (LFD) patterns are practiced by many in the United States, although their health effects, as well as the role of diet quality in the effects, are not fully understood.

OBJECTIVES: This study aimed to prospectively examine the associations of these diets, which emphasize different quantities and qualities of macronutrients, as well as their objective metabolomic indices, with coronary heart disease (CHD) risk in U.S.

METHODS: We followed 42,720 men in the Health Professionals Follow-Up Study (HPFS) (1986-2016), 64,164 women in the Nurses' Health Study (NHS) (1986-2018), and 91,589 women in NHSII (1991-2019) for CHD incidence. Five LCD and 5 LFD indices were derived based on food frequency questionnaire (FFQ) assessments, each emphasizing different sources and qualities of macronutrients (animal products vs plant-based foods, whole grains vs refined carbohydrates, etc). Multimetabolite scores of LCD and LFD indices assessed using FFQ assessments were developed through elastic net regressions among 1,146 healthy participants in the lifestyle validation studies (LVS), substudies embedded in the NHS/NHSII/HPFS.

RESULTS: During 5,248,916 person-years of follow-up, we documented 20,033 CHD cases. When comparing individuals with the highest LCD scores (emphasizing lower carbohydrate contents) and those with the lowest, the pooled multivariable-adjusted hazard ratios (95% CIs) for CHD were 1.05 (1.01-1.10) for overall LCD, 1.07 (1.02-1.12) for animal LCD, 0.94 (0.90-0.99) for vegetable LCD, 1.14 (1.09-1.20) for unhealthy LCD, and 0.85 (0.82-0.89) for healthy LCD. These estimates were 0.93 (0.89-0.98) for overall LFD, 0.94 (0.90-0.98) for animal LFD, 0.87 (0.83-0.91) for vegetable LFD, 1.12 (1.07-1.17) for unhealthy LFD, and 0.87 (0.83-0.91) for healthy LFD. The healthy versions of the LCD and LFD patterns were also linked to lower triglycerides, higher high-density lipoprotein cholesterol, and lower high-sensitivity C-reactive protein levels, as well as favorable metabolomic profiles, including increased 3-indolepropionic acid and decreased valine. Unhealthy patterns showed opposite associations. Multimetabolite scores of LCD and LFD indices were developed in the LVS (Spearman r = 0.57-0.68) and replicated in NHS, NHSII, and HPFS (r = 0.21-0.38). They showed associations with CHD risk highly consistent with those based on FFQ assessments.

CONCLUSIONS: These findings highlight the critical role of diet quality in determining health effects of low-carbohydrate and low-fat diets on CHD risk. The healthy versions of these diets may exert their health benefits through some common pathways that together entail favorable cardiovascular risk profile and lower CHD risk.

Clinical trials drive therapeutic innovation but often underrepresent populations most affected by the disease. Despite efforts to include women, minorities, and children, participation still lags behind intent. Ensuring equitable representation is essential to maximize the impact of new therapies. This perspective offers actionable insights from a diverse panel-including patients, clinicians, researchers, and advocates-shared during the 2025 American Society for Clinical Pharmacology and Therapeutics Patient Forum.

To elucidate the molecular basis underlying differential response and resistance to ibrutinib in Waldenström's macroglobulinemia (WM), we conducted a prospective phase II trial (ClinicalTrials.gov; NCT02604511) of ibrutinib monotherapy in treatment-naïve patients. Seventy-four sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multi-omics. BM cells segregated primarily into B/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B/plasma cells identified three distinct evolutionary patterns: "evolution" (early clone contraction with late clone expansion and increasing genomic complexity), "devolution" (early clone expansion with late clone contraction and genomic simplification), and "no-evolution" (stable clonal architecture). The "evolution" pattern was strongly associated with disease progression, whereas "devolution" correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström's Ibrutinib Prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combinatorial strategy. In parallel, GZMB⁺ CD8⁺ effector-memory (TEM) cells expanded post-treatment in progressing patients and co-existed with tumor "evolution". These cells exhibited persistently impaired cytotoxic programs (e.g., GNLY), a de-differentiated memory-like state, elevated PDCD1 expression, and reduced TCR diversity. Together, this study provides the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM; introduces the WIP score as a predictive biomarker for treatment response; and identifies actionable tumor-intrinsic and immune mechanisms driving resistance.

Immunotherapies revolutionized cancer treatment, yet their efficacy remains constrained by the tumor's immunosuppressive microenvironment. Here, we evaluated whether combining CD39 blockade with other modalities of immunotherapy such as IL-2/anti-IL-2 complexes (IL-2cx) administration could further enhance T cell-mediated antitumor responses and improve tumor control. We demonstrated that CD39 deficiency in MC38 tumor-bearing CD39KO (Entpd1 null) mice decreases tumor growth. This better tumor growth control was associated with increased infiltration of PD-1High CD8+ T cells, expressing elevated levels of exhaustion markers and transcription factors such as TOX. This PD-1High CD8+ T cell subset also exhibited a higher frequency of IFN-γ-producing and cytotoxic (Granzyme B+, Perforin+) cells. In contrast, the less immunogenic B16F10-OVA model did not show significant differences in tumor growth; however, CD39KO mice displayed an increased frequency of antigen-specific, pre-exhausted (PD-1Int) CD8+ T cells, a population recognized as a key target of immunotherapy. Pharmacological CD39 blockade with POM-1, when combined with IL-2cx treatment to redirect IL-2 activity, enhanced the accumulation of pre-exhausted CD8+ T cells with cytotoxic potential, thereby improving tumor control. This combinatorial strategy also reshaped the tumor immune landscape by increasing activated NK cells, elevating Granzyme B expression in CD4+ T cells, and decreasing immunosuppressive M-MDSCs expressing CD39, CD38, and CD73. Collectively, our findings demonstrate that integrating purinergic pathway inhibition with IL-2-based immunotherapies can coordinately reprogram lymphoid and myeloid compartments, attenuate immunosuppressive mechanisms within the tumor microenvironment, and amplify antitumor immunity, providing a strong rationale for advancing this strategy toward clinical translation.

The Medicaid Drug Rebate Program (MDRP) is a federal-state partnership program that aims to control prescription drug costs through contractual agreements enabling manufacturers to secure Medicaid coverage for their drugs by paying rebates to state Medicaid agencies. All states participate in MDRP, helping Medicaid beneficiaries obtain affordable access to nearly all Food and Drug Administration-approved outpatient drugs. Although the program has achieved significant cost savings for Medicaid, notable False Claims Act violations in recent years have called into question the program's operational robustness, particularly regarding the accuracy of data which underpin rebate calculations. In 2024, the Centers for Medicare and Medicaid Services made significant, necessary changes to the program; however, gaps remain. In this commentary, we review the program's operational structure, highlight ongoing challenges regarding drug misclassification and price verification, and propose recommendations for future policymaking. Further scrutiny of reporting compliance may be key to maintaining program integrity.

BACKGROUND: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) represent a unique population. Treatment regimens can vary significantly depending on whether they receive care in a pediatric or in an adult setting. They also have distinctive care needs, social risk factors, and disease behavior compared to other age groups.

OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in their decisions about the frontline management of ALL in AYAs.

METHODS: ASH formed a multidisciplinary guideline panel including hematologists, AYA psychosocial care specialists, pharmacists, methodologists, and patient representatives with efforts to minimize bias from conflicts of interest. An evidence review team at Brown University supported guideline development, including performing systematic evidence reviews up to November 2023. The panel prioritized clinical questions and outcomes according to importance for clinicians and patients. The panel used Grading of Recommendations Assessment, Development and Evaluation (GRADE), including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.

RESULTS: The panel agreed on 15 recommendations and several good practice statements.

CONCLUSIONS: Pediatric-inspired regimens containing asparaginase are recommended as frontline therapy compared to more traditional adult-inspired protocols, requiring significant supportive care and close follow up. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) isn't routinely recommended in first remission (CR1) but may be indicated for higher risk subsets or those with suboptimal responses to initial therapy. The use of targeted agents in frontline therapy is increasingly supported, though further research is needed to optimize this strategy.

PURPOSE: We developed a dynamic B0 shimming approach using a 46-channel AC/DC shim array to correct phase errors caused by eddy currents from diffusion-encoding gradients in diffusion-prepared MRI, enabling high b value imaging without the SNR loss from the use of a magnitude stabilizer.

METHODS: A 46-channel AC/DC shim array and corresponding amplifier system were built. Spin echo prescans with and without diffusion preparation were then used to rapidly measure eddy current-induced phase differences. These phase maps were used as targets in an optimization framework to compute compensatory shim currents for multi-shot 3D diffusion-prepared acquisitions.

RESULTS: The proposed method allows flexible use of the AC/DC shim array to correct undesirable eddy current effects in diffusion-prepared MRI. Phantom and in vivo experiments demonstrate whole-brain, cardiac-gated, multi-shot 3D diffusion-prepared imaging without the use of magnitude stabilizers. The approach enables preservation of full SNR while achieving reliable diffusion encoding at b values up to 2000 s/mm2.

CONCLUSIONS: This work demonstrates a new strategy for applying an AC/DC shim array to compensate for eddy current-induced phase errors in diffusion-prepared MRI. By eliminating the need for a magnitude stabilizer, it enables efficient high-quality diffusion imaging with full signal sensitivity retained.

As US homelessness grows, so too does the forced removal of individuals and their belongings from where they are staying, also known as encampment sweeps, which have been associated with increased overdose and reduced healthcare access. We examined associations between past-year experiences of encampment sweeps and suboptimal health behaviors, outcomes, and healthcare access from 155 people who use drugs (PWUD) in Massachusetts. Thirty-eight percent of participants experienced a sweep in the past year, with 73% citing difficulty accessing health or social services following sweeps. Those who had been relocated were more likely to report worse mental health symptoms and feeling unwelcome in medical settings (both p < 0.05). Findings provide additional evidence that encampment sweeps disrupt access to essential services, likely further marginalizing PWUD and people who are homeless. Strategies that support, rather than punish, these populations are needed.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry. Prim Care Companion CNS Disord 2026;28(1):25f04058. Author affiliations are listed at the end of this article.